{"doc_id": "26548f0a805861520e4097b0f1fb278f", "sentence": "Among the anti-herpesvirus agents , aciclovir , valaciclovir , penciclovir , famciclovir , idoxuridine , trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections , and ganciclovir , foscarnet , cidofovir , fomivirsen and maribavir ( the latter in the developmental stage ) are used in the treatment of cytomegalovirus infections .", "spans": [{"span_id": 0, "text": "aciclovir", "start": 36, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "valaciclovir", "start": 48, "end": 60, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "penciclovir", "start": 63, "end": 74, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "famciclovir", "start": 77, "end": 88, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "idoxuridine", "start": 91, "end": 102, "token_start": 13, "token_end": 14}, {"span_id": 5, "text": "trifluridine", "start": 105, "end": 117, "token_start": 15, "token_end": 16}, {"span_id": 6, "text": "ganciclovir", "start": 225, "end": 236, "token_start": 33, "token_end": 34}, {"span_id": 7, "text": "foscarnet", "start": 239, "end": 248, "token_start": 35, "token_end": 36}, {"span_id": 8, "text": "cidofovir", "start": 251, "end": 260, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Antiviral drugs: current state of the art. The chemotherapy of virus infections has definitely come of age. There are now 15 antiviral agents that have been formally licensed for the treatment of human immunodeficiency virus infections (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir) and several others, such as tenofovir disoproxil, emtricitabine, capravirine, emivirine, T-20 (pentafuside) and AMD3100 (bicyclam) are under clinical development. Lamivudine has been approved, and several other compounds (such as adefovir dipivoxil, emtricitabine and entecavir) are under clinical development, for the treatment of hepatitis B virus infections. Among the anti-herpesvirus agents , aciclovir , valaciclovir , penciclovir , famciclovir , idoxuridine , trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections , and ganciclovir , foscarnet , cidofovir , fomivirsen and maribavir ( the latter in the developmental stage ) are used in the treatment of cytomegalovirus infections . Following amantadine and rimantadine, the neuraminidase inhibitors, zanamivir and oseltamivir, have now become available for the therapy and prophylaxis of influenza virus infections, and so is ribavirin for the treatment of respiratory syncytial virus infections and the combination of ribavirin with interferon-alpha for the treatment of hepatitis C virus infections.", "source": null}
{"doc_id": "75080bf07d4ac4a75b2906ffb6f7e2f5", "sentence": "The present study examined the efficacy of single and combined treatment with an anticholinesterase , tetrahydroaminoacridine ( i.p . ) , and a glycine-B site partial agonist , D-cycloserine ( i.p . ; a positive allosteric modulator of NMDA receptors ) , in alleviating the deficit in water maze spatial navigation induced by electrolytic lesion of the medial septum or lidocaine infusion into the dorsal hippocampi .", "spans": [{"span_id": 0, "text": "D-cycloserine", "start": 177, "end": 190, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "lidocaine", "start": 370, "end": 379, "token_start": 60, "token_end": 61}], "rels": [], "paragraph": "Tetrahydroaminoacridine and D-cycloserine fail to alleviate the water maze spatial navigation defect induced by hippocampal inactivation.  The present study examined the efficacy of single and combined treatment with an anticholinesterase , tetrahydroaminoacridine ( i.p . ) , and a glycine-B site partial agonist , D-cycloserine ( i.p . ; a positive allosteric modulator of NMDA receptors ) , in alleviating the deficit in water maze spatial navigation induced by electrolytic lesion of the medial septum or lidocaine infusion into the dorsal hippocampi . In medial septum-lesioned rats, a combination of tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) facilitated acquisition of the water maze test more effectively than either of the drugs alone. Single or combined treatment with tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) had no effect on the water maze deficit induced by hippocampal lidocaine infusion. These results suggest that combined treatment with tetrahydroaminoacridine and D-cycloserine can effectively stimulate water maze spatial navigation, and that functioning of the hippocampus is a prerequisite for this effect.", "source": null}
{"doc_id": "401db5d57ea1f07ccd46d84bb8bb8049", "sentence": "He was initially treated with combination chemotherapy regimen of vincristine , actinomycin-D and cyclophosphamide ( VAC therapy ) .", "spans": [{"span_id": 0, "text": "vincristine", "start": 66, "end": 77, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "cyclophosphamide", "start": 98, "end": 114, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "actinomycin-D", "start": 80, "end": 93, "token_start": 11, "token_end": 12}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Rhabdomyosarcoma of the bladder: a case report]. A 15-year-old man with the chief complaint of general fatigue was referred to our hospital on November 11, 1993. Bilateral percutaneous nephrostomy was performed for postrenal anuria. X-ray examinations revealed a huge intrapelvic tumor, and it was histopathologically diagnosed as rhabdomyosarcoma by transrectal needle biopsy. He was initially treated with combination chemotherapy regimen of vincristine , actinomycin-D and cyclophosphamide ( VAC therapy ) . Pelvic exenteration was performed on December 15, 1993. Histopathological findings were alveolar rhabdomyosarcoma with degenerative change and partial necrosis. After the operation, he was given two course of VAC therapy. In May, 1994, brain metastasis occurred, so 4 courses of VAC therapy were administered. For a very short period, neurological symptoms improved, but he died of pneumonia on November 15, 1994.", "source": null}
{"doc_id": "f1ece46f77c29a69c323b215cd8e3394", "sentence": "However , when a lung mass was noted two months later , he started to receive combination chemotherapy consisting of cyclophosphamide , adriamycin , vincristine , and prednisolone every three months .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 117, "end": 133, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "vincristine", "start": 149, "end": 160, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "prednisolone", "start": 167, "end": 179, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "adriamycin", "start": 136, "end": 146, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "[Lymphomatoid granulomatosis (LYG) occurring in a patient with follicular lymphoma during remission]. A 49 years-old man presented with dry cough, low grade fever, and abnormal shadow on a chest X-ray. He had suffered from follicular lymphoma of the liver 5 years previously. He received irradiation therapy in combination with chemotherapy for approximately three years and had been in complete remission. Physical and radiological examination revealed pleural effusion and softly dense masses in the right lung. The laboratory data were within normal limits. He was diagnosed as having lymphomatoid granulomatosis (LYG) by open lung biopsy. The lung lesion was mainly infiltrated with T cells. The patient received prednisolone and the lung lesions disappeared. However , when a lung mass was noted two months later , he started to receive combination chemotherapy consisting of cyclophosphamide , adriamycin , vincristine , and prednisolone every three months . He has not shown relapse of LYG so far. To investigate the association between the preceding follicular lymphoma and subsequent LYG at this time, DNA analysis using the PCR technique was carried out. The LYG lesion did not show a rearranged band for the JH probe, while the paraffin-embedded specimen of the preceding follicular lymphoma had shown rearranged band for the JH band. Southern blot analysis of the LYG lesion, showed no rearrangement for TCR beta, gamma or JH probe. These findings indicate that the LYG was different from the preceding follicular lymphoma in terms of origin. LYG is considered to be induced in the immunosuppressive state due to lymphoma.", "source": null}
{"doc_id": "e35777804b1ff6dbcbf0e949717f6175", "sentence": "Three patients treated initially with propranolol alone have required substitution of amiodarone due to refractory congestive heart failure .", "spans": [{"span_id": 0, "text": "propranolol", "start": 38, "end": 49, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "amiodarone", "start": 86, "end": 96, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "The role of beta-blockade therapy for ventricular tachycardia induced with isoproterenol: a prospective analysis. Isoproterenol is sometimes required for ventricular tachycardia (VT) induction. However, the role of beta-blockade for treatment of such VT has not been critically assessed. The use of beta-blockade was evaluated prospectively in 14 consecutive patients who required isoproterenol 2.4 +/- 1.3 (+/- S.D.) micrograms/min to induce sustained monomorphic VT (greater than 30 seconds, or requiring termination due to hemodynamic collapse) after a negative baseline study. The VT mechanisms were enhanced automaticity (group A, six patients), triggered automaticity (group B, three patients), and reentry (group C, five patients). Groups A and B had serial intravenous electropharmacologic tests with propranolol alone (0.2 mg/kg), verapamil alone (0.15 mg/kg), and propranolol plus verapamil, and group C had serial tests with propranolol alone, procainamide or quinidine (class Ia drug) alone, and propranolol plus a class Ia drug until VT could no longer be induced. All six patients in group A responded to propranolol alone. In group B, one patient responded to verapamil alone, and two patients responded to propranolol plus verapamil. In group C, three patients responded to propranolol alone, one patient responded to a class Ia drug alone, and one patient responded to propranolol plus a class Ia drug. During a follow-up of 7 to 37 (17.9 +/- 10.7) (+/- S.D.) months, VT has not recurred in any patient. Three patients treated initially with propranolol alone have required substitution of amiodarone due to refractory congestive heart failure . In patients requiring isoproterenol for VT induction, beta-blockade alone appears to be effective in preventing reinduction of VT caused by enhanced automaticity. A heterogeneous response occurs when the VT mechanisms are triggered automaticity or reentry.", "source": null}
{"doc_id": "193a4f7cc44d0bf1d41f408cb02836dd", "sentence": "We used MCF-7 and MDA-MB231 breast cancer cells incubated with Curcumin and Quercetin for 24h , in the absence and presence of Somatostatin , at their EC50 concentrations , to evaluate membrane fatty acid-based functional lipidomics together with the follow-up of EGFR and MAPK signaling pathways .", "spans": [{"span_id": 0, "text": "Curcumin", "start": 63, "end": 71, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "Somatostatin", "start": 127, "end": 139, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "Quercetin", "start": 76, "end": 85, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effects of Somatostatin, Curcumin and Quercetin on the fatty acid profile of breast cancer cell membranes.  We used MCF-7 and MDA-MB231 breast cancer cells incubated with Curcumin and Quercetin for 24h , in the absence and presence of Somatostatin , at their EC50 concentrations , to evaluate membrane fatty acid-based functional lipidomics together with the follow-up of EGFR and MAPK signaling pathways . The two cell lines gave different membrane free fatty acid reorganization: in MCF-7 cells, the following changes observed: increase of omega-6 linoleic acid in the cells incubated with Somatostatin+Quercetin and Quercetin and decrease of omega-3 acids in the cells incubated with Somatostatin+Curcumin compared to Somatostatin, and significant increases of monounsaturated fatty acid (MUFA), mono-trans arachidonic acid levels and docosapentaenoic acid for the cells incubated with Somatostatin+Quercetin compared to the control cells. In MDA-MB231 cells, incubations with Curcumin, Quercetin and Somatostatin+Quercetin induced the most significant membrane remodeling with the increase of stearic acid, diminution of omega-6 linoleic, arachidonic acids and omega-3 (docosapentaenoic and docosahexaenoic acids). Distinct signaling pathway changes were found for these cell lines. In MCF-7 cells, separate or combined incubations with Somatostatin and Quercetin, significantly decreased EGFR and incubation with Curcumin decreased MAPK signaling. In MDA-MB231 cells, incubation with Curcumin decreased AKT1 and p-AKT1(Thr308) levels. Incubation with Curcumin and Quercetin decreased the EGFR levels.", "source": null}
{"doc_id": "67940ddd11f2888bf4d0ebec3cb0846c", "sentence": "Following corneal scrapings and culture , topical 0.5 % moxifloxacin and 0.5 % tobramycin were administered hourly .", "spans": [{"span_id": 0, "text": "moxifloxacin", "start": 56, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "tobramycin", "start": 79, "end": 89, "token_start": 13, "token_end": 14}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A case of Stenotrophomonas maltophilia keratitis effectively treated with moxifloxacin. A 70-year-old man with a long history of diabetes mellitus presented to our hospital (Department of Ophthalmology, Sahm Yook Medical Center, Seoul, Korea) complaining of severe ocular pain and visual disturbance in his left eye that had started three days prior to admission. A round 3.7 \u00d7 5.0 mm dense central stromal infiltrate with an overlying epithelial defect was noted on slit-lamp examination. Following corneal scrapings and culture , topical 0.5 % moxifloxacin and 0.5 % tobramycin were administered hourly . A few days later, Stenotrophomonas maltophilia was isolated in a bacterial culture from a corneal specimen. According to the results of susceptibility tests, topical 0.5% moxifloxacin was given every hour and 0.5% tobramycin was stopped. The patient's clinical features improved steadily with treatment. The corneal epithelium healed rapidly, and the infiltrate resolved within four weeks of the initiation of treatment. The patient's best corrected visual acuity improved from hand motion to 20 / 25.", "source": null}
{"doc_id": "372093725b8ad8e4eb9b742e47c77bde", "sentence": "Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues , translating into potentiated antitumor efficacy of cetuximab in vivo ( A431 and A549 tumors ) .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 27, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "nystatin", "start": 41, "end": 49, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "cetuximab", "start": 72, "end": 81, "token_start": 8, "token_end": 9}, {"span_id": 3, "text": "cetuximab", "start": 159, "end": 168, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Enhancement of tumor uptake and therapeutic efficacy of EGFR-targeted antibody cetuximab and antibody-drug conjugates by cholesterol sequestration. Cetuximab, a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), has been intensively investigated as a promising cancer treatment strategy. The specific mechanism of cetuximab endocytosis and its influence on cetuximab uptake, biodistribution and efficacy still remain elusive. Recently, statins have been reported to synergize with EGFR-targeting agents. Our prior work established that nystatin, a cholesterol-sequestering antifungal drug, facilitates endocytosis via the clathrin-dependent pathway. This study aimed to investigate whether nystatin regulates the uptake and efficacy of cetuximab and cetuximab-based antibody-drug conjugates (cetuximab-ADCs). In vitro and in vivo efficacies of nystatin on the uptake and activity of cetuximab/cetuximab-ADCs were studied in multiple human carcinoma cell lines and xenograft models, respectively. We identified that cholesterol sequestration by nystatin enhanced cetuximab internalization in EGFR-positive carcinoma cells by regulating EGFR trafficking/turnover and facilitating a switch from lipid rafts to clathrin-mediated endocytosis. Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues , translating into potentiated antitumor efficacy of cetuximab in vivo ( A431 and A549 tumors ) . Nystatin-enhanced internalization of cetuximab further improved the uptake and potency of cetuximab-doxorubicin and cetuximab-methotrexate conjugates in EGFR-positive cetuximab-resistant tumors. Combination therapy with nystatin plus either cetuximab or cetuximab-ADC further prolonged animal survival and significantly suppressed tumor growth, as compared with single-agent cetuximab or cetuximab-ADC. In summary, our results identify a novel mechanism whereby cholesterol sequestration enhances the uptake of EGFR-targeting mAb and ADCs, therefore providing preclinical proof-of-concept that combination with nystatin can potentiate the delivery and efficacy of these EGFR-targeted agents. ", "source": null}
{"doc_id": "b365bab924d6bf0ef690410647d720fa", "sentence": "The effects of combination therapy with chenodeoxycholic acid ( CDCA ) and simvastatin on serum cholestanol , low-density lipoprotein ( LDL ) cholesterol , and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis ( CTX ) who were on long-term treatment with CDCA .", "spans": [{"span_id": 0, "text": "chenodeoxycholic", "start": 40, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "simvastatin", "start": 75, "end": 86, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis.  The effects of combination therapy with chenodeoxycholic acid ( CDCA ) and simvastatin on serum cholestanol , low-density lipoprotein ( LDL ) cholesterol , and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis ( CTX ) who were on long-term treatment with CDCA . The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established.", "source": null}
{"doc_id": "7b04d23796fbc56edeec27c121cb1b84", "sentence": "Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) has been demonstrated to be highly effective in treating patients with advanced breast cancer , including those with anthracycline-resistant breast cancer , a fact that has led to efforts to combine paclitaxel and anthracyclines .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 268, "end": 278, "token_start": 43, "token_end": 44}, {"span_id": 2, "text": "anthracyclines", "start": 283, "end": 297, "token_start": 45, "token_end": 46}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Paclitaxel and doxorubicin in metastatic breast cancer. For the past decades the anthracyclines have been regarded as among the most active drugs for the treatment of metastatic breast cancer. However, the 5-year survival rate in patients with stage IV breast cancer continues to be below 20%, and new active drugs and drug combinations clearly must be explored. Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) has been demonstrated to be highly effective in treating patients with advanced breast cancer , including those with anthracycline-resistant breast cancer , a fact that has led to efforts to combine paclitaxel and anthracyclines . Several studies aiming to define the optimal dose and schedule of combination paclitaxel/doxorubicin have now been completed or are ongoing. Phase I/II studies have yielded encouraging preliminary response rates but quite variable toxicity profiles depending on the schedule used. These clinical trials involving combination paclitaxel/doxorubicin are reviewed, with special emphasis on the short-infusion trials.", "source": null}
{"doc_id": "1fb9d1f36c16f6d77468ee75a5f2ae85", "sentence": "However , anastrozole , exemestane and letrozole are associated with significantly fewer endometrial cancers , as well as venous and arterial vascular events , when compared with tamoxifen [ 9 , 10 ] .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 10, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "exemestane", "start": 24, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "letrozole", "start": 39, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "tamoxifen", "start": 179, "end": 188, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Erythema nodosum secondary to aromatase inhibitor use in breast cancer patients: case reports and review of the literature. Aromatase inhibitors (AI's) are increasingly being incorporated in the treatment strategy for hormone receptor positive breast cancer either alone or in combination with chemotherapy, biologics in both the adjuvant and metastatic setting [1]. They markedly suppress plasma estrogen levels by inhibiting or inactivating aromatase, the enzyme responsible for the synthesis of estrogens from androgenic substrates [1]. Currently, the three selective aromatase inhibitors that are available are anastrozole, letrozole and exemestane which reduce circulating estrogen to 1 to 10% of pretreatment levels [2]. For advanced breast cancer, aromatase inhibitors appear to be at a minimum, equivalent and perhaps even better than tamoxifen in the first line setting [3, 4]. In primary breast cancer, adjuvant therapy with anastrozole or letrozole appears to be superior to tamoxifen in reducing the risk of relapse [5, 6]. Common adverse effects associated with AI's include arthralgias (21%), myalgias (12%), other musculoskeletal disorders (28%) and an up to 60% increased risk of bone fracture [7, 8]. However , anastrozole , exemestane and letrozole are associated with significantly fewer endometrial cancers , as well as venous and arterial vascular events , when compared with tamoxifen [ 9 , 10 ] . Very rarely letrozole and anastrozole can cause a skin rash; the frequency of its occurrence has not been quantified(. )However, exemestane has not been reported to cause a skin rash [11]. To date, erythema nodosum (EN) has not been reported as a dermatologic side effect of AI's. Here, we report three cases of EN which developed in postmenopausal breast cancer patients on AI's.", "source": null}
{"doc_id": "ad345c4bc60ce36a29b6f52a115881c8", "sentence": "Additivity , synergy , or competition was observed with MIS and rapamycin , AzadC , doxorubicin , cisplatin , and paclitaxel , suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 64, "end": 73, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "doxorubicin", "start": 84, "end": 95, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "paclitaxel", "start": 114, "end": 124, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "MIS", "start": 56, "end": 59, "token_start": 9, "token_end": 10}, {"span_id": 4, "text": "AzadC", "start": 76, "end": 81, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 3], "is_context_needed": false}, {"class": "POS", "spans": [3, 4], "is_context_needed": false}, {"class": "POS", "spans": [1, 3], "is_context_needed": false}], "paragraph": "Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer. Mullerian Inhibiting Substance (MIS), a biological modifier that causes regression of Mullerian ducts in male embryos, is effective as a single agent in vitro and in vivo against human and mouse ovarian cancer cell lines expressing MIS type II receptor; however, little is known about how recombinant human MIS (rhMIS), now being scaled for preclinical trials, could be used in combination with cytotoxic or targeted chemotherapeutic agents. Mouse serous and endometrioid ovarian carcinoma cell lines were tested in vitro against rhMIS alone and with doxorubicin, paclitaxel, or cisplatin as agents in clinical use. Because MIS releases FK506 binding protein (FKBP12), which activates the mammalian target of rapamycin (mTOR) downstream of Akt, rhMIS and rapamycin combinations were tested. MIS increases p16 protein levels, and 5'-Aza-2'-deoxycytidine (AzadC) induces p16 mRNA; therefore, they were used in combination in vitro and in vivo with a human ovarian cancer cell line. A paclitaxel-resistant human ovarian cancer cell line and its parental line both respond to rhMIS in vitro. Additivity , synergy , or competition was observed with MIS and rapamycin , AzadC , doxorubicin , cisplatin , and paclitaxel , suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone . These assays and statistical analyses could be useful in selecting rhMIS and chemotherapeutic agent combinations that enhance clinical efficacy and reduce toxicity.", "source": null}
{"doc_id": "57a9e7ca1b9724efbf1fafd942564c65", "sentence": "There was no cytotoxic effect of cisplatin , ifosfamide , and etoposide .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 45, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 62, "end": 71, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Overcoming Chemoresistance of Pediatric Ependymoma by Inhibition of STAT3 Signaling. The long-term clinical outcome of pediatric intracranial epepdymoma is poor with a high rate of recurrence. One of the main reasons for this poor outcome is the tumor's inherent resistance to chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. Knockdown of STAT3 was tried to confirm the effects of STAT3 inhibition in ependymoma cells. High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin , ifosfamide , and etoposide . Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. WP1066 effectively abrogated p-STAT3 expression. An increased apoptosis and decreased Survivin expression were observed after WP1066 treatment. Knockdown of STAT3 also decreased cell survival, supporting the critical role of STAT3 in sustaining ependymoma cells. In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoma BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application. ", "source": null}
{"doc_id": "42cce37378b8dbe6a3442b1745c7b50f", "sentence": "Several first-line phase III trials , as well as ongoing trials for which only preliminary results have been published , have fueled debates on the optimal dose and schedule ; these have focused not only on weekly vs q3-weeks paclitaxel , but also on other modifications and the advisability of adding bevacizumab .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 226, "end": 236, "token_start": 39, "token_end": 40}, {"span_id": 1, "text": "bevacizumab", "start": 302, "end": 313, "token_start": 51, "token_end": 52}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Carboplatin/Paclitaxel Induction in Ovarian Cancer: The Finer Points. The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials , as well as ongoing trials for which only preliminary results have been published , have fueled debates on the optimal dose and schedule ; these have focused not only on weekly vs q3-weeks paclitaxel , but also on other modifications and the advisability of adding bevacizumab . Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available.", "source": null}
{"doc_id": "b6d7c3cad588456347fb22848316513b", "sentence": "The primary goal was achieve the correct estimation of the target plasma area against the topotecan concentration-time curve ( AUC ) in a 5 day course of cladribine followed by monitored topotecan in pediatric patients with recurrent/refractory AML .", "spans": [{"span_id": 0, "text": "topotecan", "start": 90, "end": 99, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "cladribine", "start": 154, "end": 164, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "topotecan", "start": 187, "end": 196, "token_start": 31, "token_end": 32}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Topotecan exposure estimation in pediatric acute myeloid leukemia supported by LC-MS-based drug monitoring and pharmacokinetic analysis. Individualization of the topotecan dosing can reduce inter-patient variability, toxicity, and at the same time increases chemotherapy efficacy. Topotecan dosing based on simultaneous drug monitoring and pharmacokinetic analysis can yield more accurate and precise estimation of the topotecan systemic exposure than that attainable with the fixed dosing approach. Therefore, a combined approach could provide a tool assisting the clinicians in individualization of the topotecan dosing. The aim of the study was to estimate the topotecan exposure in pediatric patients with acute myeloid leukemia (AML) based on the plasma concentration-time data and using the pharmacokinetic analysis. The primary goal was achieve the correct estimation of the target plasma area against the topotecan concentration-time curve ( AUC ) in a 5 day course of cladribine followed by monitored topotecan in pediatric patients with recurrent/refractory AML . A sensitive and selective reversed-phase liquid chromatographic-mass spectrometry (LC-MS) assay was developed to quantify total topotecan in the human plasma samples. This method, with its lower quantification limit of 1 ng/ml, was validated over a linear range of 1-150 ng/ml. Under the proposed approach, the topotecan dosing was selected so as to achieve the final AUC value of 140\u00b120 ng/ml h. The presented analytical and pharmacokinetic data demonstrate that the proposed approach can be a practical, useful, efficient, and accurate tool for individualizing the topotecan dosing in children with AML.", "source": null}
{"doc_id": "08fea7daedc8cf02c42589a462f38d3f", "sentence": "The management of EP is challenging : no standardized guidelines exist with literature suggesting cyclosporine or infliximab as first-line therapy .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 98, "end": 110, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "infliximab", "start": 114, "end": 124, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Erythrodermic psoriasis successfully and rapidly treated with brodalumab: Report of two cases. Erythrodermic psoriasis (EP) is a rare form of the disease clinically characterized by a generalized erythema covering \u226590% of the body surface area (BSA). The management of EP is challenging : no standardized guidelines exist with literature suggesting cyclosporine or infliximab as first-line therapy . However, a recent systematic review showed a positive response in EP patients treated with biologic agents. The most common biologic used for EP up until now has been ustekinumab, whereas infliximab might represent a first-line option in case of complicated EP (acute, severe, or unstable). Up until now, no case of brodalumab (a monoclonal antibody blocking IL-17 receptor) treatment for EP in real-life has ever been described. Here, we report the first two cases of efficacy and safety of brodalumab in real-life cases of EP.", "source": null}
{"doc_id": "80c7f4882c16991297c45309ebb232da", "sentence": "As single agents , curcumin and metformin are reported to exhibit chemopreventive properties , in vitro as well as in patients with oral cancer .", "spans": [{"span_id": 0, "text": "curcumin", "start": 19, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "metformin", "start": 32, "end": 41, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Effective chemoprevention is critical for improving outcomes of oral cancer. As single agents , curcumin and metformin are reported to exhibit chemopreventive properties , in vitro as well as in patients with oral cancer . In this study, the chemopreventive efficacy of this drug combination was tested in a 4-nitro quinoline-1-oxide (4NQO) induced mice oral carcinogenesis model. Molecular analysis revealed a cancer stem cell (CSC)-driven oral carcinogenic progression in this model, wherein a progressive increase in the expression of CSC-specific markers (CD44 and CD133) was observed from 8th to 25th week, at transcript (40-100-fold) and protein levels (P\u2009\u2264\u20090.0001). Chemopreventive treatment of the animals at 17th week with curcumin and metformin indicated that the combination regimen decreased tumor volume when compared to the control arm (0.69+0.03 vs 6.66+2.4\u2009mm", "source": null}
{"doc_id": "ac435f58e8e8d73f211ced3e471d8603", "sentence": "Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab .", "spans": [{"span_id": 0, "text": "brodalumab", "start": 135, "end": 145, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "ustekinumab", "start": 150, "end": 161, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Brodalumab for the Treatment of Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal. As part of the National Institute for Health and Care Excellence single technology appraisal process, brodalumab was assessed to determine the clinical and cost effectiveness of its use in the treatment of moderate-to-severe plaque psoriasis. The Centre for Reviews and Dissemination and the Centre for Health Economics Technology Assessment Group at the University of York were commissioned to act as the independent Evidence Review Group. This article provides a summary of the Evidence Review Group's review of the company's submission, the Evidence Review Group report and the National Institute for Health and Care Excellence Appraisal Committee's subsequent guidance issued in March 2018. The main clinical effectiveness data were derived from three well-conducted, multicentre, double-blind randomised controlled trials. The trials demonstrated that brodalumab statistically significantly reduced the severity of psoriasis and its impact on health-related quality of life, compared with placebo, at 12\u00a0weeks. In comparison with ustekinumab, statistically significantly more patients taking brodalumab had reduced psoriasis severity at 12\u00a0weeks. Psoriasis severity and quality of life also appeared improved at 52\u00a0weeks, although statistical significance was not assessed. Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab . A network meta-analysis was presented, comparing brodalumab with other therapies available at the same point in the treatment pathway (i.e. in patients for whom standard systemic therapy or phototherapy is inadequately effective, not tolerated or contraindicated). The network meta-analysis ranked treatments in order of effectiveness, in terms of achieving different levels of Psoriasis Area and Severity Index response. The results indicated that brodalumab had a similar probability of response to ixekizumab, secukinumab and infliximab and a higher probability of response than ustekinumab, adalimumab, etanercept, apremilast, dimethyl fumarate and placebo. The company's economic model compared nine treatment sequences that included three lines of active therapy, consisting of brodalumab and other comparators recommended by the National Institute for Health and Care Excellence, followed by best supportive care. The sequence with brodalumab in the first-line position dominated sequences that started with adalimumab, infliximab, secukinumab and ustekinumab. The incremental cost-effectiveness ratio of the brodalumab sequence compared to less effective and non-dominated sequences ranged from \u00a37145 (vs. the etanercept sequence) to \u00a313,353 (vs. the dimethyl fumarate sequence) per quality-adjusted life-year gained. The incremental cost-effectiveness ratio for the more costly and effective ixekizumab sequence was \u00a3894,010 per quality-adjusted life-year gained compared to the brodalumab sequence. At a threshold of \u00a320,000 per quality-adjusted life-year gained, the brodalumab sequence had the highest probability of being cost effective (96%). The main limitation of the company's economic model was the restrictive nature of the sequences compared. Twelve separate scenarios based on key uncertainties were explored by the Evidence Review Group. The only scenarios where brodalumab was ranked lower than first were not considered to be more appropriate or plausible than the assumptions or scenarios included in the company's base case. The treatment rankings identified in the Evidence Review Group's alternative base case were identical to those derived from the company's base case model. At the first National Institute for Health and Care Excellence Appraisal Committee meeting, the Committee concluded that brodalumab appears to be as effective as other anti-interleukin-17 agents and is cost effective, based on the discount agreed in the patient access scheme. Brodalumab is recommended as an option for treating adults with severe plaque psoriasis (defined by a total Psoriasis Area and Severity Index score of 10 or more and a Dermatology Life Quality Index score of more than 10) who have not responded to other systemic non-biological therapies. Brodalumab should be stopped at 12\u00a0weeks if the psoriasis has not responded adequately.", "source": null}
{"doc_id": "73f375202d3c607481204a1cf596ef1f", "sentence": "In patients with NPSLE , the use of high-dose corticosteroids is recommended in combination with immunosuppressants , such as mycophenolate mofetil and intravenous cyclophosphamide pulse therapy .", "spans": [{"span_id": 0, "text": "mycophenolate", "start": 126, "end": 139, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "cyclophosphamide", "start": 164, "end": 180, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "corticosteroids", "start": 46, "end": 61, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "mofetil", "start": 140, "end": 147, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 2], "is_context_needed": false}, {"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "[Neuropsychiatric Systemic Lupus Erythematosus]. Central nervous system damage, a major organ manifestation of systemic lupus erythematosus (SLE), causes significant morbidity and mortality. Designating this condition as neuropsychiatric SLE (NPSLE), the American College of Rheumatology defines it as involving the central and peripheral nervous systems and being characterized by various manifestations including stroke, seizures, and psychosis. NPSLE treatment mainly seeks to reduce damage accrual. In patients with NPSLE , the use of high-dose corticosteroids is recommended in combination with immunosuppressants , such as mycophenolate mofetil and intravenous cyclophosphamide pulse therapy . This can be accomplished by controlling the activity of the disease, minimizing the use of corticosteroids, and optimizing the management of comorbidities, including cardiovascular risk factors. An international task force analysis of a treat-to-target strategy for SLE (T2T/SLE) recommended targeting remission, preventing damage, and improving quality of life. Thus, more effective and less toxic treatments, such as those using biologics or kinase inhibitors, are still being developed for the treatment of SLE/NPSLE.", "source": null}
{"doc_id": "0e2eb0bb0954b8d253ac1dd2ee955a7a", "sentence": "Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide ( CTX ) and mitoxantrone ( MXT ) , with dose escalation of paclitaxel .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 124, "end": 140, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "mitoxantrone", "start": 153, "end": 165, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "paclitaxel", "start": 200, "end": 210, "token_start": 33, "token_end": 34}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Longitudinal effects of high-dose chemotherapy and autologous stem cell transplantation on quality of life in the treatment of metastatic breast cancer. This study determined the effects of high-dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ASCT) on quality of life (QL) in women with metastatic breast cancer prior to, and during treatment, and up to 1-year post-ASCT. Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide ( CTX ) and mitoxantrone ( MXT ) , with dose escalation of paclitaxel . Longitudinal QL data were collected using the functional living index-cancer (FLIC) and symptom scales at seven time periods: pre-induction chemotherapy (CT), post-induction CT, post-high dose CT (HDCT), and at 3, 6, 9 and 12 months post-ASCT. FLIC scores indicated that the worst problems for patients were feelings of hardship on themselves and their families, followed by psychological functioning and physical functioning problems. The time around diagnosis of the metastatic disease and following HDCT were the worst times for all levels of quality of life, but anxiety and depression symptoms continued to increase in severity across the entire follow-up period. The symptoms that were most problematic were worry about the future, loss of sexual interest, anxiety about the treatment, general worrying, and joint pain. These data highlight the problems that women with metastatic breast cancer encounter at different stages of the disease and treatment process, and can be used to tailor psychosocial interventions appropriate for treating the relevant issues at different points in time.", "source": null}
{"doc_id": "112d742207ec92e9605bd4b9e97d6d1f", "sentence": "These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide , but the lack of dramatic differences in outcome makes monotherapy reasonable , especially in patients with more indolent disease .", "spans": [{"span_id": 0, "text": "flutamide", "start": 81, "end": 90, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "bicalutamide", "start": 95, "end": 107, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The selection of hormonal therapy in prostate cancer: who, when, and for how long? Androgen deprivation is the foundation for the systemic therapy of advanced prostate cancer. Multiple trials have tested combined androgen blockade versus androgen deprivation alone in patients with advanced disease. These studies suggest a slight advantage to the combined approaches that contain flutamide and bicalutamide , but the lack of dramatic differences in outcome makes monotherapy reasonable , especially in patients with more indolent disease . Intermittent androgen deprivation is an alternative that may allow patients to reduce the total time on androgen suppression as well as possibly delay the onset of androgen independence. A number of secondary hormonal therapies, including deferred and secondary antiandrogens, ketoconazole, and estrogens have shown modest response proportions. Patients with less advanced disease such as a rising prostate-specific antigen have varied outcomes, and no standard approach exists. In this group, noncastrating forms of hormonal therapy are being evaluated. Patients undergoing definitive local therapy who have high-risk features may benefit from early, as opposed to deferred, androgen deprivation. This review examines the evidence for the current state of the art in hormonal therapy in patients with prostate cancer and focuses, in particular, on treatment composition and timing as well as the rationale for the use of hormonal therapy in early stage disease.", "source": null}
{"doc_id": "f0fd86ae2bdccfc5615dc78c2ce3b232", "sentence": "We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy ( HDC ) with autologous hematopoietic stem cell transplantation ( AHST ) for patients with HER2-positive metastatic breast cancer .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 48, "end": 58, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "trastuzumab", "start": 63, "end": 74, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Paclitaxel and Trastuzumab as Maintenance Therapy in Patients with HER2-Positive Metastatic Breast Cancer Who Underwent High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation.  We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy ( HDC ) with autologous hematopoietic stem cell transplantation ( AHST ) for patients with HER2-positive metastatic breast cancer . Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results. ", "source": null}
{"doc_id": "e2479b892d8fca52c8cd8863160d5582", "sentence": "Dual antiplatelet therapy with aspirin and clopidogrel ( the preferred thienopyridine because of its superior hematologic safety ) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents .", "spans": [{"span_id": 0, "text": "aspirin", "start": 31, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "clopidogrel", "start": 43, "end": 54, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy. Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel ( the preferred thienopyridine because of its superior hematologic safety ) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents . Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, beta-blockers, and angiotensin-converting enzyme Inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events.", "source": null}
{"doc_id": "a66cb578b3228b7980765b70f98fe955", "sentence": "Furthermore , in non-metastatic castration-resistant prostate cancer ( M0 CRPC ) , two second-generation anti-androgens , apalutamide and enzalutamide , when used in combination with ADT , have demonstrated a significant benefit in metastasis-free survival .", "spans": [{"span_id": 0, "text": "apalutamide", "start": 122, "end": 133, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "enzalutamide", "start": 138, "end": 150, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "ADT", "start": 183, "end": 186, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Recent trends in the management of advanced prostate cancer. Advanced prostate cancer includes a wide spectrum of disease ranging from hormone na\u00efve or hormone sensitive to castration resistant, both containing populations of men who have demonstrable metastatic and non-metastatic states. The mainstay of treatment for metastatic hormone-sensitive prostate cancer is androgen deprivation therapy (ADT). However, recent level 1 evidence demonstrates that the addition of chemotherapy or abiraterone acetate to ADT results in significant survival advantage as compared with ADT alone. Furthermore , in non-metastatic castration-resistant prostate cancer ( M0 CRPC ) , two second-generation anti-androgens , apalutamide and enzalutamide , when used in combination with ADT , have demonstrated a significant benefit in metastasis-free survival . Here, we review the most recent studies leading to these significant changes in the treatment of advanced prostate cancer.", "source": null}
{"doc_id": "7ff40a7350715bf8a611cc76cd640e6f", "sentence": "A screening method based on liquid chromatography-electrospray mass spectrometry for the simultaneous determination of six corticosteroids ( betamethasone 17-valerate BM 17-V , beclomethasone BC , beclomethasone dipropionate BCDP , methylprednisolone MP , budesonide BD , flunisolide FN ) was developed in order to control their illegal use in cosmetic and natural products .", "spans": [{"span_id": 0, "text": "betamethasone", "start": 141, "end": 154, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "beclomethasone", "start": 177, "end": 191, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "beclomethasone", "start": 197, "end": 211, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "methylprednisolone", "start": 232, "end": 250, "token_start": 29, "token_end": 30}, {"span_id": 4, "text": "budesonide", "start": 256, "end": 266, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "LC-MS method for the simultaneous determination of six glucocorticoids in pharmaceutical formulations and counterfeit cosmetic products.  A screening method based on liquid chromatography-electrospray mass spectrometry for the simultaneous determination of six corticosteroids ( betamethasone 17-valerate BM 17-V , beclomethasone BC , beclomethasone dipropionate BCDP , methylprednisolone MP , budesonide BD , flunisolide FN ) was developed in order to control their illegal use in cosmetic and natural products . Indeed, despite corticosteroids are banned in cosmetics, counterfeit products might be present on the market, representing a health hazard. Therefore, effective analytical methods are required to rapidly screen over the counter products in health care shops for counterfeit corticosteroids. The analytical method involves the employment of a Waters Synergy C18 column (150mm\u00d72.0mm I.D.) by using the following mobile phase: A (0.1% formic acid in acetonitrile), B (0.1% formic acid in water) in a linear gradient (from A-B 25:75, v/v to A-B 95:5, v/v in 30min) at the flow rate of 0.3mL/min. The detection was performed with an ion trap (IT) mass spectrometer in positive polarity, total ion current (TIC) and tandem mass modalities for qualitative purpose; single ion monitoring (SIM) mode was used for quantitative analysis on the ESI generated most abundant ion for each steroid. The method was fully validated in terms of precision, detection and quantification limits, linearity, recovery, and it was applied to the identification and quantification of corticosteroids in pharmaceutical formulations and cosmetic products. The mean recovery of BM 17-V, BC, BCDP, MP, BD and FN were found to be 101.3, 101.5, 98.8, 98.9, 98.1, 99.0%, respectively. Limits of quantitation (LOQ) were comprised in the range 29-95ng/mL. To the best of our knowledge, for the first time this mix of glucocorticoids were simultaneously determined in cosmetic products by using a fully validated method. BMV, in its two isomeric forms BM 17-V and BM 21-V, was found to be illegally present in one cream sample (A) with the total concentration level of 0.036% (w/w). ", "source": null}
{"doc_id": "af84f310891977875c182da890deca25", "sentence": "Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib ( MLN9708 ) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant .", "spans": [{"span_id": 0, "text": "Ixazomib", "start": 48, "end": 56, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "Fulvestrant", "start": 73, "end": 84, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "Fulvestrant", "start": 130, "end": 141, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib ( MLN9708 ) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant . fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. ### background fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. ### methods This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses. ### results Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) Cmax of 155 (122-171) ng/mL; Tmax of 1 (1-1.5) h; terminal elimination half-life of 66.6 (57.3-102.6) hr after initial dose; AUC of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51\u2009days (range 47-137). ### conclusion This drug combination has a favorable safety profile and anti-tumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.", "source": "https://pubmed.ncbi.nlm.nih.gov/33641211/"}
{"doc_id": "1a7d989c08fa3795bc567e8ab0166a64", "sentence": "Second-Line Treatment of Her2-Positive Metastatic Breast Cancer : Trastuzumab beyond Progression or Lapatinib ? A Population Based Cohort Study .", "spans": [{"span_id": 0, "text": "Trastuzumab", "start": 66, "end": 77, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "Lapatinib", "start": 100, "end": 109, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Second-Line Treatment of Her2-Positive Metastatic Breast Cancer : Trastuzumab beyond Progression or Lapatinib ? A Population Based Cohort Study . The relative efficacy of lapatinib vs. continuing trastuzumab beyond progression (TBP) in HER2-positive metastatic breast cancer (MBC) patients, who progressed on first-line trastuzumab, is still unclear. The objective of this population based cohort study was to compare outcomes of lapatinib vs. TBP in daily practice. ### methods All HER2-positive MBC patients who began second-line anti HER2 therapy between 1st January 2010 and 30th August 2013 were selected from Clalit Health Services' (CHS) electronic database. Available data on patient and disease characteristics and treatments were analyzed. The primary endpoint was overall survival (OS). Outcomes were compared using the Kaplan-Meier (log-rank) method and Cox proportional hazards model. ### results 64 patients received second-line lapatinib and 93 TBP. The two treatment groups were similar in age and co-morbidity rates, but differed in proportion of prior adjuvant trastuzumab (lapatinib: 29.7%, TBP: 16.1%, P = 0.043) and rates of prior brain metastases (lapatinib: 32.8%, TBP: 10.8%, P = 0.01). lapatinib median OS was 13.0 months (95% CI: 9.5-16.5) vs. 31.0 for TBP (95% CI: 20.6-41.4), P<0.001. On multivariate analysis, longer OS was preserved for TBP, after controlling for differences in age, adjuvant trastuzumab, duration of first-line trastuzumab therapy, brain metastases, visceral metastases and hormonal treatment [Hazard Ratio (HR) = 0.63, 95% CI: 0.40-0.99, P = 0.045]. ### conclusion In this comparative cohort study, OS of HER2-positive MBC patients treated with TBP was significantly longer than with lapatinib. These results might be especially relevant in settings where ado-trastuzumab-emtansine (TDM-1), the current preferred agent in this setting, is not available yet for patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/26375590/"}
{"doc_id": "45be342e88ac7d0acbb6a07c7492b952", "sentence": "Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80 % of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab , and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance .", "spans": [{"span_id": 0, "text": "alemtuzumab", "start": 175, "end": 186, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "rituximab", "start": 191, "end": 200, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "alemtuzumab", "start": 250, "end": 261, "token_start": 37, "token_end": 38}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80 % of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab , and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance . We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).", "source": "https://pubmed.ncbi.nlm.nih.gov/23645694/"}
{"doc_id": "6faa0980ffdd775fe223d1da82940557", "sentence": "Furthermore , the overall response rate for docetaxel in the intent-to-treat population ( 42.5 % ) is superior to the response rate of either doxorubicin as second-line therapy ( 29.3 % ) or paclitaxel ( Taxol ; Bristol-Myers Squibb Oncology , Princeton , NJ ) when used as first- or second-line therapy ( 29 % ) in metastatic disease .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 44, "end": 53, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "doxorubicin", "start": 142, "end": 153, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "paclitaxel", "start": 191, "end": 201, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Docetaxel (Taxotere): an effective agent in the management of second-line breast cancer. Despite improvements in detection and management, metastatic breast cancer remains a leading cause of death among women in industrialized countries. Chemotherapy is the initial treatment of choice for patients with a negative estrogen receptor status, as well as for those with a positive estrogen receptor status who have failed to respond to endocrine treatment. Patients who fail on first-line chemotherapy become candidates for second-line salvage chemotherapy; the outlook for these patients is poor, and new active agents continue to be sought. docetaxel (Taxotere; Rh\u00f4ne-Poulenc Rorer, Antony, France) is a semisynthetic taxoid that is an inhibitor of microtubule depolymerization. This new anticancer agent has been studied in an extensive phase II clinical trial program involving 162 patients with second-line metastatic breast cancer, 134 of whom were anthracycline resistant. Doses of 100 mg/m2 of docetaxel, administered over 1 hour every 3 weeks, produced an overall response rate of 50% (range, 41% to 58%) in 129 evaluable patients, with a median duration of 6 months (range, 2 to 17 months). The response rates achieved to date with docetaxel in anthracycline-resistant patients compare favorably with those produced by the best monotherapies currently available, and are equivalent to those achieved with current combination chemotherapy options. docetaxel also was found to be highly effective in patients with a poor prognosis, having metastases in three or more organs (53%), and/or visceral sites of disease (47%). Furthermore , the overall response rate for docetaxel in the intent-to-treat population ( 42.5 % ) is superior to the response rate of either doxorubicin as second-line therapy ( 29.3 % ) or paclitaxel ( Taxol ; Bristol-Myers Squibb Oncology , Princeton , NJ ) when used as first- or second-line therapy ( 29 % ) in metastatic disease . In conclusion, docetaxel appears to be a very effective therapeutic option for women with second-line metastatic breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/8604449/"}
{"doc_id": "8b1bb23841ae2c6e696bac92e3c4182e", "sentence": "Correlation of lidocaine induced changes in bladder capacity , compliance and number of uninhibited contractions with improvement on oral oxybutynin was 70.6 % , 64.3 % and 66.7 % , respectively .", "spans": [{"span_id": 0, "text": "lidocaine", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "oxybutynin", "start": 138, "end": 148, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "The effects of intravesical lidocaine on bladder dynamics of children with myelomeningocele. Other studies have suggested that intravesical lidocaine may temporarily improve bladder dynamics but details of these effects and their application to children have not been examined. We evaluated the effects of intravesical lidocaine on bladder urodynamics of children with myelomeningocele and tried to correlate these effects with subsequent clinical response to oral oxybutynin. ### Materials And Methods Charts of children with myelomeningocele who had undergone urodynamic examinations from 1992 to 1998 were reviewed retrospectively. In children with uninhibited contractions or poor compliance 150 to 300 mg. lidocaine were instilled for 8 minutes and cystometry was repeated. Changes in bladder capacity and compliance, number of uninhibited contractions and bladder volume at which pressure of 40 cm. H2O was reached were recorded before and after the lidocaine instillation. Clinical response to subsequent treatment with oral oxybutynin was assessed from chart review. ### results A total of 48 urodynamic studies in 22 girls and 20 boys with a mean age plus or minus standard deviation of 8.3 +/- 5.7 years and myelomeningocele were evaluable. After instillation of lidocaine, urodynamics showed increased bladder capacity in 70.8% of studies (34 of 48), with an average increase in volume of 66% (p <0.05). No change or decreased bladder capacity occurred in 29.2% of studies. Bladder compliance improved in 61.7% of the studies (29 of 47, p <0.05) and worsened in 38.3%. Bladder volume at which the pressure of 40 cm. H2O was reached increased in 77.8% of studies (14 of 18, p <0.05). After lidocaine the number of uninhibited contractions decreased by 3.2 in 56.8% of studies (21 of 37, p <0.05). Correlation of lidocaine induced changes in bladder capacity , compliance and number of uninhibited contractions with improvement on oral oxybutynin was 70.6 % , 64.3 % and 66.7 % , respectively . ### conclusions Intravesical lidocaine can improve bladder capacity and compliance and decrease the number of uninhibited contractions in many children with neurogenic bladder caused by myelomeningocele. These observations suggest that intravesical lidocaine has effects on the neurogenic bladder that improve bladder dynamics. Although intravesical lidocaine testing may not reliably predict clinical response to oral oxybutynin at the prescribed dosages, a possible therapeutic role for intravesical lidocaine or similar agents should be explored further.", "source": "https://pubmed.ncbi.nlm.nih.gov/11371945/"}
{"doc_id": "25a7dedfa19e3aaf3f8c7c38492f1afa", "sentence": "Compared with risedronate alone , at 6 months , risedronate plus atorvastatin produced significantly greater increases in the bone mineral density of the lumbar spine ( 1.58 % versus 0.75 % , p < 0.05 ) .", "spans": [{"span_id": 0, "text": "risedronate", "start": 14, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "risedronate", "start": 48, "end": 59, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "atorvastatin", "start": 65, "end": 77, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Statins have additive effects to vertebral bone mineral density in combination with risedronate in hypercholesterolemic postmenopausal women. Recent data suggest that statins used in the treatment of hypercholesterolaemia decrease fracture risk. In this study, we aimed to investigate prospectively whether statins have an additive effect to bisphosphonates (risedronate) according to the primary hypothesis that the addition of atorvastatin to risedronate would produce an increase, from baseline, in lumbar vertebrae and total hip BMD that was greater than that observed with risedronate alone. ### methods A total of 120 hypercholesterolaemic postmenopausal women with osteoporosis or osteopenia were randomized to receive risedronate (5 mg/day) or risedronate (5 mg/day) plus atorvastatin (20 mg/day). Changes in bone mineral density in the lumbar spine and hip, and serum lipid and glucose metabolism changes were assessed. ### results Compared with risedronate alone , at 6 months , risedronate plus atorvastatin produced significantly greater increases in the bone mineral density of the lumbar spine ( 1.58 % versus 0.75 % , p < 0.05 ) . We found no difference after therapy in BMD of the total hip (1.2% versus 1.1%). risedronate plus atorvastatin therapy had favorable effects on the serum lipid profile: LDL and total cholesterol. Serum fasting glucose and HbA1c levels were not affected during the treatments. ### conclusion Statins have modest additive effects to bisphosphonates in improving lumbar spine bone mineral density in hypercholesterolaemic postmenopausal women with established osteoporosis-osteopenia. A long-term study with adequate sample size is necessary to assess the effects of statins -- in combination or alone -- on the bones and prevention of fractures.", "source": "https://pubmed.ncbi.nlm.nih.gov/15866088/"}
{"doc_id": "04ad370c0e3ca668b9c417e2cfeafa8c", "sentence": "The anti-CD22 immunoconjugate , inotuzumab ozogamicin , and the anti-CD19 BiTE ( \u00ae ) antibody , blinatumomab , have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL .", "spans": [{"span_id": 0, "text": "ozogamicin", "start": 43, "end": 53, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "blinatumomab", "start": 96, "end": 108, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Novel targeted therapies in acute lymphoblastic leukemia. Chemotherapy alone cures only 25-45% of adult patients with acute lymphoblastic leukemia (ALL), making novel treatment agents and strategies desperately needed. The addition of monoclonal antibodies (rituximab, alemtuzumab, epratzumab) to chemotherapy has demonstrated encouraging results in patients with newly diagnosed and relapsed ALL. The anti-CD22 immunoconjugate , inotuzumab ozogamicin , and the anti-CD19 BiTE ( \u00ae ) antibody , blinatumomab , have demonstrated impressive single agent activity in patients with relapsed or refractory B-ALL . Early reports of chimeric antigen receptor therapies have been promising in patients with relapsed ALL. Other agents targeting NOTCH1, FLT3, the proteasome and DNA methylation are early in development. These new agents hope to improve the outcome of ALL therapy with less toxicity. The challenge going forward will be to find safe and effective combinations and determine where in the treatment schema these agents will be most effective in ALL therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/23841506/"}
{"doc_id": "133efa52c486fb60a800ef6220185463", "sentence": "Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab ( 5 mg/kg body weight i.v . every 21 days ) and oral capecitabine ( 950 mg/m(2 ) twice daily for 14 days followed by 7 days of rest ) in 2006 - 2008 .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 135, "end": 146, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "capecitabine", "start": 200, "end": 212, "token_start": 32, "token_end": 33}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC. ### methods Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab ( 5 mg/kg body weight i.v . every 21 days ) and oral capecitabine ( 950 mg/m(2 ) twice daily for 14 days followed by 7 days of rest ) in 2006 - 2008 . Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks. ### results Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I-II). Median survival after treatment initiation was 124 days. ### conclusions bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/19903796/"}
{"doc_id": "7ebb3f2cc13e75ceaad2830378a07a9f", "sentence": "Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel ( 200 mg/m(2 ) for 3 h ) and carboplatin [ area under the concentration-time curve ( AUC = 6 ) ] on day 1 and in 21 day cycles .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 89, "end": 99, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "carboplatin", "start": 129, "end": 140, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II study of paclitaxel and carboplatin in advanced gastric cancer previously treated with 5-fluorouracil and platinum. The combination of paclitaxel and carboplatin has been used to treat patients with many types of tumor, including gastric cancer. We evaluated the efficacy and safety of this combination in advanced gastric cancer patients previously treated with 5-fluorouracil and platinum. ### methods Patients who had pathologically been proven to have measurable lesions were treated with paclitaxel ( 200 mg/m(2 ) for 3 h ) and carboplatin [ area under the concentration-time curve ( AUC = 6 ) ] on day 1 and in 21 day cycles . ### results A partial response was achieved in 10 of 45 patients [22%, 95% confidence interval (CI), 10-34]. Of the 32 patients previously treated with cisplatin, four (13%) achieved partial response, whereas, of the 13 patients previously treated with heptaplatin, six (46%) achieved partial response. In all patients, the median time to progression was 14 weeks (95% CI, 10-18), and the median overall survival was 32 weeks (95% CI, 26-38). The most common grade 3/4 adverse events were neutropenia (40% of patients) and neuropathy (2.2%). Two patients developed neutropenic fever. However, there were no treatment-related deaths. ### conclusions Combination chemotherapy with paclitaxel and carboplatin is feasible in patients with advanced gastric cancer who were previously treated with 5-fluorouracil and platinum.", "source": "https://pubmed.ncbi.nlm.nih.gov/15886269/"}
{"doc_id": "e3807edae1596e1c8d9abf185e0a3c2b", "sentence": "With regard to efficacy in metastatic disease , exemestane is superior to megestrol acetate after progression on tamoxifen .", "spans": [{"span_id": 0, "text": "exemestane", "start": 48, "end": 58, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "megestrol", "start": 74, "end": 83, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "tamoxifen", "start": 113, "end": 122, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Long-term efficacy and safety of exemestane in the treatment of breast cancer. exemestane, a steroidal aromatase inhibitor, is licensed for postmenopausal patients with estrogen receptor (ER)-positive breast cancer as second-line therapy in metastatic disease following antiestrogen failure and as part of sequential adjuvant therapy following initial tamoxifen. This study is a systematic literature review, evaluating exemestane in different clinical settings. The Ovid Medline (1948-2012), Embase (1980-2012), and Web of Science (1899-2012) databases were searched. Forty-two relevant articles covering randomized controlled trials were reviewed for efficacy and safety, and three for adherence. With regard to efficacy in metastatic disease , exemestane is superior to megestrol acetate after progression on tamoxifen . There is evidence for noninferiority to fulvestrant (following a prior aromatase inhibitor) and to nonsteroidal aromatase inhibitors in the first-line setting. Combined use with everolimus is shown to be more efficacious than exemestane alone following previous aromatase inhibitor use. In the adjuvant setting, a switch to exemestane after 2-3 years of tamoxifen is superior to 5 years of tamoxifen. exemestane is noninferior to 5 years of tamoxifen as upfront therapy, and may have a role as an extended adjuvant therapy. Used as neoadjuvant therapy, increased breast conservation is achievable. As chemoprevention, exemestane significantly reduces the incidence of breast cancer in \"at-risk\" postmenopausal women. exemestane is associated with myalgias and arthralgias, as well as reduced bone mineral density and increased risk of fracture, which do not appear to persist at follow-up, with subsequent return to pretreatment values. Compared with tamoxifen, there is a reduced incidence of endometrial changes, thromboembolic events, and hot flashes. Limited evidence shows nonadherence in 23%-32% of patients. Evidence is growing in support of exemestane in all clinical settings. It is generally more efficacious and has a better safety profile than tamoxifen. How it compares with the nonsteroidal aromatase inhibitors remains to be established. Further studies are required on adherence to ensure that maximum benefit is obtained.", "source": "https://pubmed.ncbi.nlm.nih.gov/23569364/"}
{"doc_id": "0c5e3efa2736c3c9b15160e5b87b1966", "sentence": "Aim of the study was to measure plasma levels of specific miRNAs ( miRNA-223 , -150 , -21 and -126 ) after physician-driven cessation of chronic P2Y12 inhibition and to study differences in the expression levels of these miRNAs between the different oral P2Y12 inhibitors clopidogrel , prasugrel and ticagrelor , respectively .", "spans": [{"span_id": 0, "text": "clopidogrel", "start": 272, "end": 283, "token_start": 45, "token_end": 46}, {"span_id": 1, "text": "prasugrel", "start": 286, "end": 295, "token_start": 47, "token_end": 48}, {"span_id": 2, "text": "ticagrelor", "start": 300, "end": 310, "token_start": 49, "token_end": 50}], "rels": [], "paragraph": "Course of platelet miRNAs after cessation of P2Y12 antagonists. Circulating platelet micro-RNAs (miRNAs) may be used to monitor platelet function during dual antiplatelet therapy (DAPT). Aim of the study was to measure plasma levels of specific miRNAs ( miRNA-223 , -150 , -21 and -126 ) after physician-driven cessation of chronic P2Y12 inhibition and to study differences in the expression levels of these miRNAs between the different oral P2Y12 inhibitors clopidogrel , prasugrel and ticagrelor , respectively . ### design Patients with coronary artery disease (CAD) on DAPT maintenance dose (including aspirin 100\u00a0mg OD, plus clopidogrel 75\u00a0mg OD, or prasugrel 10\u00a0mg OD, or ticagrelor 90\u00a0mg BID) were prospectively enrolled before cessation of the P2Y12-inhibitor therapy. MiRNA-223, -150, -21 and -126 were determined at baseline (=last day of P2Y12-inhibitor intake) and 10, 30 and 180\u00a0days thereafter. ### results Cessation of P2Y12-inhibitor therapy did not significantly change miRNA levels. However, in ticagrelor-treated patients, miRNA levels were significantly increased at baseline (miRNA-223 and -21), day 10 (miRNA-223, -150, -21, -126) and day 30 (miRNA-223, -150, -21, -126) as compared to prasugrel, and at day 10 (miRNA-150 and -21) and day 30 (miRNA-150) as compared to clopidogrel (all P\u00a0<\u00a00.05). At day 180, only miRNA-126 levels differed significantly with respect to the P2Y12 inhibitor used (P\u00a0<\u00a00.05). After adjustment for confounders, choice of P2Y12-inhibitor was the strongest predictor of miRNA levels (P\u00a0<\u00a00.001), while cessation of P2Y12-inhibitor therapy did not significantly impact miRNA levels. ### conclusion In patients with CAD, ticagrelor intake is associated with increased levels of platelet miRNAs as compared to clopidogrel and prasugrel. Platelet miRNAs are not useful to monitor platelet function after cessation of P2Y12 inhibitors.", "source": "https://pubmed.ncbi.nlm.nih.gov/31172515/"}
{"doc_id": "186c1f47aa16e787370c97d07b302bc4", "sentence": "Eligible patients received ramucirumab ( 10mg/kg ) + dacarbazine ( 1000 mg/m(2 ) ) ( Arm A ) or ramucirumab only ( 10mg/kg ) ( Arm B ) every 3 weeks .", "spans": [{"span_id": 0, "text": "ramucirumab", "start": 27, "end": 38, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "dacarbazine", "start": 53, "end": 64, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "ramucirumab", "start": 96, "end": 107, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma. To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-na\u00efve patients with metastatic melanoma (MM). ### methods Eligible patients received ramucirumab ( 10mg/kg ) + dacarbazine ( 1000 mg/m(2 ) ) ( Arm A ) or ramucirumab only ( 10mg/kg ) ( Arm B ) every 3 weeks . The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety. ### findings Of 106 randomised patients, 102 received study treatment (Arm A, N=52; Arm B, N=50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities. ### interpretation ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm.", "source": "https://pubmed.ncbi.nlm.nih.gov/24930625/"}
{"doc_id": "f1925d2766cc1edf272bbf736587e34d", "sentence": "The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid , apigenin , alone and in combination with the antitumor drugs , cyclophosphamide and doxorubicin , in vitro and in vivo .", "spans": [{"span_id": 0, "text": "apigenin", "start": 119, "end": 127, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "cyclophosphamide", "start": 182, "end": 198, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "doxorubicin", "start": 203, "end": 214, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The effect of apigenin on cyclophosphamide and doxorubicin genotoxicity in vitro and in vivo.  The aim of this study was to investigate the mutagenic and antigenotoxic effects of different doses of the flavonoid , apigenin , alone and in combination with the antitumor drugs , cyclophosphamide and doxorubicin , in vitro and in vivo . Using bacterial reverse mutation inhibition in vitro, with and without metabolic activation, the effect of apigenin (10-400 \u03bcg/plate) was studied on genotoxicity induced by cyclophosphamide (800 \u03bcg/plate) and by doxorubicin (0.2 \u03bcg/plate). Subsequent to a dose-finding study in vivo, CD1 mice were treated with either cyclophosphamide (40 mg/kg, i.p.) or doxorubicin (5 mg/kg, i.p.) with or without co-administration of apigenin (1-100 mg/kg, p.o.). Micronuclei were determined microscopically in blood smears and glutathione peroxidase (GPX), superoxide dismutase (SOD) and total antioxidative status (TAS) in whole blood, erythrocytes and plasma, respectively. Apigenin decreased doxorubicin-induced, but not cyclophosphamide-induced mutagenicity in vitro. In vivo, apigenin caused a statistically significant decrease in micronucleus frequency in response to cyclophosphamide, possibly due to active flavonoid metabolite formation or inhibition of cyclophosphamide metabolic activation. In animals treated with apigenin and doxorubicin, a significant decrease in micronucleus frequency was not observed, probably due to interindividual variability. No changes in GPX, SOD or TAS were observed in response to either cytotoxic agents or the flavonoid, possibly due to limited metabolic transformation of the drugs at the doses used. The results of the present study provide further evidence for the chemo-preventative properties of apigenin.", "source": "https://pubmed.ncbi.nlm.nih.gov/21469013/"}
{"doc_id": "29e6970b74408855d05ebb70363a839d", "sentence": "The novel agents , romidepsin , pralatrexate , and brentuximab vedotin , are currently approved in the relapsed/refractory setting .", "spans": [{"span_id": 0, "text": "romidepsin", "start": 19, "end": 29, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "pralatrexate", "start": 32, "end": 44, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "vedotin", "start": 63, "end": 70, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Treatment of peripheral T-cell lymphoma: are we data driven or driving the data? Peripheral T-cell lymphomas (PTCL) are a group of uncommon and heterogeneous malignancies arising from a postthymic or mature T-lymphocyte. The treatment of PTCL remains a challenging endeavor. Compared with the more common aggressive B-cell lymphomas, more patients with PTCL will be refractory to initial therapy and those who achieve responses often will have shorter progression-free survival. Despite retrospective data that suggest that anthracycline-based multiagent chemotherapy regimens may not provide a benefit compared with nonanthracycline regimens, nonanthracycline-based regimens, with the notable exception of L-asparaginase regimens for extranodal NK/T-cell lymphoma, have been disappointing so far. Based on phase II evidence and subset analyses available, we believe that the addition of etoposide to standard regimens and consolidation of first remissions with autologous stem cell transplantation (autoSCT) provides the best outcome in patients with PTCL and currently use CHOEP followed by ASCT for eligible patients with the common PTCL subtype: PTCL-NOS, AITL, and ALK negative ALCL. For those with ALK-positive ALCL standard CHOP or CHOEP is appropriate with consideration of ASCT only for those with high-risk disease. Other strategies to incorporate additional agents, such as with dose-adjusted EPOCH or sequential CHOP-ICE regimens are logical options; however, they lack the supporting literature of CHOEP. Whereas the above recommendation is our current off-protocol approach, with the possible exception of low risk ALK positive ALCL, none of these choices is supported by strong enough data to supplant a well-conceived clinical trial as the truly preferred strategy in PTCL. The novel agents , romidepsin , pralatrexate , and brentuximab vedotin , are currently approved in the relapsed/refractory setting . These agents are being studied as additions or substitutions for other agents in up-front multiagent chemotherapy regimens. In the relapsed/refractory setting, both pralatrexate and romidepsin remain well-studied choices with some patients achieving a response with durability. Clinical trials of new agents in PTCL continue to be a valuable option and an important part of routine patient management as progressive disease often is seen. Lastly, we believe patients with relapsed/refractory PTCL should be considered for allogeneic stem cell transplantation if a suitable response is demonstrated and a willing donor is available.", "source": "https://pubmed.ncbi.nlm.nih.gov/23568456/"}
{"doc_id": "aef93dee5953fbbbf30f53423ef2c08b", "sentence": "More effective regimens are urgently needed for squamous cell carcinoma of esophagus ( SCCE ) , therefore , we conducted a phase I/II trial of a combination of docetaxel , platinum , and fluorouracil ( TPF ) for treating metastatic SCCE .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 160, "end": 169, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "platinum", "start": 172, "end": 180, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "fluorouracil", "start": 187, "end": 199, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I/II study of docetaxel/cisplatin/fluorouracil combination chemotherapy against metastatic esophageal squamous cell carcinoma.  More effective regimens are urgently needed for squamous cell carcinoma of esophagus ( SCCE ) , therefore , we conducted a phase I/II trial of a combination of docetaxel , platinum , and fluorouracil ( TPF ) for treating metastatic SCCE . ### methods This phase I/II trial (n = 12/39) was conducted in our institute from April 2005 to June 2008. Progression-free survival (PFS) and overall survival were analyzed by the Kaplan-Meier method. ### results The recommended dose of docetaxel was determined to be 50 mg/m in phase I. In phase II with a mean follow-up period of 13.3 months, the objective response rate was 66.6%, a median survival period of 13 months and PFS of 7 months was achieved, and the 1-year survival and PFS rates were 52.9% and 19.6%, respectively. Grade 3/4 toxicities of leukopenia, neutropenia, and anorexia were observed in 53.8%, 43.6%, and 25.6%, respectively. ### conclusions A TPF regimen against metastatic SCCE was well tolerated and achieved a favorable objective response rate and survival benefit compared with other recently reported regimens. Randomized phase III trials of the TPF regimen are warranted and urgently required.", "source": "https://pubmed.ncbi.nlm.nih.gov/19898259/"}
{"doc_id": "9dc9c448c1cfe0ae6228e1de335aa21a", "sentence": "Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat .", "spans": [{"span_id": 0, "text": "Gemcitabine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cyclosporine", "start": 17, "end": 29, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "tacrolimus", "start": 38, "end": 48, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Gemcitabine with cyclosporine or with tacrolimus exerts a synergistic effect and induces tolerance in the rat . This study investigated the effect of the antineoplastic agent gemcitabine (dFdC) in combination with cyclosporine (CsA) or with FK506 on acute heart allograft rejection in a rat model. ### methods Transplantations were performed in the fully allogeneic Lewis-to-Brown Norway strain combination. dFdC, CsA, and FK506 single-drug therapy and combinations of dFdC with CsA and FK506 were administered at various dosages starting on day 1 to prevent and on day 4 to treat acute rejection until day 20. Animals who did not reject their graft were intraperitoneally injected with 108 splenic donor-type lymphocytes. In addition, Lewis and third-party skin grafts were transplanted to these animals. ### results Mean graft survival times under CsA, FK506, and dFdC monotherapy were 18.3/63.7 days (1 mg/5 mg per kg), 41.7 days, and 24.7/38.7 days (100 microg/150 microg per kg), respectively. CsA and FK506 in combination with dFdC prolonged graft survival to more than 100 days (CsA) and more than 95.2 days (FK506). Graft survival after treatment of an ongoing rejection was 21.5/38.3 days for CsA (1 mg/5 mg per kg) and 17.7/59.2 days for dFdC (100 microg/150 microg per kg). The combination of CsA+dFdC prompted indefinite survival of five of six hearts. Lymphocyte inoculation did not induce graft rejection. Notably, none of the Lewis, but all third-party, skin grafts were rejected immediately. Histomorphologic analysis of grafted hearts, however, demonstrated typical features of chronic rejection. ### conclusions The combination of CsA and FK506 with low-dose dFdC exerts a synergistic effect in the prevention and treatment of acute allograft rejection in this model. Although chronic rejection could not be prevented, strain-specific tolerance was achieved. Therefore, combining standard immunosuppressants with dFdC is a novel, promising strategy for prevention and treatment of acute allograft rejection.", "source": "https://pubmed.ncbi.nlm.nih.gov/14557751/"}
{"doc_id": "a44da7163dbe0769202832b6392742c8", "sentence": "Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells .", "spans": [{"span_id": 0, "text": "Erythropoietin", "start": 0, "end": 14, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "trastuzumab", "start": 61, "end": 72, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells . Resistance to trastuzumab is a major issue in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several potential resistance mechanisms have been investigated, but the results are controversial and no conclusion has been reached. erythropoietin receptor (EPOR) may function in cell growth, and expressed in various cancer cells. Because the downstream signaling pathways for EPOR and HER2 partially overlapped, we hypothesized that EPOR may play a role in the inhibition effect of trastuzumab and resistance to trastuzumab. Here, we detected the expression of EPOR mRNA and protein in HER2-positive breast cancer cell lines and tissues. EPOR expressed in SKBR3, MDA-MB-453, and UACC-812 cell lines, but not in BT474. Of the 55 HER2-positive cancer tissues, EPOR was positive in 42 samples and highly expressed (H-score \u2265 25) in 24 by immunohistochemistry. The difference between EPOR expression and Ki67 index was significant (P = 0.033), and EPOR expression also positively correlated with higher pathological stage (Spearman correlation coefficient = 0.359; P = 0.007). Exogenous EPO antagonized trastuzumab-induced inhibition of cell proliferation in HER2/EPOR dual-positive breast cancer cells. We then exposed SKBR3 cells to trastuzumab for 4 months to obtain trastuzumab-resistant SKBR3 cell line, which demonstrated higher phosphorylated EPOR level, higher EPO expression and more extracellular secretion than non-resistant parental SKBR3 cells. Downregulation EPOR expression using short hairpin RNA resensitized trastuzumab-resistant cells to this drug, and SKBR3 cells with EPOR downregulation demonstrated attenuated trastuzumab resistance after the same resistance induction. EPOR downregulation plus trastuzumab produced a synergetic action in the inhibition of cell proliferation and invasion in SKBR3 and MDA-MB-453 cell lines. Therefore, EPOR expression may be involved in tumor progression and proliferation in HER2-positive breast cancer. EPO/EPOR contributes to the mechanism of trastuzumab resistance in SKBR3 cell lines, and EPOR downregulation can reverse the resistance to trastuzumab and increase the inhibition effect of this drug.", "source": "https://pubmed.ncbi.nlm.nih.gov/23117856/"}
{"doc_id": "2f3b2589dc0ee0e5195219864acdb46e", "sentence": "Both paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) and ifosfamide have been demonstrated to be active agents in patients with clinically defined platinum-refractory ovarian cancer .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 5, "end": 15, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "ifosfamide", "start": 78, "end": 88, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Rationale for examining the combination of paclitaxel and ifosfamide in the treatment of advanced ovarian cancer.  Both paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) and ifosfamide have been demonstrated to be active agents in patients with clinically defined platinum-refractory ovarian cancer . While there might be interest in combining these two drugs as salvage therapy for this disease, the recent inclusion of paclitaxel as initial therapy for advanced ovarian cancer, along with a platinum agent (cisplatin or carboplatin), makes it unlikely that paclitaxel and ifosfamide will be used clinically in this malignancy. However, if alkylating agents are not to be used as part of the initial chemotherapy strategy for women with advanced ovarian cancer, it will be important to evaluate the activity of ifosfamide as salvage therapy in individuals treated only with, and demonstrated to be refractory to, a platinum agent and paclitaxel. If significant activity for ifosfamide is observed in this clinical setting, evaluation of the potential utility of a three-drug combination regimen comprising ifosfamide, paclitaxel, and cisplatin or carboplatin may be quite relevant.", "source": "https://pubmed.ncbi.nlm.nih.gov/7597438/"}
{"doc_id": "4043013291b0d04e965a2d139866788c", "sentence": "All M. simiae complex species proved susceptible to clarithromycin and , to a lesser extent , rifabutin , clofazimine , streptomycin and moxifloxacin .", "spans": [{"span_id": 0, "text": "clarithromycin", "start": 52, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "rifabutin", "start": 94, "end": 103, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "clofazimine", "start": 106, "end": 117, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "streptomycin", "start": 120, "end": 132, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "moxifloxacin", "start": 137, "end": 149, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae complex disease. The Mycobacterium simiae complex bacteria can cause opportunistic infections in humans. In the case of definite disease, there are no evidence-based treatment regimens and outcomes are very disappointing. To increase the evidence base underpinning treatment regimens for M. simiae complex disease, drug susceptibility patterns and rifampicin/ethambutol synergy were assessed retrospectively in 69 clinical M. simiae complex isolates from 60 patients (22 patients with M. simiae, 24 with Mycobacterium lentiflavum, 8 with Mycobacterium triplex, 5 with Mycobacterium parascrofulaceum and 1 with Mycobacterium stomatepiae) submitted to the mycobacteriology laboratory at National Jewish Health (Denver, CO). Quantitative drug susceptibility testing (DST) was performed using the radiometric BacTec 460 macrodilution method. Results were related to pharmacokinetic (PK) measurements, where available. All M. simiae complex species proved susceptible to clarithromycin and , to a lesser extent , rifabutin , clofazimine , streptomycin and moxifloxacin . Synergy or additive action between rifampicin and ethambutol was observed for all species except M. simiae. Mycobacterium simiae is poorly susceptible in vitro to rifampicin and ethambutol alone as well as in combination; PK measurements support the limited efficacy of these drugs against M. simiae. The triple-drug regimen of a rifamycin, ethambutol and a macrolide may be advised to treat disease caused by M. lentiflavum, M. triplex, M. parascrofulaceum and M. stomatepiae; for M. simiae, this regimen appears less active. These findings may partly explain the limited treatment results in M. simiae disease. A treatment regimen including a macrolide, moxifloxacin and one or two additional drugs based on DST results may be advisable; clofazimine and amikacin or streptomycin are potential candidates.", "source": "https://pubmed.ncbi.nlm.nih.gov/22099521/"}
{"doc_id": "78070d46a5752185cc2d9f118c577564", "sentence": "Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells , which were slightly more resistant to cytostatic drugs .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 99, "end": 108, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "erlotinib", "start": 113, "end": 122, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "A human model of epithelial to mesenchymal transition to monitor drug efficacy in hepatocellular carcinoma progression. The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC(50) values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells , which were slightly more resistant to cytostatic drugs . Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/21364009/"}
{"doc_id": "9d29356786d19764fd35e5c55994cb45", "sentence": "To compare the effectiveness and safety of adalimumab and infliximab in biologic-na\u00efve patients with CD , in a nationwide register-based propensity score-matched cohort study in Denmark .", "spans": [{"span_id": 0, "text": "adalimumab", "start": 43, "end": 53, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "infliximab", "start": 58, "end": 68, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Comparison of infliximab with adalimumab in 827 biologic-na\u00efve patients with Crohn's disease: a population-based Danish cohort study. There are conflicting data on comparative effectiveness of adalimumab and infliximab in patients with Crohn's disease (CD). ### aims To compare the effectiveness and safety of adalimumab and infliximab in biologic-na\u00efve patients with CD , in a nationwide register-based propensity score-matched cohort study in Denmark . ### methods A total of 2908 Danish adults with CD had been treated with adalimumab or infliximab as their first biologic agent between 2005-2014. By Cox regression, we compared rates of all-cause hospitalisation, CD-related hospitalisation, major abdominal surgery and serious infections after variable 2:1 propensity score matching, accounting for baseline disease characteristics, healthcare utilisation and use of CD-related medications. ### results After propensity-score matching, we included 315 adalimumab- (34.9 \u00b1 12.9 years, 41.9% males) and 512 infliximab-treated (33.6 \u00b1 12.6 years, 40.8% males) patients, with median disease duration 4.0 years; 36.9% had prior abdominal surgery. Over a median follow-up 2.3 years after starting biological therapy, there were no significant differences in rate of CD-related hospitalisation (hazard ratio [HR], 0.81 [95% CI, 0.55-1.20]) or major abdominal surgery (HR, 1.24 [0.66-2.33]) between adalimumab- and infliximab-treated patients, though rate of all-cause hospitalisation was lower in adalimumab-treated patients (HR, 0.74 [0.56-0.97]). There was no significant difference in incidence of serious infections requiring hospitalisation (HR, 1.06 [0.26-4.21]). These results were stable in patients treated with biological monotherapy (all-cause hospitalisation: HR, 0.75 [0.53-1.05]; CD-related hospitalisation: HR, 0.82 [0.51-1.32], abdominal surgery: HR, 1.47 [0.63-3.47]) or in combination with immunomodulators (all-cause hospitalisation: HR, 0.70 [0.44-1.11]; CD-related hospitalisation: HR, 0.80 [0.42-1.52], abdominal surgery: HR, 1.02 [0.39-2.64]). ### conclusions In this population-based, propensity score matched, real-life cohort study using administrative claims, there was no significant difference in effectiveness and safety of adalimumab and infliximab in biologic-na\u00efve patients with CD.", "source": "https://pubmed.ncbi.nlm.nih.gov/29239001/"}
{"doc_id": "f9e6f79e5313dcceeafb28a5d3c04a7b", "sentence": "Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil ( occurring in 40 % v 19 % of patients ) .", "spans": [{"span_id": 0, "text": "bendamustine", "start": 113, "end": 125, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "chlorambucil", "start": 136, "end": 148, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL). ### Patients And Methods Patients (<or= 75 years of age) were randomly assigned to receive bendamustine 100 mg/m(2)/d intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca's normal weight) orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response to treatment was assessed according to National Cancer Institute Working Group criteria, and the final determination of response was made by a blinded independent review committee. ### results A total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157 chlorambucil-treated patients (P < .0001). More patients showed complete responses with bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6 months with bendamustine and 8.3 months with chlorambucil (P < .0001). bendamustine was also associated with an improvement in duration of remission, compared with chlorambucil (median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil ( occurring in 40 % v 19 % of patients ) . Severe infections (grade 3 to 4) occurred in 8% of bendamustine-treated patients and 3% of chlorambucil-treated patients. ### conclusion bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.", "source": "https://pubmed.ncbi.nlm.nih.gov/19652068/"}
{"doc_id": "9f41b57d1dbe5a07e388863d29a381a2", "sentence": "We determined the effects of diclofenac sodium , octreotide , and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice .", "spans": [{"span_id": 0, "text": "diclofenac", "start": 29, "end": 39, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "octreotide", "start": 49, "end": 59, "token_start": 8, "token_end": 9}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Diclofenac Sodium Treatment Ameliorates Extrapancreatic Organ Injuries in a Murine Model of Acute Pancreatitis Induced by Caerulein.  We determined the effects of diclofenac sodium , octreotide , and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice . ### methods A total of 58 BALB-C male mice (25\u2009g) were divided into seven groups and used to create a caerulein-induced acute pancreatitis model. diclofenac sodium, octreotide, and their combination were given for treatment of caerulin-induced acute pancreatitis in mice. At the end of the experiment, the lung, liver, kidney, and stomach were removed for histopathologic assessment. ### results Histopathologic investigation revealed a statistically significant difference between the groups in mean congestion, edema, tubular injury, perirenal fat tissue inflammation, and tubular stasis scores in kidney tissue ( ### conclusion diclofenac sodium alone ameliorates lung edema due to caerulin-induced acute pancreatitis.", "source": "https://pubmed.ncbi.nlm.nih.gov/30515205/"}
{"doc_id": "5ad27773a3ec299ab3f8bcf2f358c135", "sentence": "Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models .", "spans": [{"span_id": 0, "text": "Caspofungin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "amphotericin", "start": 16, "end": 28, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[Successful treatment of a persistent rhino-cerebral mucormycosis in a pediatric patient with a debut of acute lymphoblastic leukemia]. The fungi of the order Mucorales cause mucormycosis, which usually presents as an invasive fungal disease with rapid angioinvasion in immunocompromised patients. Rhinocerebral is the most common presentation. The lipid formulations of amphotericin B are used as primary treatment in invasive mucormycosis; the combined use of posaconazole could allow a reduction in the dose of amphotericin B improving tolerance and adherence to treatment. Caspofungin and amphotericin B association has been shown to be synergistic in vitro and effective in murine models . We present the case of a preschool patient that during the debut of acute lymphoblastic leukemia developed a rhinocerebral mucormycosis successfully responding to antifungal treatment with the combination of liposomal amphotericin and caspofungin. ", "source": null}
{"doc_id": "e1316656233af591253a96acba045ca5", "sentence": "Canine leishmaniosis is most frequently treated with the drugs meglumine antimoniate , allopurinol , amphotericin B , or a combination of meglumine antimoniate and allopurinol .", "spans": [{"span_id": 0, "text": "meglumine", "start": 63, "end": 72, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "allopurinol", "start": 87, "end": 98, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "amphotericin", "start": 101, "end": 113, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "meglumine", "start": 138, "end": 147, "token_start": 21, "token_end": 22}, {"span_id": 4, "text": "allopurinol", "start": 164, "end": 175, "token_start": 24, "token_end": 25}, {"span_id": 5, "text": "antimoniate", "start": 73, "end": 84, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [3, 4], "is_context_needed": false}, {"class": "POS", "spans": [1, 2, 5], "is_context_needed": false}], "paragraph": "Chemotherapy of canine leishmaniosis. Visceral leishmaniosis is a widespread and potentially fatal disease of dogs and humans common in the Mediterranean region, the Middle East, and South America. Canine leishmaniosis is most frequently treated with the drugs meglumine antimoniate , allopurinol , amphotericin B , or a combination of meglumine antimoniate and allopurinol . Therapy with the currently used drugs often achieves temporary clinical improvement and changes in immunologic parameters with restoration of the ability to mount parasite-specific cell mediated responses and decrease in anti-leishmanial antibody titers. However, treatment usually does not prevent relapse of disease or eliminate parasite carriage. Due to the current lack of an ultimate and effective therapy for canine leishmaniosis, new drugs, delivery systems and treatment strategies are necessary to achieve a consistent parasitological cure in infected dogs.", "source": null}
{"doc_id": "56d69e4f3b906e7c44c8241207cf7be6", "sentence": "Haloperidol , carbamazepine and levomepromazine were then discontinued .", "spans": [{"span_id": 0, "text": "Haloperidol", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "carbamazepine", "start": 14, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pituitary microadenoma treated with antipsychotic drug aripiprazole. Male patient 24 years old with a pituitary microadenoma and mental and behavioural disorders due to multiple drug use and use of other psychoactive substances (cocaine, cannabis and alcohol) were treated with haloperidol (dopamine receptor blocker) 10 mg daily. In the last control, the patient presented mammary hypertrophy; laboratory testing and brain magnetic resonance imaging (MRI) was performed, reporting the presence of a pituitary microadenoma syndrome with hormonal alteration (Prolactin levels 28.4 ng/ml). Haloperidol , carbamazepine and levomepromazine were then discontinued . He was started on aripiprazole 15 mg po daily for 4 days; the dosage was then increased to 30 mg po daily, with valproic Acid 500 mg po tid. After 3 weeks on aripiprazole, the mammary hypertrophy that had increased in the patient had resolved. After 10 weeks follow up of prolactin revealed a normal level, at 4.33 ng/ml. Insomnia, aggressiveness, irritability, visual, tactile and auditory hallucinations remained absent after treatment with aripiprazole which is not a first line drug in multiple drug use patient with psychosis. We also consider the correlation of drug use in patient with psychosis, haloperidol treatment, pituitary microadenoma syndrome, hyperprolactinemia, and dopamine D2- receptor partial agonist aripiprazole treatment. This article also summarizes some relevant patents.", "source": null}
{"doc_id": "02cd54bccbdd558f7e6bc91910d42d6d", "sentence": "Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenous verapamil , because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors .", "spans": [{"span_id": 0, "text": "quinidine", "start": 77, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "verapamil", "start": 103, "end": 112, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Additive competitive interaction of verapamil and quinidine at alpha-adrenergic receptors of isolated cardiac guinea pig myocytes and human platelets.  Recent clinical work has questioned the safety of a combined therapy of oral quinidine and intravenous verapamil , because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors . In order to obtain further quantitative information on the underlying mechanism, we used the radioligands (3H)-prazosin and (3H)-yohimbine to perform binding studies on intact cells, with predominantly alpha-1 (isolated myocytes) or alpha-2 subtypes (human platelets) of adrenergic receptors. Our studies confirm that both verapamil and quinidine possess a distinct alpha-adrenergic receptor blocking activity and do not discriminate between the alpha-1 and alpha-2 subtype (Ki-values were between 0.24-0.28 mumol/l for alpha-1 receptors and 0.49-0.50 mumol/l for alpha-2 receptors). Their interaction was competitive and in the presence of both drugs inhibition of radioligand binding was additive. The alpha-adrenergic blockade by verapamil was stereospecific as D-verapamil increased the dissociation constant of the radioligand to a much lesser degree than L-verapamil (Ki = 1.67 +/- 0.29 mumol/l for D-verapamil). The calcium channel blocker nitrendipine, a 1,4-dihydropyridine derivative, did not show any competition up to concentrations of 10 mumol/l. Our results thus give evidence that verapamil and quinidine have already at therapeutic blood levels significant alpha-adrenergic blocking activities which may be of clinical interest. In addition our results show that adult cardiac myocytes are very well suited for pharmacological adrenergic interaction studies.", "source": null}
{"doc_id": "78214ae4a7c12afa3da296121dce7807", "sentence": "The mean duration of total ( i.v . and oral ) therapy was significantly shorter for the azithromycin group than for the cefuroxime group ( 6.2 days vs 10.1 days ) .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 88, "end": 100, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "cefuroxime", "start": 120, "end": 130, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Clinical efficacy and safety of a short regimen of azithromycin sequential therapy vs standard cefuroxime sequential therapy in the treatment of community-acquired pneumonia: an international, randomized, open-label study. An international, randomized, open-label, comparative study was undertaken in order to assess the efficacy and safety of azithromycin and cefuroxime, short sequential vs standard sequential therapy, respectively, in the treatment of patients with community-acquired pneumonia (CAP). 180 adult patients were included in the study. 89 patients received azithromycin 500 mg intravenously (i.v.) once daily for 1-4 days followed by azithromycin 500 mg orally once daily for 3 days. 91 patients received cefuroxime 1.5 g i.v. three times daily for 1-4 days followed by cefuroxime axetil 500 mg orally twice daily for 7 days. Clinical efficacy was achieved in 67/82 (81.7%) patients treated with azithromycin, and in 73/89 (82.0%) patients treated with cefuroxime. The mean duration of total ( i.v . and oral ) therapy was significantly shorter for the azithromycin group than for the cefuroxime group ( 6.2 days vs 10.1 days ) . Adverse events were recorded in 38.2% of patients treated with azithromycin, and in 29.7% of patients treated with cefuroxime (p = 0.20). Shorter sequential i.v.-to-oral azithromycin therapy of patients with CAP was as effective as standard sequential i.v.-to-oral cefuroxime therapy.", "source": null}
{"doc_id": "7ab70148e0d2476ff23e259f31c9296e", "sentence": "To increase the dose-intensity of two drugs in metastatic breast cancer , we tested the feasibility , in phase I studies , of two schedules of epirubicin ( E ) and cyclophosphamide ( C ) - sequential ( E-- > C ) and alternating ( E/C ) - with respect to the standard combination ( EC ) .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 143, "end": 153, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "cyclophosphamide", "start": 164, "end": 180, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer.  To increase the dose-intensity of two drugs in metastatic breast cancer , we tested the feasibility , in phase I studies , of two schedules of epirubicin ( E ) and cyclophosphamide ( C ) - sequential ( E-- > C ) and alternating ( E/C ) - with respect to the standard combination ( EC ) . Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8%). Non-haematological toxicity was mild: about 20% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61% of patients) and bone pain (55.5% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active.", "source": null}
{"doc_id": "55905a93b140ba124c6d5f6a8048e7cd", "sentence": "On February 3 , 2015 , the FDA granted accelerated approval to palbociclib ( IBRANCE , Pfizer Inc. ) , an inhibitor of cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ) , for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive , HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease .", "spans": [{"span_id": 0, "text": "palbociclib", "start": 63, "end": 74, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "letrozole", "start": 200, "end": 209, "token_start": 39, "token_end": 40}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.  On February 3 , 2015 , the FDA granted accelerated approval to palbociclib ( IBRANCE , Pfizer Inc. ) , an inhibitor of cyclin-dependent kinases 4 and 6 ( CDK4 and CDK6 ) , for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive , HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease . The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2.", "source": null}
{"doc_id": "91531be71fcd789d55fde620412620cc", "sentence": "a combination treatment : estramustine phosphate , cyproterone acetate or estrogens plus bromocriptine .", "spans": [{"span_id": 0, "text": "estramustine", "start": 26, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "cyproterone", "start": 51, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "bromocriptine", "start": 89, "end": 102, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "estrogens", "start": 74, "end": 83, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "[Current aspects of hormonal therapy in prostate cancer]. The following endocrine treatment modalities have been used in advanced prostatic carcinoma: 1. orchiectomy plus estrogens; 2. primary orchiectomy with delayed estrogen employment; 3. initial estrogen therapy with delayed orchiectomy; 4. initial cyproterone acetate or medroxyprogesterone acetate; 5. a combination treatment : estramustine phosphate , cyproterone acetate or estrogens plus bromocriptine . The application of phase-III studies permits the subsequent conclusions: Simultaneous orchiectomy is to no advantage (exception: urinary stasis). cyproterone acetate does neither yield better nor worse results regarding survival than estrogen alone, but has fewer side effects. Estrogens and cyproterone acetate produce a rise of serum prolactin justifying the use of bromocriptine (or lisuride). estramustine phosphate should be reserved for relapsing prostatic cancer.", "source": null}
{"doc_id": "a8de81b4cbe9501ded6c855ae5e36b28", "sentence": "Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge .", "spans": [{"span_id": 0, "text": "halothane", "start": 150, "end": 159, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "succinylcholine", "start": 164, "end": 179, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Differential diagnosis of thyroid crisis and malignant hyperthermia in an anesthetized porcine model. The intra-operative differential diagnosis between thyroid crisis and malignant hyperthermia can be difficult. Also stress alone can trigger MH. The purposes of this study were: 1) to investigate the metabolic and hemodynamic differences between thyroid crisis and MH, 2) determine how thyroid crisis affects the development of MH, and 3) determine if the stress of thyroid crisis can trigger MH in susceptible individuals. We studied MH susceptible and normal swine. Two groups of animals (MH susceptible and normal) were induced into thyroid crisis (critical core hyperthermia, sustained tachycardia and increase in oxygen consumption) by pretreatment with intraperitoneal triiodothyronine (T3) followed by large hourly intravenous injections of T3. Two similar groups were given intravenous T3 but no pretreatment. These animals did not develop thyroid crisis and served as controls. Thyroid crisis did not result in metabolic changes or rigidity characteristic of an acute episode of MH. When the animals were subsequently challenged with MH triggering agents (halothane plus succinylcholine) dramatic manifestations of fulminant MH episodes (acute serious elevation in exhaled carbon dioxide, arterial CO2, rigidity and acidemia) were noted only in the MH susceptible animals. Although thyroid crisis did not trigger MH in the susceptible animals it did decrease the time to trigger MH (14.1 +/- 7.2 minutes versus 47.2 +/- 17.7 minutes, p < 0.01) in susceptible animals. Hormone induced elevations in temperature and possibly other unidentified factors during thyroid crisis may facilitate the triggering of MH following halothane and succinylcholine challenge .", "source": null}
{"doc_id": "290cf7b2e12423a284bce59adc4db1bf", "sentence": "Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer .", "spans": [{"span_id": 0, "text": "Mitomycin", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "vinblastine", "start": 17, "end": 28, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Mitomycin C and vinblastine in anthracycline-resistant metastatic breast cancer: a phase II study. The purpose of this phase II study was to evaluate the clinical efficacy of mitomycin C and vinblastine in patients with anthracycline-resistant metastatic breast cancer. This single-center, non-randomized trial enrolled 39 patients. Eligible patients must have received at least three chemotherapy regimens with epirubicin or CAF and had treatment failure while on chemotherapy or within 6 months of completing therapy. Treatment consisted of mitomycin C at a starting dose of 8 mg/m2 on day 1 and vinblastine (8 mg/m2, days 1 and 28). The regimen was repeated every 6 weeks with a 20% dose escalation of both drugs after the first cycle in the absence of grade III hematologic or other toxicity. On an intent-to-treat basis, 38 patients were eligible for assessment; 9 (23.7%, 95% confidence interval 1.92-2.45%) achieved a partial response and 13 (34.2%) had stable disease. The median time to disease progression was 6.21+/-4.26 months (range, 1-15; 95% confidence interval, 4.81-7.61), and the median survival was 10.76+/-7.6 (range, 1-29; 95% confidence interval 8.0-13.1%). Responsive patients had a significantly better survival than those with stable and progressive disease. Treatment was well tolerated. Anemia and neutropenia (grade I-III) developed in 28.9% and 26.3% of the patients, respectively. One patient with grade III granulocytopenia developed fever and infection that required hospitalization. Moderate neurotoxicity, myalgia, constipation, diarrhea and alopecia were observed. No toxic death occurred. Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer .", "source": null}
{"doc_id": "b0eb9d479b021a567638acb562ded0df", "sentence": "An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects .", "spans": [{"span_id": 0, "text": "olmesartan", "start": 43, "end": 53, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "azelnidipine", "start": 88, "end": 100, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats.  An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects . In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.", "source": null}
{"doc_id": "67f94ec99205e319ec06899312f45e8f", "sentence": "Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 172, "end": 184, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "cyclophosphamide", "start": 289, "end": 305, "token_start": 48, "token_end": 49}, {"span_id": 2, "text": "prednisone", "start": 324, "end": 334, "token_start": 54, "token_end": 55}, {"span_id": 3, "text": "5-fluorouracil", "start": 202, "end": 216, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Combination chemotherapy for advanced breast cancer: response and effect on survival.  Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle . Only 2 of 25 patients responded to hormonal therapy or endocrine ablation. Twenty-seven of the 40 patients (68%) had a complete response (8 patients) or partial response (19 patients). Lung, soft tissue, and nodal metastases were the most responsive sites. The median survival of 18 months for the responding group. The nonresponders had a median survival of 4 months. The toxicity was primarily hematologic and was especially severe in patients with functional liver impairment due to metastatic disease.", "source": null}
{"doc_id": "7c23493ded73984347e6db7d0d161392", "sentence": "At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 111, "end": 120, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "sorafenib", "start": 125, "end": 134, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "everolimus", "start": 149, "end": 159, "token_start": 27, "token_end": 28}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma . Although the recognization of muramyltripepetide phosphatidyl-ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival.", "source": null}
{"doc_id": "0c79def432df905a1e8d84e8539054d9", "sentence": "Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses .", "spans": [{"span_id": 0, "text": "succinylcholine", "start": 83, "end": 98, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "pancuronium", "start": 115, "end": 126, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Neuromuscular blockade for critical patients in the emergency department. This retrospective study examines the indications and the effects of 119 doses of succinylcholine or pancuronium given in the emergency department during a 24-month period to patients considered to have immediately life-threatening emergencies. The most common indication for succinylcholine was to accomplish tracheal intubation (20 of 25 patients). Indications for pancuronium included computerized tomography of the head (60 of 94), control of agitation (40 of 94), facilitation of tracheal intubation (20 of 94), control of ventilation (12 of 94), and control of seizure unresponsive to anticonvulsants (4 of 94). Deterioration following succinylcholine occurred in three cases. These included two involving bradycardia and one involving ventricular tachycardia. Major complications following pancuronium included four incidences of ventricular arrhythmias. Intubation failure requiring surgical airway occurred in one patient given succinylcholine, two patients given pancuronium, and one patient who received both succinylcholine and pancuronium. Inadequate documentation of neurological examination prior to blockade was noted in six of 25 succinylcholine and nine of 94 pancuronium cases. Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses . Neuromuscular blocking agents facilitate expeditious management of selected critical patients in the ED. Their prudent use requires anticipation of potential complications, preparation for surgical airway should intubation fail, documentation of physical examination before paralysis, and prior sedation when the patient responds to pain.", "source": null}
{"doc_id": "24e63c61b098a59e672cadbad22bbe1e", "sentence": "Thirty-one isolates were classified as resistant to amprolium , 23 resistant to monensin , 10 resistant to diclazuril , and 6 resistant to clopidol .", "spans": [{"span_id": 0, "text": "amprolium", "start": 52, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "diclazuril", "start": 107, "end": 117, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "clopidol", "start": 139, "end": 147, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Sensitivity of isolates of Eimeria from turkey flocks to the anticoccidial drugs amprolium, clopidol, diclazuril, and monensin. The sensitivity of field isolates of turkey coccidia from the United States to the anticoccidial drugs amprolium, clopidol, diclazuril, and monensin was investigated. clopidol and diclazuril were the most effective, followed by monensin and amprolium. Thirty-one isolates were classified as resistant to amprolium , 23 resistant to monensin , 10 resistant to diclazuril , and 6 resistant to clopidol . Six isolates were partially resistant to monensin, 10 partially resistant to clopidol, and 11 partially resistant to diclazuril. Four isolates were sensitive to monensin, 12 sensitive to diclazuril, and 17 sensitive to clopidol.", "source": null}
{"doc_id": "0e23f19dad084cb3a722f3e520128414", "sentence": "Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention .", "spans": [{"span_id": 0, "text": "lidocaine", "start": 138, "end": 147, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "dexamethasone", "start": 152, "end": 165, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "cystodistention", "start": 178, "end": 193, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Electromotive drug administration and hydrodistention for the treatment of interstitial cystitis.  Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention . After a mean follow-up of 10 (range 3-22) months, 8/13 (62%) of the patients reported complete resolution of bladder symptoms lasting an average 4.5 (range 0.75-17) months. Partial or short-term improvement of bladder symptoms was observed in three patients, while two patients reported aggravation of pain for several days after therapy. A significant increase in bladder capacity, to an average 166% of the pretreatment capacity, was observed in all patients. Whenever symptoms recurred after initially effective therapy, retreatments were performed with equal efficacy in 11 patients. This promising new therapeutic approach, performed on an outpatient basis, may become first-line treatment for patients with interstitial cystitis.", "source": null}
{"doc_id": "8029f6b883c38288c2c68dc356e36630", "sentence": "Drug therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin .", "spans": [{"span_id": 0, "text": "omega-3", "start": 22, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "niacin", "start": 58, "end": 64, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "colesevelam hydrochloride", "start": 67, "end": 92, "token_start": 10, "token_end": 12}, {"span_id": 3, "text": "ezetimibe", "start": 128, "end": 137, "token_start": 19, "token_end": 20}, {"span_id": 4, "text": "simvastatin", "start": 148, "end": 159, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Lipoprotein-associated phospholipase A2 mass is significantly reduced in dyslipidemic patients treated with lifestyle modification and combination lipid-modifying drug therapy. Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin . The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.", "source": null}
{"doc_id": "fb72460a3108fabc35b87b9907696656", "sentence": "Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 84, "end": 94, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "folinic acid", "start": 97, "end": 109, "token_start": 12, "token_end": 14}, {"span_id": 2, "text": "fluorouracil", "start": 116, "end": 128, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "fluorouracil", "start": 149, "end": 161, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "bevacizumab", "start": 185, "end": 196, "token_start": 25, "token_end": 26}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 . In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status. ", "source": null}
{"doc_id": "946b6c730d129f5629f71b419dc0fb41", "sentence": "Patients received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 18, "end": 29, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "carboplatin", "start": 77, "end": 88, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I/II trial of vinorelbine and divided-dose carboplatin in advanced non-small cell lung cancer. vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression . Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted.", "source": null}
{"doc_id": "060a83e0337e3cebe9a672cf318d7346", "sentence": "Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion .", "spans": [{"span_id": 0, "text": "Dexamethasone", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 46, "end": 56, "token_start": 6, "token_end": 7}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of paclitaxel/dexamethasone intra-tumoral delivery in treating orthotopic mouse breast cancer. The effect of topical co-administration of promoter drugs with paclitaxel to increase anti-tumor effects of paclitaxel was investigated. Mice with orthotopic 4T1-Luc breast cancer received single intra-tumoral injection of a polymeric formulation with paclitaxel and a specific promoter drug. Several promoter drugs were evaluated, including: dexamethasone, losartan, nicotinamide, Azone, and oleic acid. Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion . However, this effect was accompanied by systemic effects of dexamethasone, and inability to prevent tumor metastasis to the lungs. Topical co-administration of promoter drugs with anti-cancer agents can enhance their anti-tumor effects. Further investigations are needed to identify the most efficient combinations of promoter and anti-cancer drugs, and their suitability for the clinical management of the breast cancer disease.", "source": null}
{"doc_id": "5b6f7ce634e82dcb2432c7f10ee0a2a7", "sentence": "The first available studies demonstrate the value of these compounds with an improved prognosis of metastatic patients in combination with endocrine therapy ( palbociclib , ribociclib ) or in monotherapy ( abemaciclib ) .", "spans": [{"span_id": 0, "text": "palbociclib", "start": 159, "end": 170, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "ribociclib", "start": 173, "end": 183, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "abemaciclib", "start": 206, "end": 217, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "[Cell cycle inhibitors in endocrine receptor positive breast cancer]. Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4\u00a0and 6\u00a0revived interest in this therapeutic class after the failure of pan-inhibitors. palbociclib, ribociclib, and abemaciclib are the 3\u00a0drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation. The first available studies demonstrate the value of these compounds with an improved prognosis of metastatic patients in combination with endocrine therapy ( palbociclib , ribociclib ) or in monotherapy ( abemaciclib ) . The results of ongoing studies will clarify the role of these agents in our new strategies and the individualisation of biomarkers will help to define patients who benefit most from this approach.", "source": null}
{"doc_id": "01488860ce8a1f2064d637382e61dcc7", "sentence": "Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective .", "spans": [{"span_id": 0, "text": "Flunarizine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "diltiazem", "start": 110, "end": 119, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers. Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective . Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.", "source": null}
{"doc_id": "7c380c02bd3fbd1115606724ac821b1c", "sentence": "We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 50, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "itraconazole", "start": 70, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "itraconazole", "start": 138, "end": 150, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "itraconazole", "start": 169, "end": 181, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions. The interaction between polyenes and azoles is not well understood. We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories . Synergy was found at combinations with low concentrations of amphotericin B (<0.125 mg/L), whereas antagonism was found at combinations with higher concentrations of amphotericin B. For itraconazole-resistant isolates, synergistic interactions were observed at high concentrations of itraconazole (>0.5 mg/L). Synergy was more frequently observed for the itraconazole-resistant isolates than for the itraconazole-susceptible isolates.", "source": null}
{"doc_id": "629f2afd9f04075555356b672f8630aa", "sentence": "This study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) .", "spans": [{"span_id": 0, "text": "inotuzumab", "start": 48, "end": 58, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "ozogamicin", "start": 59, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "rituximab", "start": 155, "end": 164, "token_start": 24, "token_end": 25}, {"span_id": 3, "text": "HDT-aSCT", "start": 278, "end": 286, "token_start": 48, "token_end": 49}], "rels": [{"class": "COMB", "spans": [0, 2, 3], "is_context_needed": true}], "paragraph": "A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma.  This study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) . The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL. ", "source": null}
{"doc_id": "cc696918283e488232e6e3aa8ef89b9e", "sentence": "These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin .", "spans": [{"span_id": 0, "text": "methylprednisolone", "start": 99, "end": 117, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "mycophenolate", "start": 122, "end": 135, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "immunoglobulin", "start": 211, "end": 225, "token_start": 35, "token_end": 36}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4, causing enhanced T-cell reaction, antitumor response, and significant improvement of the overall survival of patients with metastatic melanoma. Patients treated with ipilimumab can develop immune-related adverse effects, primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in phase I-III studies, 64.2% of all patients suffered from immune-related adverse effects, ocular adverse effects occurred in 1.3% only. In the cases reported below, 2 patients with metastatic melanoma developed severe ocular myositis after treatment with ipilimumab. These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin .", "source": null}
{"doc_id": "258df1cdd27778c584adcdc22e0d0eb5", "sentence": "The introduction of the selective serotonin reuptake inhibitors , moclobemide and mianserin has been a major advance in the treatment of depression , and is already leading to major shifts in the pattern of antidepressants prescribing .", "spans": [{"span_id": 0, "text": "moclobemide", "start": 66, "end": 77, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "mianserin", "start": 82, "end": 91, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "The management of depression. The place of the new antidepressants. Part 1. General overview.  The introduction of the selective serotonin reuptake inhibitors , moclobemide and mianserin has been a major advance in the treatment of depression , and is already leading to major shifts in the pattern of antidepressants prescribing . These antidepressants are safe, well tolerated and effective, and in conjunction with older agents such as the tricyclics, provide the clinician with a broad range of treatments for this common and disabling disorder. This two-part review will focus on the management of depression in general practice.", "source": null}
{"doc_id": "44576795e1d4a224dc2c88ac25c408d3", "sentence": "Four of these had equivocal plasma levels of both norepinephrine and epinephrine , suggesting that overnight clonidine suppression may be of particular value when tumor secretion is intermittent or low .", "spans": [{"span_id": 0, "text": "epinephrine", "start": 69, "end": 80, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "clonidine", "start": 109, "end": 118, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Overnight clonidine suppression test in the diagnosis and exclusion of pheochromocytoma. In a prospective study designed to differentiate pheochromocytoma from other forms of hypertension, urinary catecholamines were measured after sleep and clonidine administration in 12 patients with pheochromocytoma, 19 hypertensive patients in whom pheochromocytoma was suspected but later excluded, and 31 hypertensive patients in whom pheochromocytoma was never suspected. The test correctly identified all 12 patients in whom pheochromocytoma was present. Four of these had equivocal plasma levels of both norepinephrine and epinephrine , suggesting that overnight clonidine suppression may be of particular value when tumor secretion is intermittent or low . When pheochromocytoma was not present, urinary norepinephrine and epinephrine levels were suppressed below 60 and 20 nmol/mmol creatinine, respectively, after sleep and clonidine, the two in combination giving better suppression than sleep alone. Since urinary catecholamines can be determined relatively easily by high-pressure liquid chromatography with electrochemical detection, this test may be more widely applicable than suppression tests based on plasma measurements.", "source": null}
{"doc_id": "f112ca056732ab95e87bed0eac7b0a3e", "sentence": "In conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine .", "spans": [{"span_id": 0, "text": "ATGAM", "start": 43, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "tacrolimus", "start": 53, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "steroids", "start": 126, "end": 134, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "cyclosporine", "start": 139, "end": 151, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine .", "source": null}
{"doc_id": "2bdca5594e92c0fa8209ac4727e17d4d", "sentence": "Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel .", "spans": [{"span_id": 0, "text": "pertuzumab", "start": 90, "end": 100, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "trastuzumab", "start": 114, "end": 125, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "docetaxel", "start": 129, "end": 138, "token_start": 20, "token_end": 21}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel. pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 \u00b5g/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel . In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer. ", "source": null}
{"doc_id": "bebf5e7b7aae549b7a98aa08fe3a6e12", "sentence": "This study was designed to test the hypothesis that positively charged dendrimers form a complex with enoxaparin , a low-molecular weight heparin ( LMWH ) , and that the resulting drug-dendrimer complex is effective in preventing deep vein thrombosis after pulmonary administration .", "spans": [{"span_id": 0, "text": "enoxaparin", "start": 102, "end": 112, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "heparin", "start": 138, "end": 145, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin.  This study was designed to test the hypothesis that positively charged dendrimers form a complex with enoxaparin , a low-molecular weight heparin ( LMWH ) , and that the resulting drug-dendrimer complex is effective in preventing deep vein thrombosis after pulmonary administration . Fourier Transform Infrared (FTIR) spectroscopy and the azure A assay were used to evaluate interactions between dendrimers and enoxaparin. The efficacy of polyamidoamine (PAMAM) dendrimers in enhancing pulmonary absorption of enoxaparin was studied by administering enoxaparin-dendrimer formulations into the lungs of anesthetized rats and monitoring drug absorption by measuring plasma anti-factor Xa activity. The optimized formulations were evaluated for their efficacy in preventing deep vein thrombosis in a rodent model. The safety of the formulations was tested by studying their effects on mucociliary transport rate (MTR) in a frog palate model and by measuring injury markers in rat bronchoalveolar fluid. The FTIR data and azure A assay revealed ionic interactions between the amino groups of cationic dendrimers and the carboxylic and sulfate groups of enoxaparin. Positively charged dendrimers increased the relative bioavailability of enoxaparin by 40%, while a negatively charged dendrimer had no effect. Formulations containing 1% G2 or 0.5% G3 PAMAM dendrimer plus enoxaparin were as efficacious in preventing deep vein thrombosis in a rat model as subcutaneously administered enoxaparin. The formulations did not adversely affect the MTR or produce extensive damage to the lungs. Positively charged dendrimers are a suitable carrier for pulmonary delivery of enoxaparin. They enhance pulmonary absorption of LMWH probably by reducing negative surface charge density of the drug molecule.", "source": null}
{"doc_id": "768337984609fbfa1979e5a454e65f0d", "sentence": "We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 \u03bcM ) and fast ( 0.25 s \u2265 \u03c4 \u2265 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and \u03b1- and \u03b2-cyclodextrins .", "spans": [{"span_id": 0, "text": "ibuprofen", "start": 227, "end": 236, "token_start": 44, "token_end": 45}, {"span_id": 1, "text": "S-flurbiprofen", "start": 239, "end": 253, "token_start": 46, "token_end": 47}, {"span_id": 2, "text": "salicylic acid", "start": 256, "end": 270, "token_start": 48, "token_end": 50}, {"span_id": 3, "text": "phenylbutazone", "start": 275, "end": 289, "token_start": 51, "token_end": 52}, {"span_id": 4, "text": "\u03b2-cyclodextrins", "start": 303, "end": 318, "token_start": 56, "token_end": 57}], "rels": [{"class": "COMB", "spans": [0, 4], "is_context_needed": true}, {"class": "COMB", "spans": [1, 4], "is_context_needed": true}, {"class": "COMB", "spans": [3, 4], "is_context_needed": true}], "paragraph": "Revealing equilibrium and rate constants of weak and fast noncovalent interactions. Rate and equilibrium constants of weak noncovalent molecular interactions are extremely difficult to measure. Here, we introduced a homogeneous approach called equilibrium capillary electrophoresis of equilibrium mixtures (ECEEM) to determine k(on), k(off), and K(d) of weak (K(d) > 1 \u03bcM) and fast kinetics (relaxation time, \u03c4 < 0.1 s) in quasi-equilibrium for multiple unlabeled ligands simultaneously in one microreactor. Conceptually, an equilibrium mixture (EM) of a ligand (L), target (T), and a complex (C) is prepared. The mixture is introduced into the beginning of a capillary reactor with aspect ratio >1000 filled with T. Afterward, differential mobility of L, T, and C along the reactor is induced by an electric field. The combination of differential mobility of reactants and their interactions leads to a change of the EM peak shape. This change is a function of rate constants, so the rate and equilibrium constants can be directly determined from the analysis of the EM peak shape (width and symmetry) and propagation pattern along the reactor. We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 \u03bcM ) and fast ( 0.25 s \u2265 \u03c4 \u2265 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and \u03b1- and \u03b2-cyclodextrins . The affinity of the drugs was significantly higher for \u03b2-cyclodextrin than \u03b1-cyclodextrin and mostly determined by the rate constant of complex formation.", "source": null}
{"doc_id": "daefc547a89f7ce7f0dc7b13ae5937ef", "sentence": "We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 61, "end": 71, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "etoposide", "start": 77, "end": 86, "token_start": 11, "token_end": 12}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer. High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease . ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.", "source": null}
{"doc_id": "1363fe5e83c9f5c523828ec013b8a56b", "sentence": "Esomeprazole , a proton-pump inhibitor ( PPI ) , is the S-isomer of omeprazole .", "spans": [{"span_id": 0, "text": "Esomeprazole", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "omeprazole", "start": 68, "end": 78, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Esomeprazole: a clinical review. The pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy, and adverse effects of esomeprazole are reviewed. Esomeprazole , a proton-pump inhibitor ( PPI ) , is the S-isomer of omeprazole . esomeprazole has FDA-approved labeling for use in the treatment of symptomatic gastroesophageal reflux disease (GERD), including healing and maintenance of healing of erosive esophagitis and as part of a triple-drug regimen for Helicobocter pylori infection. esomeprazole is structurally similar to other PPIs but is the first PPI to include only the active isomer, which may lead to improved pharmacokinetic and pharmacodynamic characteristics. esomeprazole maintains intragastric pH at a higher level and above 4 for a longer period than other PPIs. Clinical studies have shown that esomeprazole is at least equivalent in safety and efficacy to other drugs in the class. esomeprazole has demonstrated efficacy in the treatment of erosive esophagitis, the maintenance of healing of erosive esophagitis, and the treatment of signs and symptoms of GERD. Effective dosages are 20 or 40 mg orally every day or as needed. esomeprazole magnesium 40 mg once daily in combination with amoxicillin and clarithromycin is effective in eradicating H. pylori infection. The potential for interacting with other drugs is limited and is similar to that of omeprazole. The most common adverse effects are headache, respiratory infection, and abdominal symptoms. esomeprazole has pharmacokinetic properties that may make it more effective than omeprazole in some patients.", "source": null}
{"doc_id": "34085f618946f6f3b105553ee700b4ba", "sentence": "This increase in the number of vasopressin and oxytocin containing neurons in the pig hypothalamus is much later in development than has ever been reported so far .", "spans": [{"span_id": 0, "text": "vasopressin", "start": 31, "end": 42, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "oxytocin", "start": 47, "end": 55, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "A vasopressin and oxytocin containing nucleus in the pig hypothalamus that shows neuronal changes during puberty. A vasopressin and oxytocin containing nucleus is described for the first time in the pig hypothalamus. It is located near the third ventricle, just dorsal to the suprachiasmatic nucleus, and consists of magnocellular neurons, similar to those of the supraoptic nucleus and paraventricular nucleus. Morphometric analysis of neuronal number, size, density, and volume was performed at four different ages: 1 day, 7 weeks, 16 weeks, and 30 weeks postnatally. No sex difference in these parameters was observed. In this period the volume of the nucleus increased gradually from 6.6 x 10(-3) to 54.2 x 10(-3) mm3. One day after birth 1,215 +/- 191 (mean +/- SEM) neurons were present in the vasopressin and oxytocin containing nucleus, followed by a decrease to 771 +/- 80 neurons at 7 weeks and 697 +/- 116 at 16 weeks. Between 16 and 30 weeks (puberty) there was a dramatic increase in neuron number up to 1,765 +/- 214 neurons. This increase in the number of vasopressin and oxytocin containing neurons in the pig hypothalamus is much later in development than has ever been reported so far .", "source": null}
{"doc_id": "4d1c93db896cd77cb92357c8cd08b272", "sentence": "Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity .", "spans": [{"span_id": 0, "text": "alkylating agents", "start": 16, "end": 33, "token_start": 2, "token_end": 4}, {"span_id": 1, "text": "fludarabine", "start": 38, "end": 49, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "cladribine", "start": 53, "end": 63, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression. Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity . Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser.", "source": null}
{"doc_id": "44961781380ebcb4e76b2474630bdd4c", "sentence": "The pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study .", "spans": [{"span_id": 0, "text": "trazodone", "start": 47, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "amitriptyline", "start": 70, "end": 83, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "ethanol", "start": 126, "end": 133, "token_start": 24, "token_end": 25}, {"span_id": 3, "text": "placebo", "start": 97, "end": 104, "token_start": 19, "token_end": 20}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Evaluation of possible interactions between ethanol and trazodone or amitriptyline.  The pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study . Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co-administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, 'clearheadedness', aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced 'clearheadedness' and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity, which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks.", "source": null}
{"doc_id": "f6d6d6d6c7e5d3b223469c4647ae830c", "sentence": "A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases .", "spans": [{"span_id": 0, "text": "5-fluorouracil/leucovorin", "start": 75, "end": 100, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "irinotecan", "start": 103, "end": 113, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "bevacizumab", "start": 120, "end": 131, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban. Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases . Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer.", "source": null}
{"doc_id": "cb78de3312276734322bda401ae26214", "sentence": "Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5\u2011Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone .", "spans": [{"span_id": 0, "text": "imatinib", "start": 79, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "irinotecan", "start": 112, "end": 122, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "5\u2011Fu", "start": 126, "end": 130, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Imatinib\u2011induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress. imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR\u2011ABL, c\u2011KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in\u00a0vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria\u2011mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress\u2011associated activation of c\u2011Jun NH2\u2011terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time\u2011\u00a0and dose\u2011dependent manner. Cell cycle analysis revealed that imatinib\u2011treated AGS cells were arrested in the G2/M\u00a0phase of the cell cycle. Moreover, imatinib\u2011treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor\u00a0C/EBP homologous protein, an ER stress\u2011associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5\u2011Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone . These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress\u2011associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet\u2011derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer.", "source": null}
{"doc_id": "1f7554912aff5c289e111df0ba0da420", "sentence": "We concluded that ifosfamide is an active agent even in patients with tumours resistant to cyclophosphamide .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 18, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "cyclophosphamide", "start": 91, "end": 107, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Ifosfamide in the treatment of high-grade recurrent non-Hodgkin's lymphomas. We report the results of two phase II trials of ifosfamide in very high risk patients with either partially responsive or recurrent non-Hodgkin's lymphomas. In the first study, in which patients were extremely heavily pretreated (50 per cent had received a very intensive salvage regimen containing very high dose cyclophosphamide), there were two complete responses, two partial responses and one objective (minimal) response among 14 patients treated. Toxicity was acceptable even in this end-stage patient group. We concluded that ifosfamide is an active agent even in patients with tumours resistant to cyclophosphamide . The second trial was a pilot study in 13 patients of a regimen incorporating VP16, ifosfamide/mesna, and high dose ara-C (VIPA). There were four complete responses, five partial responses and two objective responses. Two patients died in complete remission from toxic complications, while a third, with a stably regressed mediastinal mass died after completion of the protocol. While very toxic, we considered that this regimen was highly effective, and have since incorporated a slightly less intensive combination of the same drugs into the primary therapy of high risk patients. Since the primary toxicity of the VIPA combination was myelosuppression, the use of a modified protocol incorporating colony stimulating factors to ameliorate the side-effects and possibly increase dose rate is worthy of further exploration in patients with recurrent B cell tumours.", "source": null}
{"doc_id": "38dba7074fb0f572a099da86370fab35", "sentence": "The combination of a fluoropyrimidine ( 5-fluorouracil or capecitabine ) with either oxaliplatin or irinotecan has been widely accepted as standard cytotoxic chemotherapy for either the first- or second-line treatment of mCRC .", "spans": [{"span_id": 0, "text": "fluoropyrimidine", "start": 21, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "oxaliplatin", "start": 85, "end": 96, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "irinotecan", "start": 100, "end": 110, "token_start": 14, "token_end": 15}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Options for Second-Line Treatment in Metastatic Colorectal Cancer. Colorectal cancer (CRC) remains a major public health problem in the United States and worldwide. The majority of patients who have CRC eventually present with metastatic disease. The overall therapeutic goals for most patients with metastatic CRC (mCRC) are to control the disease, prolong life span, and maximize quality of life. Therefore, the ratio of efficacy to toxicity is one of the most important factors in choosing among treatment options and sequencing regimens. In addition, the choice of first-line systemic therapy will affect the options for second-line treatment. Several newer cytotoxic agents for the treatment of mCRC have been approved during the past 2 decades by the US Food and Drug Administration (FDA), including irinotecan, oxaliplatin, and capecitabine. The combination of a fluoropyrimidine ( 5-fluorouracil or capecitabine ) with either oxaliplatin or irinotecan has been widely accepted as standard cytotoxic chemotherapy for either the first- or second-line treatment of mCRC . The FDA has approved several pathway-targeting agents for the treatment of mCRC; these include agents that target the vascular endothelial growth factor receptor pathway (bevacizumab, ziv-aflibercept, and ramucirumab) and those that target the epidermal growth factor receptor pathway (cetuximab and panitumumab). Here, we review the current clinical options for the second-line treatment of mCRC and the rationales for their use. ", "source": null}
{"doc_id": "26176aad604a52fd2bb4bcc904127ead", "sentence": "In 1517 poor prognosis patients , 21 regimens were used , the commonest being CAV , EV ( etoposide , vincristine ) , CbE , CAV alternating with PE , and oral etoposide .", "spans": [{"span_id": 0, "text": "etoposide", "start": 89, "end": 98, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "vincristine", "start": 101, "end": 112, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "etoposide", "start": 158, "end": 167, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "A national survey of the chemotherapy regimens used to treat small cell lung cancer (SCLC) in the United Kingdom. Many chemotherapy regimens are used for treating SCLC in the United Kingdom, but it is not known, in any detail, which regimens are used, by which specialists, for which types of patient. We conducted a survey among all medical and clinical oncologists, respiratory physicians and general physicians with respiratory interest in the United Kingdom to find out. The questionnaire asked for the number of SCLC patients treated annually; how many were given chemotherapy; the drugs, doses and schedules chosen according to prognostic group (as defined by the clinician); and the reasons for choice of regimen. 1214 questionnaires were sent out, and responses were received from 1070 (88%) clinicians; 266 (25%) of these treated SCLC with chemotherapy. Of 4674 patients given chemotherapy annually, 36% were given it by clinical oncologists, 30% by medical oncologists, 27% by respiratory physicians, and 7% by general physicians. In all, 34 regimens were reported with 151 different combinations of dose and schedule. In 2311 good prognosis patients, 23 regimens were used, the commonest being ACE (doxorubicin, cyclophosphamide, etoposide), ICbE (ifosfamide, carboplatin, etoposide), CAV (cyclophosphamide, doxorubicin, vincristine), CbE (carboplatin, etoposide), and PE (cisplatin, etoposide). In 1517 poor prognosis patients , 21 regimens were used , the commonest being CAV , EV ( etoposide , vincristine ) , CbE , CAV alternating with PE , and oral etoposide . 452 patients were treated regardless of prognosis and for 219 no prognostic criteria were specified. The remaining 175 were given second-line chemotherapy or were given regimens chosen to avoid toxicity or because of intercurrent disease or other reasons. The main reasons affecting choice of regimen were routine local practice, patients' convenience, quality of life considerations, trial results and cost. The results show wide variation in routine practice and will be useful in reporting and planning clinical trials and in deciding on local treatment policies.", "source": null}
{"doc_id": "c87bef0baeedd5907639f42835450242", "sentence": "Utilizing this data , we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 38, "end": 47, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ipilimumab", "start": 53, "end": 63, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "cabozantinib", "start": 68, "end": 80, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors. Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data , we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients . For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.", "source": null}
{"doc_id": "2086edd2e2d105c3fd82dcf2747792c3", "sentence": "The aim of this study was to evaluate all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes .", "spans": [{"span_id": 0, "text": "piperacillin", "start": 141, "end": 153, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "netilmicin", "start": 159, "end": 169, "token_start": 26, "token_end": 27}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Piperacillin-resistant Escherichia coli bacteraemia: relation to empiric therapy and clinical outcome. Escherichia coli is a leading cause of bacteraemia. The aim of this study was to evaluate all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes . We measured the incidence of piperacillin-resistant E. coli bacteraemia among haematological and non-haematological patients, described the importance of previous antibiotic treatment for resistance development in E. coli and evaluated the impact of piperacillin resistance on the clinical outcome of E. coli bacteraemia. 114 episodes of E. coli bacteraemia in 104 patients were recorded and 98 episodes in 88 patients (42 males and 46 females) with a median age of 64 y (range 19-85 y) were evaluated. In 81.6% of the episodes the patients had a haematological disorder, dominated by acute leukaemia (41.3%), chronic leukaemia (16.3%) and lymphoma (10%). The proportion of piperacillin-resistant E. coli was higher among haematological patients than non-haematological patients (25% vs 0%, p=0.02) and resistance was associated with piperacillin therapy during the previous month (p=0.05). No difference in clinical outcome was found between haematological patients infected with piperacillin-susceptible or -resistant E. coli (intensive care 12% vs 15%; mortality 22% vs 25%).", "source": null}
{"doc_id": "d86c5461771613501c2aa3b8c0ef2d53", "sentence": "Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 58, "end": 67, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "docetaxel", "start": 115, "end": 124, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "thalidomide", "start": 129, "end": 140, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. New therapeutic alternatives are needed to improve outcomes in patients with androgen-independent prostate cancer (AIPC). For several years, researchers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process. thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels. In a recent phase II trial of thalidomide in AIPC, 28% of patients achieved a prostate-specific antigen (PSA) decrease of >40%. The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC. Thus, based on the single-agent activity of thalidomide and docetaxel, we initiated a randomized phase II study of weekly docetaxel with or without thalidomide, 200 mg at bedtime, in patients with chemotherapy-naive metastatic AIPC. docetaxel, 30 mg/m(2) intravenously, was administered every 7 days for 3 weeks, followed by a 1-week rest period. Both regimens have been well tolerated among the first 59 treated patients, with a near absence of grade (3/4) myelosuppression. Fatigue, hyperglycemia, and pulmonary toxicity were seen in both groups. Thrombotic events have been seen in the combination arm. Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management.", "source": null}
{"doc_id": "eab1f4116fcece11689b6ced429d2980", "sentence": "Evidence-based guidelines recommend nicotine replacement therapy , bupropion SR , and varenicline as effective alternatives for smoking cessation therapy , especially when combined with behavioral interventions .", "spans": [{"span_id": 0, "text": "nicotine", "start": 36, "end": 44, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bupropion", "start": 67, "end": 76, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "varenicline", "start": 86, "end": 97, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Smoking cessation intervention: an evidence-based approach. Cigarette smoking represents the most important source of preventable morbidity and premature mortality worldwide. Approximately 100 million deaths were caused by tobacco use in the 20th century. There are >1 billion smokers worldwide, and globally the use of tobacco products is increasing, with the epidemic shifting to the developing world. Tobacco dependence is a chronic condition that often requires repeated intervention for success. Just informing a patient about health risks, although necessary, is usually not sufficient for a decision to change. Smokers should be provided with counseling when attempting to quit. Pharmacologic smoking cessation aids are recommended for all smokers who are trying to quit, unless contraindicated. Evidence-based guidelines recommend nicotine replacement therapy , bupropion SR , and varenicline as effective alternatives for smoking cessation therapy , especially when combined with behavioral interventions . Combination pharmacotherapy is indicated for highly nicotine-dependent smokers, patients who have failed with monotherapy, and patients with breakthrough cravings. An additional form of nicotine replacement therapy or an addition of a non-nicotine replacement therapy oral medication (bupropion or varenicline) may be helpful. The rate of successful smoking cessation at 1 year is 3% to 5% when the patient simply tries to stop, 7% to 16% if the smoker undergoes behavioral intervention, and up to 24% when receiving pharmacological treatment and behavioral support.", "source": null}
{"doc_id": "7a45554d0d2040d636c725b31394506f", "sentence": "The efficacy of methotrexate ( MTX ) as a single graft-versus-host disease ( GVHD ) prophylaxis agent was compared to that of cyclosporin A ( CSA ) in 62 pediatric patients ( median age : 8 years ) with hematological malignancies who had undergone bone marrow transplantation ( BMT ) from HLA-identical sibling donors at National Kyushu Cancer Center since 1977 .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 16, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "cyclosporin", "start": 126, "end": 137, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Methotrexate vs Cyclosporin A as a single agent for graft-versus-host disease prophylaxis in pediatric patients with hematological malignancies undergoing allogeneic bone marrow transplantation from HLA-identical siblings: a single-center analysis in Japan.  The efficacy of methotrexate ( MTX ) as a single graft-versus-host disease ( GVHD ) prophylaxis agent was compared to that of cyclosporin A ( CSA ) in 62 pediatric patients ( median age : 8 years ) with hematological malignancies who had undergone bone marrow transplantation ( BMT ) from HLA-identical sibling donors at National Kyushu Cancer Center since 1977 . In all, 30 patients received MTX by intravenous bolus injection, with a dose of 15 mg/m(2) on day +1, followed by 10 mg/m(2) on days +3, +6, and +11, and then once a week until day +100. A total of 32 patients were treated with CSA, which was given intravenously in the early stages and orally thereafter until day +100, and then gradually tapered and stopped 6 months after BMT. There were no differences between the groups in terms of rates of hematopoietic recovery after BMT. The probabilities of acute GVHD (grades II-IV) and chronic GVHD were 29.6 vs 40.6% (P=0.294) and 19 vs 20% (MTX vs CSA), respectively. Relapse rates and event-free survival were identical. These results suggest that MTX and CSA were equally effective when given after BMT in Japanese pediatric patients with hematological malignancies. Since MTX was given over a shorter time than CSA, it might be more practical in the management of such patients.", "source": null}
{"doc_id": "6aa32e480cf9ee6187d23672321fb66f", "sentence": "Owing to the wide spread activation of this pathway in numerous neoplasms , trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations .", "spans": [{"span_id": 0, "text": "trametinib", "start": 76, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "cobimetinib", "start": 91, "end": 102, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved \u03b23-lysine and they make numerous hydrophobic contacts with residues within the \u03b1C-helix, the \u03b25 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms , trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations . Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough.", "source": null}
{"doc_id": "1f40155876a82805baff26c32ebc9de0", "sentence": "All these isolates were found to survive in presence of heavy metals like cadmium , lead and zinc and were resistant to antibiotics like ampicillin , tetracycline , streptomycin , penicillin and chloramphenicol as indicated by their Minimum Inhibitory Concentrations ( MIC ) .", "spans": [{"span_id": 0, "text": "ampicillin", "start": 137, "end": 147, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "tetracycline", "start": 150, "end": 162, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "streptomycin", "start": 165, "end": 177, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "chloramphenicol", "start": 195, "end": 210, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Identification and Characterization of the microbial communities found in electronic industrial effluent and their potential for bioremediation. Microbial communities are dynamic systems that develop depending on the ecological niche in which they survive. Electronic industry effluent, rich in heavy metals and salts is one such ecosystem where diverse heavy metal resistant microbes exist. Taxonomic identification of this microbial community would be interesting as no information on the microbial diversity from electronic industry effluent is available till date. Our paper attempts to characterize the microbial inhabitants of this niche. Culture dependent microbiological methods were used to establish and identify various microbial species from the effluent. Culture independent methods of identification involving biochemical tests and molecular biology based methods like 16 S- r DNA sequencing and lipid analyses (FAME analysis) were also carried out to confirm the identity of isolated species. Our study, first of its kind revealed the presence of a diverse group of resistant aerobic microbes and disclosed a total of ten bacterial and two fungal isolates. All these isolates were found to survive in presence of heavy metals like cadmium , lead and zinc and were resistant to antibiotics like ampicillin , tetracycline , streptomycin , penicillin and chloramphenicol as indicated by their Minimum Inhibitory Concentrations ( MIC ) . Such resistant isolates harbor possibilities of metal adaptive/selective pathways which render them as economically beneficial bio-sorbent alternatives in bioremediation of heavy metals.", "source": null}
{"doc_id": "51927614ff11b96d6d8c367030196710", "sentence": "Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 118, "end": 128, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "pemetrexed", "start": 151, "end": 161, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "cisplatin", "start": 136, "end": 145, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma. To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed . Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance. ", "source": null}
{"doc_id": "76c1b10dff966a31783801aacb7c157e", "sentence": "In conclusion , the combination of thalidomide and cyclosporine in subtherapeutic doses may be useful for the treatment of skin allografts .", "spans": [{"span_id": 0, "text": "thalidomide", "start": 35, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "cyclosporine", "start": 51, "end": 63, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in rabbits. The present study evaluated the effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in 42 rabbits divided into the following groups (n = 6): group 1, autograft control; group 2, allograft control; group 3, allografts under thalidomide (100 mg/kg/d); group 4, allografts under sodium diclofenac (2 mg/kg/d); group 5, allografts under cyclosporine (10 mg/kg/d); group 6, allografts under cyclosporine (5 mg/kg/d); group 7, allografts under cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). The drugs were given via the orogastric tube the day before transplantation and daily during the postoperative period. Total circular skin grafts from the ear were exchanged between California and White New Zealand rabbits. cyclosporine (10 mg/kg/d) increased allograft survival, an effect that was comparable to cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). thalidomide and diclofenac given alone had minimally significant effects on the mean survival of skin allografts. The number of eosinophils around the necrotic skin was higher in the diclofenac group. The group receiving cyclosporine combined with thalidomide displayed the lowest number of eosinophils surrounding the allograft. In conclusion , the combination of thalidomide and cyclosporine in subtherapeutic doses may be useful for the treatment of skin allografts .", "source": null}
{"doc_id": "5697e211a87cb40532bd2a6c0209c3f6", "sentence": "We now wish to report that , under these conditions , the pss-8 mutant is hypersensitive to certain antibiotics , especially to streptomycin , kanamycin , and gentamicin , although also to ampicillin and novobiocin .", "spans": [{"span_id": 0, "text": "streptomycin", "start": 128, "end": 140, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "kanamycin", "start": 143, "end": 152, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "gentamicin", "start": 159, "end": 169, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "ampicillin", "start": 189, "end": 199, "token_start": 32, "token_end": 33}, {"span_id": 4, "text": "novobiocin", "start": 204, "end": 214, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "Envelope composition and antibiotic hypersensitivity of Escherichia coli mutants defective in phosphatidylserine synthetase. Mutants of Escherichia coli K12, defective in phosphatidylserine synthetase (pss), can be isolated as temperature-sensitive, conditional lethals. When cultivated at intermediate temperatures (30 degrees), such mutants contain approximately 3 times more phosphatidylglycerol plus cardiolipin (and less phosphatidylethanolamine) than normal. We now wish to report that , under these conditions , the pss-8 mutant is hypersensitive to certain antibiotics , especially to streptomycin , kanamycin , and gentamicin , although also to ampicillin and novobiocin . At 30 degrees, the membrane protein and fatty acid composition of pss-8 is nearly normal, i.e. identical with an isogenic pss+ organism. Radiochemical labeling and bacteriophage growth studies show that lipopolysaccharide is also unaltered. Therefore, the antibiotic hypersensitivity of pss-8 differs from previously reported hypersensitivities, associated with lipopolysaccharide defects. These results suggest that the polar phospholipid headgroups may play an important role in maintaining the barrier function of the outer gramnegative membrane and that putative inhibitors of the phosphatidylserine synthetase might potentiate the action of numerous antibiotics currently in clinical use.", "source": null}
{"doc_id": "cd6a412fcb3306448aa13a6679d7e767", "sentence": "During the first 5 min of cooling , CVC decreased at control sites ( lactated Ringer solution ) to -45 + /- 6 % ( P < 0.001 ) , increased at adrenoceptor-antagonized sites ( yohimbine + propranolol ) to 15 + /- 14 % ( P = 0.002 ) , and remained unchanged at both Rho kinase-inhibited ( fasudil ) and adrenoceptor-antagonized + Rho kinase-inhibited sites ( yohimbine + propranolol + fasudil ) ( -9 + /- 1 % , P = 0.4 and -6 + /- 2 % , P = 0.4 , respectively ) .", "spans": [{"span_id": 0, "text": "yohimbine", "start": 174, "end": 183, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "propranolol", "start": 186, "end": 197, "token_start": 37, "token_end": 38}, {"span_id": 2, "text": "fasudil", "start": 286, "end": 293, "token_start": 59, "token_end": 60}, {"span_id": 3, "text": "yohimbine", "start": 356, "end": 365, "token_start": 68, "token_end": 69}, {"span_id": 4, "text": "propranolol", "start": 368, "end": 379, "token_start": 70, "token_end": 71}, {"span_id": 5, "text": "fasudil", "start": 382, "end": 389, "token_start": 72, "token_end": 73}], "rels": [], "paragraph": "Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Cutaneous vasoconstriction (VC) is the initial thermoregulatory response to cold exposure and can be elicited through either whole body or localized skin cooling. However, the mechanisms governing local cold-induced VC are not well understood. We tested the hypothesis that Rho kinase participates in local cold-induced cutaneous VC. In seven men and women (20-27 yr of age), up to four ventral forearm skin sites were instrumented with intradermal microdialysis fibers for localized drug delivery during cooling. Skin blood flow was monitored at each site with laser-Doppler flowmetry while local skin temperature was decreased and maintained at 24 degrees C for 40 min. Cutaneous vascular conductance (CVC; laser-Doppler flowmetry/mean arterial pressure) was expressed as percent change from 34 degrees C baseline. During the first 5 min of cooling , CVC decreased at control sites ( lactated Ringer solution ) to -45 + /- 6 % ( P < 0.001 ) , increased at adrenoceptor-antagonized sites ( yohimbine + propranolol ) to 15 + /- 14 % ( P = 0.002 ) , and remained unchanged at both Rho kinase-inhibited ( fasudil ) and adrenoceptor-antagonized + Rho kinase-inhibited sites ( yohimbine + propranolol + fasudil ) ( -9 + /- 1 % , P = 0.4 and -6 + /- 2 % , P = 0.4 , respectively ) . During the last 5 min of cooling, CVC further decreased at all sites when compared with baseline values (control, -77 +/- 4%, P < 0.001; adrenoceptor antagonized, -61 +/- 3%, P < 0.001; Rho kinase inhibited, -34 +/- 7%, P < 0.001; and adrenoceptor antagonized + Rho kinase inhibited sites, -35 +/- 3%, P < 0.001). Rho kinase-inhibited and combined treatment sites were significantly attenuated when compared with both adrenoceptor-antagonized (P < 0.01) and control sites (P < 0.0001). Rho kinase mediates both early- and late-phase cold-induced VC, supporting in vitro findings and providing a putative mechanism through which both adrenergic and nonadrenergic cold-induced VC occurs in an in vivo human thermoregulatory model.", "source": null}
{"doc_id": "e85037de90f9d9227fd3c680bd0ce306", "sentence": "Rats were subchronically primed with nicotine , clozapine or saline .", "spans": [{"span_id": 0, "text": "nicotine", "start": 37, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "clozapine", "start": 48, "end": 57, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "saline", "start": 61, "end": 67, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Nicotine and clozapine cross-prime the locus coeruleus noradrenergic system to induce long-lasting potentiation in the rat hippocampus. A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine , clozapine or saline . Twenty-one to twenty-eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an \u03b12 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine-primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine.", "source": null}
{"doc_id": "09d51495e2d83ea5f32d530926d8541c", "sentence": "The chimeric anti- EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease ( FDA ) .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 44, "end": 53, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "irinotecan", "start": 191, "end": 201, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "The future of anti-EGFR therapy. We report here on the state of our knowledge of the target--namely, the epidermal growth factor (EGF) and its receptor--and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti- EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease ( FDA ) . cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.", "source": null}
{"doc_id": "22c52fc95d8815028638dbd0c82cb2ea", "sentence": "New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 30, "end": 40, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "oxaliplatin", "start": 45, "end": 56, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "taxane", "start": 21, "end": 27, "token_start": 5, "token_end": 6}, {"span_id": 3, "text": "cisplatin", "start": 94, "end": 103, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "5-FU", "start": 108, "end": 112, "token_start": 20, "token_end": 21}], "rels": [{"class": "COMB", "spans": [2, 3, 4], "is_context_needed": true}, {"class": "COMB", "spans": [0, 3, 4], "is_context_needed": true}, {"class": "COMB", "spans": [1, 3, 4], "is_context_needed": true}], "paragraph": "Chemotherapy for advanced gastric cancer: slow but further progress. Gastric cancer remains a significant problem in terms of global health, and is the most common cancer in Korea. Surgery is the only potentially curative treatment for localized gastric cancer, but most cases present at an advanced stage. Randomized trials have demonstrated that chemotherapy for advanced gastric cancer improves the quality of life and extends survival, by 4 approximately 6 months, compared with best supportive care alone. Single agents with a proven activity in a first-line setting include 5-fluorouracil (5-FU), doxorubicin, mitomycin C, cisplatin, taxanes (docetaxel and paclitaxel) and oral fluoropyrimidines (capecitabine and TS-1). Based on the results from several large scale randomized trials, FP (5-FU/cisplatin) and ECF (epirubicin/cisplatin/5-FU) combinations are the most widely used regimen against advanced gastric cancer. Phase II studies of the FP and ECF combination reported a 40~51% response rate in previously untreated patients, and this regimen also produced a significantly higher response rate than the FAM (5-FU/doxorubicin/mitomycin) and FAMTX (5-FU/doxorubicin/methotrexate) regimens, respectively. However, significant treatment related-toxicities and discomfort were reported from ECF, which prevents this combination from becoming the standard treatment regimen. While no one combination chemotherapy regimen is accepted as the standard for advanced gastric cancer, FP is currently considered a suitable reference regimen worldwide. New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes . Also, oral 5-FU prodrugs are replacing the cumbersome 5-FU long-term infusion due to its convenience and superior toxicity profile. However, the low complete response rate and short response duration are still the main obstacles in the chemotherapy for gastric cancer. Only large scale comparative clinical trials will give clues to improve the results of gastric cancer treatments.", "source": null}
{"doc_id": "1007329826934be65ae5d787ac699734", "sentence": "Taxinol , Gemcitabine ( GEM ) , Navelbine ( NVB ) , Edatrexate ( ETX ) , CPT-11 and high dose Epirubicin ( EPI HD ) are recommended as new effective drugs .", "spans": [{"span_id": 0, "text": "Gemcitabine", "start": 10, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "Epirubicin", "start": 94, "end": 104, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Non-surgical therapy for patients with advanced non-small cell lung cancer. Advanced non-small cell lung cancer (NSCLC) denotes those of TNM stage III and IV. NSCLC has its specific characteristics in respect of oncological behaviour, molecular biology, sensitivity to chemotherapy (CT) and radiotherapy (RT), and requires different therapeutic strategies in comparison with small cell lung cancer. The therapies include: (1) surgery in combination with new effective drugs is resulted in improved RR from 15% a decade ago to 40-60% today. Cisplatin (C-DDP) is the most attractive drug in the treatment of NSCLC, in lengthening the life-span of Stage IV NSCLC patients and as an indispensable sensitizer in RT. Taxinol , Gemcitabine ( GEM ) , Navelbine ( NVB ) , Edatrexate ( ETX ) , CPT-11 and high dose Epirubicin ( EPI HD ) are recommended as new effective drugs . Response rates recently reported for the combination CT with the drugs mentioned above for NSCLC are from 30-65%, and with 8-42 weeks of MST. Induction or neoadjuvant therapies for advanced NSCLC, with 40-69% of RR, 25-29% of complete resection rate, 8-34% of CR and 17-45% of one year SR are reviewed. Eight random studies comparing MST between CT with C-DDP and best supportive care for NSCLC are statistically significant. (2) RT for Stage III NSCLC with 2 year and 5 year survivals of 20 and 5% respectively. Although such outcome is hardly acceptable, RT sensitizer, modified RT techniques and chemoradiotherapy (CRT) are imperative to improve the effect of RT in advanced NSCLC. Clinical literature suggest that CRT is better than RT, though without marked difference. Further studies and sufficient follow-up are necessary to judge the efficacy in terms of long-term survival and toxic reaction. (3) Biological therapy: gene therapy of NSCLC is still in the experimental and developmental stage. Of biological response modifier (BRM), alpha IFN in 11 cases of NSCLC with RR of 9% and MST of 14 months, IL-2 and LAK cell treatment in 11 cases with RR of 9% and MST of 18 months are reported. Instillation of BRM such as IL-2 or alpha-IFN into the pleura after drainage of cancerous effusion has been reported as the most effective for those whose RR is of 80-90% and the clinical response time is fairly long. Hematological cytokine as a protective adjuvant therapy against CT/RT toxicity makes high dose of CT possible and raises the response and patient tolerance. In multimodality therapy, it plays an important role to reduce post CT infection and septicemia.", "source": null}
{"doc_id": "5462aa5679ca8723fbb384a42f1503a3", "sentence": "One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group .", "spans": [{"span_id": 0, "text": "enalapril", "start": 20, "end": 29, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "lovastatin", "start": 99, "end": 109, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "puromycin", "start": 246, "end": 255, "token_start": 48, "token_end": 49}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The combination of lovastatin and enalapril in a model of progressive renal disease. puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group . Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)", "source": null}
{"doc_id": "46c1af10ca741651727ab83341728298", "sentence": "Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy .", "spans": [{"span_id": 0, "text": "fosfomycin", "start": 81, "end": 91, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "vancomycin", "start": 121, "end": 131, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "teicoplanin", "start": 135, "end": 146, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "In vitro activity of fosfomycin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy. fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy . MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides.", "source": null}
{"doc_id": "f4bb3b5302fc3c34787fb3c978b1644e", "sentence": "Combination therapy with mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer .", "spans": [{"span_id": 0, "text": "mitomycin", "start": 25, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "tamoxifen", "start": 37, "end": 46, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "UFT", "start": 53, "end": 56, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "UFT and mitomycin plus tamoxifen for stage II, ER-positive breast cancer. Hokkaido ACETBC Study Group. A trial was designed to examine the combination of UFT and mitomycin (Mutamycin) plus tamoxifen (Nolvadex) as postoperative adjuvant therapy in the treatment of patients with stage II, estrogen receptor (ER)-positive primary breast cancer. mitomycin was administered intravenously at 13 mg/m2 on the day of surgery. Patients judged to be ER-positive were randomly allocated to either group A, which received oral tamoxifen 20 mg/day 14 days after surgery for 2 years, or group B, receiving oral UFT 400 mg/day plus tamoxifen 20 mg/day. A total of 219 patients were enrolled in group A, of which 213 (97.3%) were determined to be eligible; 225 patients enrolled in group B and 223 (99.1%) were eligible. The 5-year survival rates were 93.0% for group A and 95.4% for group B, with no significant difference between groups. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, a significant advantage (P = .020) for the UFT plus tamoxifen group. Combination therapy with mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer .", "source": null}
{"doc_id": "70ee0c1e56cac0e3bb9d3c835721416e", "sentence": "The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 81, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "methotrexate", "start": 100, "end": 112, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "mycophenolate", "start": 116, "end": 129, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) . Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors. ", "source": null}
{"doc_id": "b83939edbb4e56478efb8e3be32e53e1", "sentence": "Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected .", "spans": [{"span_id": 0, "text": "Propranolol", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "propranolol", "start": 250, "end": 261, "token_start": 41, "token_end": 42}, {"span_id": 2, "text": "lacidipine", "start": 140, "end": 150, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers. The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected . With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension.", "source": null}
{"doc_id": "f471cf9397ea607071e678ff48f72b27", "sentence": "The patient received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide .", "spans": [{"span_id": 0, "text": "vincristine", "start": 45, "end": 56, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "doxorubicin", "start": 75, "end": 86, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "cyclophosphamide", "start": 105, "end": 121, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "actinomycin", "start": 59, "end": 70, "token_start": 7, "token_end": 8}, {"span_id": 4, "text": "cisplatin", "start": 89, "end": 98, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Autologous peripheral blood stem cell transplantation in a patient with relapsed pleuropulmonary blastoma. Pleuropulmonary blastoma (PPB) is a rare and aggressive primary intrathoracic neoplasma of children. The prognosis is extremely poor with frequent metastasis to the brain and bone. We present a 4-year-old girl with a tumor mass in the right hemithorax initially diagnosed as pneumoniae. Tumor resection was performed and the histologic report indicated the diagnosis of PPB. The patient received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide . Irradiation was performed with total 45 Gy at the right lower pulmonary lobe. She relapsed 29 months later at the pleura between the right middle and lower pulmonary lobe. Tumor resection and total 45 Gy of irradiation were performed again. High-dose chemotherapy comprising cisplatin, adriamycin, and cyclophosphamide was performed followed by autologous peripheral blood stem cell transplantation (PBSCT). The patient achieved complete hematologic recovery. Thirty-one months after PBSCT, no signs of relapse have been observed. Although it might be that the patient could have been cured with second surgery alone or by the surgery and subsequent chemotherapy, high-dose chemotherapy and PBSCT should be considered for the treatment of relapsed PPB.", "source": null}
{"doc_id": "c27cefd30656336acf4b74f488e05d74", "sentence": "It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol .", "spans": [{"span_id": 0, "text": "nicotine", "start": 86, "end": 94, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "haloperidol", "start": 113, "end": 124, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Nicotine and ethanol enhancements of acoustic startle reflex are mediated in part by dopamine in C57BL/6J mice. nicotine has been shown to have additive as well as antagonistic effects on behavior stimulated by ethanol. Here, we examine the effects of nicotine, ethanol, and the coadministration of each drug on acoustic startle responding in C57BL/6J mice. Mice were tested at a range of decibel levels (80-115 dB, 5 dB increments), with administration of 0.031, 0.062, 0.125, and 0.25 mg/kg nicotine or 0.5, 1.0, 1.5, and 2.0 g/kg ethanol. nicotine and ethanol each caused an increase in the acoustic startle response at the highest and lowest doses tested, respectively. mecamylamine, a nicotinic receptor antagonist, administered in combination with nicotine or ethanol attenuated these increases in acoustic startle responding. nicotine and ethanol, administered together, did not produce greater enhancement of startle than when administered alone. haloperidol (1 mg/kg) was administered in combination with nicotine or ethanol to investigate if dopamine modulated nicotine or ethanol enhancement of acoustic startle. It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol . Thus, ethanol or nicotine may enhance the acoustic startle reflex through a common dopaminergic mechanism.", "source": null}
{"doc_id": "813dcb872eb1f84227a34f52386ba8d0", "sentence": "The use of tacrolimus ( 88 % vs 77 % , P=.02 ) and cytolytic therapy ( 81 % vs 46 % , P < .0001 ) was likewise greater among patients who received ganciclovir prophylaxis .", "spans": [{"span_id": 0, "text": "tacrolimus", "start": 11, "end": 21, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "ganciclovir", "start": 147, "end": 158, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "Ganciclovir prophylaxis delays but does not prevent cytomegalovirus infection in renal transplant recipients. Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among renal transplant recipients. The purpose of this study was to examine the effect of routine prophylaxis with 12 weeks of oral ganciclovir on the incidence of CMV infection in a center that predominantly uses antibody induction together with tacrolimus/mycophenolate mofetil-based maintenance immunosuppressive therapy. The control group consisted of a historical patient cohort transplanted immediately prior to the use of oral ganciclovir prophylaxis. The use of tacrolimus ( 88 % vs 77 % , P=.02 ) and cytolytic therapy ( 81 % vs 46 % , P < .0001 ) was likewise greater among patients who received ganciclovir prophylaxis . CMV infection occurred in 20 (9%) patients in the ganciclovir era and 4 (3%) patients in the preganciclovir era (P=.003). The mean time to CMV infection was longer in patients who received ganciclovir prophylaxis than in patients in the preganciclovir era (23.4 +/- 10.9 weeks vs 9.8 +/- 5.6 weeks, P=.03). We conclude that 12 weeks of ganciclovir prophylaxis delays but does not prevent CMV infection from occurring in renal transplant recipients. These results suggest that with the use of 12 weeks of ganciclovir prophylaxis, vigilance for CMV infection is needed well beyond 24 weeks posttransplant.", "source": null}
{"doc_id": "c0ee5c12e6ffd1a92a439a953fce6247", "sentence": "Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically \" targeted \" agents .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 8, "end": 19, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "gemcitabine", "start": 171, "end": 182, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "bevacizumab", "start": 276, "end": 287, "token_start": 41, "token_end": 42}, {"span_id": 3, "text": "cetuximab", "start": 292, "end": 301, "token_start": 43, "token_end": 44}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [1, 3], "is_context_needed": true}], "paragraph": "First-line treatment for advanced pancreatic cancer. Highlights from the \"2011 ASCO Gastrointestinal Cancers Symposium\". San Francisco, CA, USA. January 20-22, 2011. Pancreatic adenocarcinoma remains a treatment-refractory cancer. Although pancreatic adenocarcinoma is only the 10th most common cause of new cancer in the United States, it is the fourth most common cause of cancer-related death. Most cases are not suitable for resection and a majority is metastatic at presentation. gemcitabine, with or without erlotinib, has been the standard chemotherapy in this setting but the benefit is only modest. Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically \" targeted \" agents . At large this approach has not been successful and novel strategies are clearly needed. In this article, the authors summarizes the data from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, including: Abstract #175 (review of survival data in a large cohort); Abstract #286 (rapid change in prescriber patterns after the suggestion of benefit of a new regimen, FOLFIRINOX); Abstracts #238, #277, #304, and #315 (phase II trials looking at combinations that utilized EGFR blockade); Abstracts #221, #266, and #284 (phase I/II trials including VEGF blockade, anticoagulation, and traditional Chinese medicines).", "source": null}
{"doc_id": "38329cd40dbe6ad6067d19e9582d38cb", "sentence": "Gemcitabine and recently FOLFIRINOX ( 5-flourouracil , leucovorin , oxaliplatin and irinotecan ) have provided some limited survival advantage in advanced pancreatic cancer .", "spans": [{"span_id": 0, "text": "Gemcitabine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "leucovorin", "start": 55, "end": 65, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "oxaliplatin", "start": 68, "end": 79, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "irinotecan", "start": 84, "end": 94, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Immunotherapy updates in pancreatic cancer: are we there yet? Pancreatic cancer is a lethal disease and remains one of the most resistant cancers to traditional therapies. Historically, chemotherapy or radiotherapy did not provide meaningful survival benefit in advanced pancreatic cancer. Gemcitabine and recently FOLFIRINOX ( 5-flourouracil , leucovorin , oxaliplatin and irinotecan ) have provided some limited survival advantage in advanced pancreatic cancer . Targeted agents in combination with gemcitabine had not shown significant improvement in the survival. Current therapies for pancreatic cancer have their limitations; thus, we are in dire need of newer treatment options. Immunotherapy in pancreatic cancer works by recruiting and activating T cells that recognize tumor-specific antigens which is a different mechanism compared with chemotherapy and radiotherapy. Preclinical models have shown that immunotherapy and targeted therapies like vascular endothelial growth factor and epidermal growth factor inhibitors work synergistically. Hence, new immunotherapy and targeted therapies represent a viable option for pancreatic cancer. In this article, we review the vaccine therapy for pancreatic cancer.", "source": null}
{"doc_id": "69e1dda67a8c14cb6423a43d0b603f56", "sentence": "No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations .", "spans": [{"span_id": 0, "text": "ampicillin", "start": 125, "end": 135, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "chloramphenicol", "start": 173, "end": 188, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "ampicillin", "start": 215, "end": 225, "token_start": 33, "token_end": 34}, {"span_id": 3, "text": "penicillin", "start": 140, "end": 150, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "penicillin", "start": 201, "end": 211, "token_start": 31, "token_end": 32}], "rels": [{"class": "COMB", "spans": [0, 3], "is_context_needed": true}, {"class": "POS", "spans": [1, 4], "is_context_needed": false}, {"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "[Bactericidal action of chloramphenicol and synergism with beta-lactam antibiotics]. Excellent clinical results were observed with the combination therapy of chloramphenicol with beta-lactam-antibiotics in the treatment of purulent meningitis. This came as a surprise as bacteriostatic antibiotics like chloramphenicol are commonly thought to antagonize the bactericidal action of penicillin or ampicillin. We reevaluated the mode of action of chloramphenicol against the three most common meningeal pathogens after the newborn period. chloramphenicol was found to be bactericidal against H. influenzae, Streptococcus pneumoniae and Neisseria meningitidis at clinically achievable levels in the CSF. In addition chloramphenicol showed synergistic action with ampicillin against H. influenzae which can possess clinical relevance particularly with the high inoculum of 10(7) organisms/ml which is frequently seen in bacterial meningitis. No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations .", "source": null}
{"doc_id": "161afbd8e6bbb825a43f76766b0d37a0", "sentence": "Similarly , nifedipine , nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects .", "spans": [{"span_id": 0, "text": "nifedipine", "start": 12, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "hydralazine", "start": 43, "end": 54, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Treatment of acute severe hypertension: current and newer agents. Approximately 72 million people in the US experience hypertension. Worldwide, hypertension may affect as many as 1 billion people and be responsible for approximately 7.1 million deaths per year. It is estimated that approximately 1% of patients with hypertension will, at some point, develop a hypertensive crisis. Hypertensive crises are further defined as either hypertensive emergencies or urgencies, depending on the degree of blood pressure elevation and presence of end-organ damage. Immediate reduction in blood pressure is required only in patients with acute end-organ damage (i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension without acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral antihypertensive agents. The primary goal of intervention in a hypertensive crisis is to safely reduce blood pressure. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Patients with hypertensive emergencies are best treated in an intensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hypertensive emergencies should be avoided. Similarly , nifedipine , nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects .", "source": null}
{"doc_id": "d1848c9d6ebf91e701d7f2875f077be8", "sentence": "Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients .", "spans": [{"span_id": 0, "text": "Bendamustine", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "rituximab", "start": 36, "end": 45, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Bendamustine in chronic lymphocytic leukemia and refractory lymphoma. bendamustine is a water-soluble, bifunctional chemotherapeutic agent with characteristics of both an alkylator and a purine analog. bendamustine combined with rituximab in vitro shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that bendamustine plus rituximab is highly effective in relapsed and refractory patients with indolent lymphoma. The results have been found in rituximab-naive, rituximab-pretreated, and rituximab-refractory patients with excellent response rates and toxicity profiles. Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients . Interim results from a phase III, randomized trial comparing bendamustine and rituximab to a standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab regimen suggest that combination bendamustine and rituximab may provide a viable alternative for treatment of many indolent lymphomas.", "source": null}
{"doc_id": "d95caf8d1b6b298d37ffecb80c7bbbed", "sentence": "Ten micromoles of gefitinib reversed topotecan , SN-38 , and mitoxantrone resistance , and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 18, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "topotecan", "start": 37, "end": 46, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "SN-38", "start": 49, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "mitoxantrone", "start": 61, "end": 73, "token_start": 10, "token_end": 11}, {"span_id": 4, "text": "topotecan", "start": 119, "end": 128, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Gefitinib (\"Iressa\", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. gefitinib (\"Iressa\", ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non-small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan , SN-38 , and mitoxantrone resistance , and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells . Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the K(i) value was 1.01 +/- 0.09 micromol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.", "source": "https://pubmed.ncbi.nlm.nih.gov/15735043/"}
{"doc_id": "9553267587970e290dcd162f832fc386", "sentence": "The effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer .", "spans": [{"span_id": 0, "text": "vincristine", "start": 54, "end": 65, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "cyclophosphamide", "start": 68, "end": 84, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "methotrexate", "start": 99, "end": 111, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "5-fluorouracil", "start": 114, "end": 128, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "adriamycin", "start": 131, "end": 141, "token_start": 18, "token_end": 19}, {"span_id": 5, "text": "prednisolone", "start": 146, "end": 158, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "The effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer . Thirty-eight patients with advanced breast cancer were treated with the 'VEMFAH' multiple-drug combination chemotherapy, consisting of vincristine (V), cyclophosphamide (Endoxan; E), methotrexate (M), 5-fluorouracil (F), adriamycin (A), and prednisolone (H). Disease response was evaluated by the UICC criteria. Among the 35 evaluable cases, 4 complete responses (CR), 23 partial responses (PR), 2 cases of no change (NC), and 6 of progressive disease (PD) were observed. The response rate (CR + PR) was 77.1%. The median duration of response was 52 weeks (8-192 weeks) or 12 months. In 32 patients who received more than two courses of therapy the 50% survival time of responders was 27.0 months, which was significantly longer than the 10.3 months of nonresponders (P less than 0.05). Except for 2 patients who developed myocardial damage, the therapy was never terminated because of side effects. Cumulative cardiotoxicity was not apparent in this study. This multiple-drug combination chemotherapy with 'VEMFAH' is concluded to be an effective treatment for advanced and disseminated breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/3902267/"}
{"doc_id": "1e789327329484c793977a63b0ab0cfa", "sentence": "Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 76, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "mitoxantrone", "start": 106, "end": 118, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "prednisone", "start": 124, "end": 134, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "docetaxel", "start": 141, "end": 150, "token_start": 20, "token_end": 21}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer . cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrate-resistant prostate cancer (CRPC) after receiving docetaxel. ### Materials And Methods Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m(2) intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m(2) I.V. (400 mg/m(2) day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP). ### results A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n = 24) and without rash (n = 51) in the CMP arm was 10.3 months vs. 2.8 months (P = .004). On multivariable analysis,rash was significantly associated with TTP (hazard ratio [HR] = 0.43; P = .01). ### conclusions The treatment with CMP is not recommended in unselected men with docetaxel-treated CRPC, although rash might help develop tailored therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/22340631/"}
{"doc_id": "0a4f78997b6f89533c19850c90d7954f", "sentence": "CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples , while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex .", "spans": [{"span_id": 0, "text": "imipramine", "start": 121, "end": 131, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "fluoxetine", "start": 136, "end": 146, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Antidepressant treatment is associated with epigenetic alterations of Homer1 promoter in a mouse model of chronic depression. Understanding the neurobiology of depression and the mechanism of action of therapeutic measures is currently a research priority. We have shown that the expression of the synaptic protein Homer1a correlates with depression-like behavior and its induction is a common mechanism of action of different antidepressant treatments. However, the mechanism of Homer1a regulation is still unknown. ### methods We combined the chronic despair mouse model (CDM) of chronic depression with different antidepressant treatments. Depression-like behavior was characterized by forced swim and tail suspension tests, and via automatic measurement of sucrose preference in IntelliCage. The Homer1 mRNA expression and promoter DNA methylation were analyzed in cortex and peripheral blood by qRT-PCR and pyrosequencing. ### results CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples , while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex . The quantitative analyses of the methylation of 7 CpG sites, located on the Homer1 promoter region containing several CRE binding sites, show a significant increase in DNA methylation in the cortex of CDM mice. In contrast, antidepressant treatments reduce the methylation level. ### limitations Homer1 expression and promotor methylation were not analyzed in different blood cell types. Other CpG sites of Homer1 promoter should be investigated in future studies. Our experimental approach does not distinguish between methylation and hydroxymethylation. ### conclusions We demonstrate that stress-induced depression-like behavior and antidepressant treatments are associated with epigenetic alterations of Homer1 promoter, providing new insights into the mechanism of antidepressant treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/33128940/"}
{"doc_id": "e1a456796512f6ad85c23e8577c8be04", "sentence": "A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion , and among them , 61 received thoracic hyperthermic perfusion with recombinant human endostatin ( ES ) plus nedaplatin ( Endostatin group ) , while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone ( Cisplatin group ) .", "spans": [{"span_id": 0, "text": "endostatin", "start": 199, "end": 209, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "nedaplatin", "start": 222, "end": 232, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "Endostatin", "start": 235, "end": 245, "token_start": 37, "token_end": 38}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effect of thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin in treating pleural effusion in patients with advanced non-small cell lung cancer. To explore the efficacy and safety of thoracic hyperthermia perfusion with recombinant human endostatin plus nedaplatin in the treatment of pleural effusion in patients with advanced non-small cell lung cancer (NSCLC). ### methods A retrospective analysis was conducted on the clinical data of 122 advanced NSCLC patients with pleural effusion , and among them , 61 received thoracic hyperthermic perfusion with recombinant human endostatin ( ES ) plus nedaplatin ( Endostatin group ) , while the other 61 underwent thoracic hyperthermic perfusion with cisplatin alone ( Cisplatin group ) . The short-term efficacy, changes in the pleural effusion and serum immunological indicators before and after treatment, quality of life, and incidence of adverse reactions were compared between the two groups of patients. Finally, the progression of pleural effusion in patients were followed up and recorded. ### results After treatment, the overall response rate of patients in endostatin group was considerably higher than that in Cisplatin group (p=0.030). At 2 weeks after treatment, the level of alanine transferase (ALT) rose notably, while that of carcinoembryonic antigen (CEA) declined dramatically in both groups of patients, and the patients in endostatin group had markedly lower levels of ALT and CEA than those in Cisplatin group (p=0.007, p=0.003). After treatment, the Karnofsky Performance status (KPS) score of patients was prominently raised in the two groups, and endostatin group exhibited considerably higher KPS scores than Cisplatin group (p=0.045). The incidence rates of nausea and vomiting as well as diarrhea in endostatin group were prominently lower than those in Cisplatin group (p=0.039, p=0.048). According to the follow-up results, the median time to the progression of pleural effusion in endostatin group was markedly longer than that in Cisplatin group (p=0.008). ### conclusions Compared with the thoracic hyperthermic perfusion with cisplatin alone, the thoracic hyperthermic perfusion with recombinant human endostatin plus nedaplatin showed dramatically potential efficacy, decrease of the incidence rate of adverse reactions in the digestive system, improvement of quality of life of patients, and prolongation of progression of pleural effusion.", "source": "https://pubmed.ncbi.nlm.nih.gov/33455108/"}
{"doc_id": "0bae4bf9eca270aebdabe9ab47f382f2", "sentence": "In addition , stimulation of erythropoiesis with recombinant human erythropoietin , supplemental iron therapy , and improving haemostasis by aprotinin may further reduce homologous blood requirements .", "spans": [{"span_id": 0, "text": "erythropoietin", "start": 67, "end": 81, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "iron", "start": 97, "end": 101, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "aprotinin", "start": 141, "end": 150, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Reduction in the use of donated blood in surgical medicine]. After rapid changes in transfusion practice over the past few years, blood conservation techniques have become standard in modern perioperative management. As a result, the amount of homologous blood products transfused has been markedly reduced in some types of surgical procedures. Provided that skillful surgical technique is applied and the use of blood products is restricted, autologous transfusion techniques (predonation of autologous blood, preoperative plasmapheresis, acute normovolaemic haemodilution, and intra- and postoperative blood salvage) can be performed with an acceptable risk for patients. In addition , stimulation of erythropoiesis with recombinant human erythropoietin , supplemental iron therapy , and improving haemostasis by aprotinin may further reduce homologous blood requirements . All patients undergoing elective surgery have to be informed about the side effects of transfusion of homologous blood products and the possibility of blood-saving methods. An individual blood conservation plan, based on the patient's status and surgery, the equipment available, and personal experience should be worked out by the responsible anaesthesiologist, whereby a combination of different methods may be most effective. If storage is necessary, autologous blood products should be preparated like homologous products. The feasibility of predonation and retransfusion of autologous blood in patients with infectious diseases like hepatitis or acquired immune deficiency syndrome and the amount of labaratomy testing are still under discussion. Although blood conservation programs are time-consuming and more expensive, they reduce the various risks of using homologous blood products.", "source": "https://pubmed.ncbi.nlm.nih.gov/7762780/"}
{"doc_id": "661e745b70596299921deeab58a3d21e", "sentence": "In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction , respectively , in the growth of the 9L glioma .", "spans": [{"span_id": 0, "text": "heparin", "start": 19, "end": 26, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "cortisone", "start": 31, "end": 40, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "cortisone", "start": 48, "end": 57, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate. Malignant gliomas are difficult to treat systemically because of exclusion of many chemotherapeutic agents by the blood brain barrier. Furthermore, as opposed to other neoplasms, malignant gliomas recur locally, at the site of original presentation. These tumors are remarkably vascular and hence may be more dependent on angiogenesis for continued growth than other tumors. The inhibition of tumor angiogenesis can control tumor growth by preventing the exponential vascular growth phase. We report the inhibition of the growth of the 9L glioma by the localized, controlled release of known angiogenesis inhibitors administered in a biodegradable polyanhydride polymer matrix. In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction , respectively , in the growth of the 9L glioma . We compared these results to the inhibition of tumor neovascularization in the rabbit cornea by the localized delivery of the same agents. In the rabbit cornea model, the local release of heparin and cortisone and of cortisone alone resulted in a 2.5- and 2.0-fold reduction, respectively, in the angiogenesis response evoked by the VX2 carcinoma. This study introduces two new potential therapeutic modalities for the treatment of malignant gliomas: the use of the combination of heparin and cortisone as antineoplastic agents and the use of polymeric carriers for the local delivery of such agents in the central nervous system.", "source": "https://pubmed.ncbi.nlm.nih.gov/1702149/"}
{"doc_id": "7dffebdf49843e64c3a7aa9b3812bcc1", "sentence": "Dibutyryl cAMP , forskolin and theophylline stimulated secretion of pancreastatin and somatostatin .", "spans": [{"span_id": 0, "text": "theophylline", "start": 31, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "somatostatin", "start": 86, "end": 98, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Interaction between phosphoinositide turnover system and cyclic AMP pathway for the secretion of pancreastatin and somatostatin from QGP-1N cells. It is found that secretion of pancreastatin and somatostatin from QGP-1N cells is regulated through muscarinic receptor-mediated activation of phosphatidylinositide hydrolysis system. In this report, whether the cAMP pathway interacts with the phosphoinositide turnover system for the secretion of pancreastatin and somatostatin from QGP-1N cells through muscarinic receptors was studied. Stimulation of QGP-1N cells with carbachol increased intracellular cAMP levels. The carbachol-induced increase in cAMP levels was inhibited by atropine. Calcium ionophore (A23187) and phorbol 12-myristate 13-acetate increased cAMP synthesis. Dibutyryl cAMP , forskolin and theophylline stimulated secretion of pancreastatin and somatostatin . When either dibutyryl cAMP, forskolin or theophylline was added in culture medium with A23187, phorbol ester or carbachol, a synergistic effect was found on pancreastatin and somatostatin secretion. These results suggest that interaction between the phosphoinositide turnover system and the cAMP pathway occurs in QGP-1N cells through muscarinic receptor stimulation for the secretion of pancreastatin and somatostatin.", "source": "https://pubmed.ncbi.nlm.nih.gov/1352680/"}
{"doc_id": "b8c0eb9ae6e7ea066e515e69ee2799b5", "sentence": "It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin ( XELOX ) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer ( mCRC ) .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 66, "end": 77, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "capecitabine", "start": 80, "end": 92, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "bevacizumab", "start": 118, "end": 129, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "capecitabine", "start": 132, "end": 144, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "oxaliplatin", "start": 147, "end": 158, "token_start": 22, "token_end": 23}, {"span_id": 5, "text": "bevacizumab", "start": 176, "end": 187, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3, 4], "is_context_needed": true}], "paragraph": "Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial.  It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin ( XELOX ) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer ( mCRC ) . ### methods Patients received either bevacizumab (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m(2) twice daily on days 1-14 + oxaliplatin 130 mg/m(2) on day 1 every 3 weeks) until disease progression (arm A) or the same doses of bevacizumab + XELOX for 6 cycles followed by bevacizumab + capecitabine until disease progression (arm B). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. ### results One hundred and twenty-three patients were randomized. Treatment compliance was similar in both groups. Median PFS was significantly longer for arm B than for arm A (11.0 vs. 8.3 months; p = 0.002). There was no significant difference between the two arms for ORR (66.7 vs. 59.0%; p = 0.861) or median OS (23.8 vs. 20.2 months; p = 0.100). Tolerability was acceptable in both treatment arms; the most frequent grade 3/4 treatment-related adverse events (arm B vs. arm A) were fatigue (6.6 vs. 16.1%), diarrhoea (3.3 vs. 11.3%), anorexia (3.3 vs. 11.3%), and neuropathy (1.6 vs. 8.1%). ### conclusions Maintenance therapy with bevacizumab + capecitabine can be considered an appropriate option following induction bevacizumab + XELOX in patients with mCRC instead of continuation of bevacizumab + XELOX.", "source": "https://pubmed.ncbi.nlm.nih.gov/24247559/"}
{"doc_id": "6f09f4aa6c650b00d751ef90c70bf1df", "sentence": "We chose to assess the chemopreventive effect of three different drugs : pioglitazone , lanreotide and S-trans-trans-farnesylthiosalicylic acid ( FTS ) .", "spans": [{"span_id": 0, "text": "pioglitazone", "start": 73, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "lanreotide", "start": 88, "end": 98, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "S-trans-trans-farnesylthiosalicylic", "start": 103, "end": 138, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Chemoprevention of hepatocellular carcinoma. Proof of concept in animal models. In the present work, we have evaluated the possibility of preventing liver carcinogenesis in rats at two stages of development. In the first series of experiments, we induced foci of altered hepatocytes, (FAH) which represent the first events in rodent liver carcinogenesis, using the chemical mutagens diethylnitrosamine (DEN) and acetylaminofluorene (AAF). In the second part of the work, we used repeated weekly injections of DEN only that gave rise to significant fibrosis at 11 weeks and the development of malignant tumours at 16 weeks. We chose to assess the chemopreventive effect of three different drugs : pioglitazone , lanreotide and S-trans-trans-farnesylthiosalicylic acid ( FTS ) . pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptor gamma (PPARg), itself a member of the nuclear receptor superfamily, responsible for the modulation of a number of metabolic pathways, including cell differentiation, metabolism of lipids and inflammation. lanreotide (LAN) is a somatostatin analogue that has an inhibitory effect on the release of several hormones, such as growth hormone and serotonine. FTS is a specific antagonist of the protoocogene Ras, tested here based on the rationale that Ras is activated in many hepatocellular carcinomas (HCC). We showed that both PGZ and LAN were efficient in the first, pre-neoplastic model, by reducing the size of FAH, decreasing proliferation specifically in FAH by interacting with proteins of the cell cycle. We could also demonstrate that LAN increased apoptosis. In the second model, LAN was able to diminish the number of established HCC by decreasing proliferation, in parallel with an anti-fibrotic action. Furthermore, enhanced apoptosis and antiangiogenic effects were observed when LAN was given from the start of the carcinogenic induction by DEN. The cellular mechanisms leading to its effects warrant further investigations. FTS also strongly inhibited the appearance of FAH and HCC in the second model, through a complete inhibition of Ras activation and the induction of pro-apoptotic pathways. On the contrary, PGZ did not prevent the appearance of neoplastic lesions. For these reasons, we did not analyse further its mechanism of action in the second model. Altogether, the results we obtained demonstrate an activity of both LAN and FTS, at the early onset of liver carcinogenesis, and later on when advanced fibrosis, cirrhosis and HCC are induced. These anti-tumoural effects could be complementary and will be tested in combination in the future.", "source": "https://pubmed.ncbi.nlm.nih.gov/21563652/"}
{"doc_id": "70606f6869fb0cb024b34ef2853f9163", "sentence": "Etoposide ( 25 mg , twice daily ) and prednisone ( 5 mg , twice daily ) were administered orally .", "spans": [{"span_id": 0, "text": "Etoposide", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "prednisone", "start": 38, "end": 48, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Oral etoposide and oral prednisone for the treatment of castration resistant prostate cancer. Treatment options for patients with castration-resistant prostate cancer (CRPC) are limited. The purpose of our study was to investigate the safety and efficacy in terms of prostate-specific antigen (PSA) response of a low-dose oral combination of etoposide and prednisone in patients with CRPC. Thirty-nine patients with prostate cancer (median age, 77.9 years) with progressive disease after standard hormonal therapy were enrolled. Etoposide ( 25 mg , twice daily ) and prednisone ( 5 mg , twice daily ) were administered orally . Each cycle comprised 21 consecutive days of treatment followed by a 7-day drug holiday. All patients previously treated with an antiandrogen were required to undergo antiandrogen withdrawal prior to entry into the\u00a0study. A total of 226 cycles were administered with a median of 6.7 cycles per patient (range, 1-18 cycles). Sixteen of 39 patients (41%) with elevated PSA levels at baseline achieved at least a 50% reduction in PSA levels. Median progression-free survival for all patients was 5.9 months (range, 1-17 months). No Grade 4 toxicities were observed. The predominant toxicities were mucositis, nausea, fatigue, and anemia in twelve, nine, eight, and seven patients, respectively. Hematologic toxicity was infrequent, with no episodes of febrile neutropenia. The combination of low-dose etoposide and prednisone is an efficacious and reasonably well-tolerated oral regimen in the treatment of elderly patients with CRPC. This regimen can be easily administered in an outpatient setting and does not require frequent patient visits.", "source": "https://pubmed.ncbi.nlm.nih.gov/24444537/"}
{"doc_id": "1a4eea0fb32e8a01c262faf7fad66861", "sentence": "Rosuvastatin + ezetimibe , simvastatin + ezetimibe , and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels .", "spans": [{"span_id": 0, "text": "Rosuvastatin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "ezetimibe", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "simvastatin", "start": 27, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "ezetimibe", "start": 41, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "atorvastatin", "start": 57, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 5, "text": "ezetimibe", "start": 72, "end": 81, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [2, 3], "is_context_needed": false}, {"class": "POS", "spans": [4, 5], "is_context_needed": false}], "paragraph": "The cost effectiveness of statin therapies in Spain in 2010, after the introduction of generics and reference prices. HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness. ### objectives The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives. ### methods The following treatments were evaluated: rosuvastatin 5-20\u2009mg/day; atorvastatin, simvastatin, and pravastatin 10-40\u2009mg/day; lovastatin and fluvastatin 20-80\u2009mg/day; and combination therapy with a statin plus either cholestyramine 12-24\u2009g/day or ezetimibe 10\u2009mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels. ### results The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10\u2009mg/day to 55% for atorvastatin 80\u2009mg/day. Annual treatment costs ranged from Euro 189.7 for simvastatin 10\u2009mg/day to Euro 759.3 for atorvastatin 80\u2009mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: Euro 6 for simvastatin, Euro 10-12 for rosuvastatin, Euro 10 for lovastatin, Euro 13-16 for atorvastatin, Euro 13-14 for fluvastatin, and Euro 14-20 for pravastatin. Rosuvastatin + ezetimibe , simvastatin + ezetimibe , and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels . rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of Euro 516. simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of Euro 217 and Euro 190, respectively. ### conclusion rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices.", "source": "https://pubmed.ncbi.nlm.nih.gov/21090830/"}
{"doc_id": "5385813964fa22e9fdbad267cad739de", "sentence": "This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil , amlodipine besylate , and hydrochlorothiazide ( OM/AML/HCTZ ) in 2112 participants with moderate to severe hypertension .", "spans": [{"span_id": 0, "text": "Olmesartan", "start": 82, "end": 92, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "Amlodipine", "start": 105, "end": 115, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "Hydrochlorothiazide", "start": 122, "end": 141, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "olmesartan", "start": 257, "end": 267, "token_start": 34, "token_end": 35}, {"span_id": 4, "text": "amlodipine", "start": 280, "end": 290, "token_start": 37, "token_end": 38}, {"span_id": 5, "text": "hydrochlorothiazide", "start": 306, "end": 325, "token_start": 41, "token_end": 42}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Long-term efficacy and safety of triple-combination therapy with olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide for hypertension. J Clin Hypertens (Greenwich). 2012;14:149-157. \u00a92012 Wiley Periodicals, Inc. Most patients with hypertension require combination therapy in order to achieve blood pressure (BP) goals. This 40-week open-label extension of the 12-week double-blind Triple Therapy With Olmesartan Medoxomil , Amlodipine , and Hydrochlorothiazide in Hypertensive Patients Study ( TRINITY ) evaluated the efficacy and safety of triple-combination treatments with olmesartan medoxomil , amlodipine besylate , and hydrochlorothiazide ( OM/AML/HCTZ ) in 2112 participants with moderate to severe hypertension . Following 2\u2003weeks of initial treatment with OM 40/AML 5/HCTZ 12.5\u2003mg, participants not achieving BP goal were titrated to OM 40/AML 5/HCTZ 25\u2003mg or OM 40/AML 10/HCTZ 12.5\u2003mg on a randomized basis. At week 16, participants who did not achieve BP goal were further titrated to OM 40/AML 10/HCTZ 25\u2003mg. At the end of the study, 44.5% to 79.8% of participants reached BP goal and the mean BP decreased from 168.6/100.7\u2003mm\u2003Hg (baseline BP at randomization) to 125.0 to 136.8 mm Hg/77.8 to 82.5\u2003mm\u2003Hg, depending on treatment. Long-term treatment with OM/AML/HCTZ was well tolerated and effective with no new safety concerns.", "source": "https://pubmed.ncbi.nlm.nih.gov/22372774/"}
{"doc_id": "13d227c15f3afba751d934f49d59e018", "sentence": "Nithiamide and chlortetracycline + sulfamethazine + penicillin were least effective in preventing SD during the infection + medication and postmedication periods .", "spans": [{"span_id": 0, "text": "chlortetracycline", "start": 15, "end": 32, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "sulfamethazine", "start": 35, "end": 49, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "penicillin", "start": 52, "end": 62, "token_start": 6, "token_end": 7}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "A swine dysentery model for evaluation of drug prophylaxis: efficacy of various drugs in the control of swine dysentery. A swine dysentery (SD) model that produces consistent, homogeneous, and severe SD was used in 2 experiments to compare the prophylactic effectiveness of 5 commercially available swine feed additive products. Under the conditions of these studies, carbadox and carbadox + sulfamethazine proved to be the most effective agents in preventing SD during the infection + medication and postmedication periods. Olaquindox was effective in preventing SD in the infection + medication period; however, SD recurrence was high during the postmedication period. Nithiamide and chlortetracycline + sulfamethazine + penicillin were least effective in preventing SD during the infection + medication and postmedication periods .", "source": "https://pubmed.ncbi.nlm.nih.gov/7224318/"}
{"doc_id": "5c88fa895583c022261c8290cb802c4e", "sentence": "The largest number of strains was resistant to gentamicin , followed by erythromycin .", "spans": [{"span_id": 0, "text": "gentamicin", "start": 47, "end": 57, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "erythromycin", "start": 72, "end": 84, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Sensitivity of antibacterials of Staphylococcus aureus isolated from impetigo patients. We measured the sensitivity to antibacterials of Staphylococcus aureus isolated from impetigo lesions during one year (from July 1994 to July 1995). The largest number of strains was resistant to gentamicin , followed by erythromycin . Few methicillin-resistant S. aureus strains were isolated and few strains were resistant to more than one drug. We conclude that nadifloxacin and tosufloxacin are likely to be most effective against S. aureus, but fusidic acid is more suitable for the treatment of children.", "source": "https://pubmed.ncbi.nlm.nih.gov/9283995/"}
{"doc_id": "5b3c9e4fed209076e7d197b42242c429", "sentence": "Behavioural impact of intraseptally released vasopressin and oxytocin in rats .", "spans": [{"span_id": 0, "text": "vasopressin", "start": 45, "end": 56, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "oxytocin", "start": 61, "end": 69, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Behavioural impact of intraseptally released vasopressin and oxytocin in rats . The two nonapeptides arginine vasopressin and oxytocin are not only secreted from the neurohypophysis into the general circulation but are also released intracerebrally. Our recent research has focused on the release patterns and effects of oxytocin and vasopressin in brain areas, such as the septum and hypothalamus, that are thought to be involved in the regulation of (1) behavioural responses and (2) responses of the hypothalamo-neurohypophysial system (HNS) to stressor exposure in rats. The results demonstrate that combined physical and emotional stress (induced by exposure to forced swimming) selectively triggers the release of vasopressin within all brain areas under study but not into the general circulation. Under emotional stress conditions (induced by exposure to the 'social defeat' procedure), however, oxytocin rather than vasopressin release increased within the hypothalamus and septum. Experiments aimed at revealing the neuroendocrine and behavioural relevance of the local nonapeptide release provided evidence for an involvement of vasopressin in the regulation of HNS activity (within the hypothalamus) and, moreover, in acute stress-coping strategies, anxiety-related behaviour and learning and memory processes (within the septum). The observed dissociation between central and peripheral nonapeptide release not only supports the hypothesis that plasma vasopressin and oxytocin concentrations do not necessarily reflect central release patterns but also suggests vasopressin and oxytocin neurones are able to independently release their nonapeptide from different parts of their neuronal surface (e.g. from somata/dendrites vs. axon terminals). This remarkable regulatory capacity provides the basis for an differential involvement of vasopressin, and probably also oxytocin, in the co-ordination of neuroendocrine activity, emotionality and cognition at different brain levels to ensure an appropriate behavioural response of the organism to stressful stimuli.", "source": "https://pubmed.ncbi.nlm.nih.gov/10795914/"}
{"doc_id": "923b1d414c3afb26d65e3beafbdfddf8", "sentence": "Optimized 14 day sequential therapy was non-inferior to , but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance .", "spans": [{"span_id": 0, "text": "bismuth", "start": 91, "end": 98, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "clarithromycin", "start": 202, "end": 216, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "14\u2009day sequential therapy versus 10\u2009day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial. Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown. ### objectives To compare the efficacy and tolerability of optimized 14\u2009day sequential therapy and 10\u2009day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy. ### methods We recruited 620 adult patients (\u226520\u2009years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14\u2009day sequential therapy or 10\u2009day bismuth quadruple therapy, both containing esomeprazole 40\u2009mg twice daily. Those who failed after 14\u2009day sequential therapy received rescue therapy with 10\u2009day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855. ### results The eradication rates of 14\u2009day sequential therapy and 10\u2009day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%-94.1%) and 91.6% (284 of 310, 95% CI 87.8%-94.3%) in the ITT analysis, respectively (difference -0.3%, 95% CI -4.7% to 4.4%, P\u2009=\u20090.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10\u2009day bismuth quadruple therapy than those treated with 14\u2009day sequential therapy (74.4% versus 36.7% P\u2009<\u20090.0001). The eradication rate of 14\u2009day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P\u2009<\u20090.0001). ### conclusions Optimized 14 day sequential therapy was non-inferior to , but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance .", "source": "https://pubmed.ncbi.nlm.nih.gov/29846605/"}
{"doc_id": "5c6c7ff9d0b179779cae4a24b94343f9", "sentence": "Initial treatment with either neoadjuvant chemoradiation ( CRT ) or induction FOLFOX ( 5-Fluorouracil , leucovorin , and oxaliplatin ) chemotherapy followed by CRT is considered standard treatment for locally advanced rectal cancer .", "spans": [{"span_id": 0, "text": "5-Fluorouracil", "start": 87, "end": 101, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "leucovorin", "start": 104, "end": 114, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "oxaliplatin", "start": 121, "end": 132, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Induction Chemotherapy Reduces Patient-reported Toxicities During Neoadjuvant Chemoradiation with Intensity Modulated Radiotherapy for Rectal Cancer.  Initial treatment with either neoadjuvant chemoradiation ( CRT ) or induction FOLFOX ( 5-Fluorouracil , leucovorin , and oxaliplatin ) chemotherapy followed by CRT is considered standard treatment for locally advanced rectal cancer . We compared patient-reported outcomes (PRO) during CRT in patients who had received induction chemotherapy versus those who did not. ### Patients And Methods We reviewed records of patients with locally advanced rectal cancer who were treated with CRT between September 2009 and October 2014, and who had completed\u00a0\u2265 4 PRO assessments during treatment. Clinician- and patient-reported toxicities were collected each week during treatment. We fit binomial generalized linear models to maximum toxicity scores across all patients' visits. ### results Of 123 patients with\u00a0\u2265 4 PRO assessments, 87 (71%) patients reported a clinically meaningful PRO score of 3 or higher for diarrhea, and 91 (74%) patients reported a PRO score of\u00a0\u2265 3 for urgency, during 1 or more weeks of treatment, corresponding to 'very frequent' or worse. Of 116 patients who had also completed\u00a0\u2265 4 clinician-reported assessments for descriptive analysis, clinically significant diarrhea (Common Terminology Criteria for Adverse Events grade\u00a0\u2265 2) was reported in 9% of patients, and grade 2 proctitis and cystitis were reported in 20% and 4%, respectively. Eighty-four (68%) patients had undergone induction chemotherapy prior to CRT. Patients who received induction chemotherapy had 68% lower odds of experiencing significant urgency (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.11-0.95; P\u00a0= .04), 76% lower odds of bleeding (OR, 0.24; 95% CI, 0.1-0.62; P\u00a0< .01), and 75% lower odds of tenesmus (OR, 0.25; 95% CI, 0.11-0.6; P\u00a0< .01) versus those treated with upfront CRT. ### conclusion Based on PROs, a high proportion of patients experienced clinically significant symptoms during pelvic CRT, with diarrhea and urgency being most commonly reported. This appears to be under-reported on clinician-reported assessments. Delivery of induction chemotherapy was associated with lower odds of experiencing urgency, bleeding, and tenesmus on PROs during subsequent CRT, with no significant impact on diarrhea and rectal pain.", "source": "https://pubmed.ncbi.nlm.nih.gov/31104990/"}
{"doc_id": "64dae357e4b90c9b29bcfa07ba6af307", "sentence": "Prior to the procedure , the child was administered a dental cocktail containing chloral hydrate , hydroxyzine , and methadone .", "spans": [{"span_id": 0, "text": "chloral hydrate", "start": 81, "end": 96, "token_start": 13, "token_end": 15}, {"span_id": 1, "text": "hydroxyzine", "start": 99, "end": 110, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "methadone", "start": 117, "end": 126, "token_start": 19, "token_end": 20}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A fatality due to an accidental methadone substitution in a dental cocktail. A 6-year-old male child was scheduled for a dental procedure requiring conscious sedation. Prior to the procedure , the child was administered a dental cocktail containing chloral hydrate , hydroxyzine , and methadone . After returning from the dentist, the child appeared groggy and was allowed to sleep. A few hours later, he was found unresponsive, and following resuscitation attempts at a local medical center, he was pronounced dead. Toxicological analyses of femoral blood indicated the presence of hydroxyzine at less than 0.54 \u03bcg/mL, trichloroethanol (TCE) at 8.3 \u03bcg/mL, and methadone at 0.51 \u03bcg/mL. No meperidine was detected. The cause of death was reported to be due to the toxic effects of methadone. The toxicological analysis was corroborated by the analysis of the contents of the dental cocktail, which revealed the presence of hydroxyzine, chloral hydrate, and methadone. Residue from a control sample obtained from the same pharmacy, but administered to a different subject, was found to contain hydroxyzine, chloral hydrate, and meperidine. This report represents the first known fatality due to accidental substitution of methadone in a dental cocktail.", "source": "https://pubmed.ncbi.nlm.nih.gov/21871161/"}
{"doc_id": "e447b67e96d1d9d23058ebfd3961dda4", "sentence": "We aimed to compare the effect of four TK inhibitors ( axitinib , sunitinib , vandetanib , and XL184 ) on cell proliferation , RET expression and autophosphorylation , and ERK activation in cell lines expressing a MEN2A ( MTC-TT ) , a MEN2B ( MZ-CRC-1 ) mutation , and a RET/PTC ( TPC-1 ) rearrangement .", "spans": [{"span_id": 0, "text": "axitinib", "start": 55, "end": 63, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "sunitinib", "start": 66, "end": 75, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "vandetanib", "start": 78, "end": 88, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. Medullary and papillary thyroid carcinoma (MTC and PTC) are two types of thyroid cancer that can originate from activating mutations or rearrangements in the RET gene. Therapeutic options are limited in recurrent disease, but because RET is a tyrosine kinase (TK) receptor involved in cellular growth and proliferation, treatment with a TK inhibitor might be promising. Several TK inhibitors have been tested in clinical trials, but it is unknown which inhibitor is most effective and whether there is any specificity for particular RET mutations. ### objective We aimed to compare the effect of four TK inhibitors ( axitinib , sunitinib , vandetanib , and XL184 ) on cell proliferation , RET expression and autophosphorylation , and ERK activation in cell lines expressing a MEN2A ( MTC-TT ) , a MEN2B ( MZ-CRC-1 ) mutation , and a RET/PTC ( TPC-1 ) rearrangement . ### design The three cell lines were cultured and treated with the four TK inhibitors. Effects on cell proliferation and RET and ERK expression and activation were determined. ### results XL184 and vandetanib most effectively inhibited cell proliferation, RET autophosphorylation in combination with a reduction of RET expression, and ERK phosphorylation in MTC-TT and MZ-CRC-1, respectively. TPC-1 cells showed a decrease in RET autophosphorylation after treatment with XL184, but no effect was observed on ERK activation. ### conclusion There is indeed specificity for different RET mutations, with XL184 being the most potent inhibitor in MEN2A and PTC and vandetanib the most effective in MEN2B in vitro. No TK inhibitor was superior for all the cell lines tested, indicating that mutation-specific therapies could be beneficial in treating MTC and PTC.", "source": "https://pubmed.ncbi.nlm.nih.gov/21470995/"}
{"doc_id": "27860521bbec4e5bd55327f4454516d5", "sentence": "Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia .", "spans": [{"span_id": 0, "text": "fenofibrate", "start": 31, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "atorvastatin", "start": 57, "end": 69, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia . We compared vascular and metabolic responses (and adverse responses) to statin and fibrate therapies alone or in combination in patients with combined hyperlipidemia. ### background The mechanisms of action for statins and fibrates are distinct. ### methods Fifty-six patients were given atorvastatin 10 mg and placebo, atorvastatin 10 mg and fenofibrate 200 mg, or fenofibrate 200 mg and placebo daily during each two-month treatment period of a randomized, double-blind, placebo-controlled crossover trial with two washout periods of two months' each. ### results Lipoproteins were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone. Flow-mediated dilator response to hyperemia and plasma high-sensitivity C-reactive protein and fibrinogen levels were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone (p < 0.001, p = 0.182, and p = 0.015 by analysis of variance [ANOVA], respectively). The effects of combined therapy or fenofibrate alone on plasma adiponectin levels and insulin sensitivity (determined by the Quantitative Insulin-Sensitivity Check Index [QUICKI]) were significantly greater than those of atorvastatin alone (p = 0.022 for adiponectin and p = 0.049 for QUICKI by ANOVA). No patients were withdrawn from the study as the result of serious adverse effects. ### conclusions Combination therapy is safe and has beneficial additive effects on endothelial function in patients with combined hyperlipidemia.", "source": "https://pubmed.ncbi.nlm.nih.gov/15893182/"}
{"doc_id": "88854df818fcc017ecd02baae0d05e44", "sentence": "S. sciuri exhibited pronounced multiresistance , and many isolates were characterised by the carriage of a number of uncommon (multi)resistance genes ( e.g. cfr , apmA , fexA ) and decreased susceptibility towards last resort antibiotics such as linezolid and daptomycin .", "spans": [{"span_id": 0, "text": "linezolid", "start": 246, "end": 255, "token_start": 38, "token_end": 39}, {"span_id": 1, "text": "daptomycin", "start": 260, "end": 270, "token_start": 40, "token_end": 41}], "rels": [], "paragraph": "Antibiotic resistance profiles of coagulase-negative staphylococci in livestock environments. Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) have globally emerged in animal husbandry. In addition to methicillin resistance, LA-MRSA may carry a variety of novel and uncommon antimicrobial resistance genes. Occurrence of the same resistance genes in coagulase-negative staphylococci (CoNS) and S. aureus suggests an ongoing genetic exchange between LA-MRSA and other staphylococci whose driving forces in the ecological niche of the farm environment are, however, still poorly understood. To assess the potential of CoNS as putative reservoirs for antibiotic resistance genes, we analysed the antimicrobial susceptibility of CoNS from dust and manure samples obtained in 41 pig farms in Germany, most of them (36 of 41) with a proven LA-MRSA/MSSA history. Among the 344 isolates analysed, 18 different CoNS species were identified and S. sciuri represented the most prevalent species (46%). High resistance rates were detected for tetracycline (71%), penicillin (65%) and oxacillin (64%) as well as fusidic acid (50%), which was mainly due to reduced susceptibility among S. sciuri isolates. S. sciuri exhibited pronounced multiresistance , and many isolates were characterised by the carriage of a number of uncommon (multi)resistance genes ( e.g. cfr , apmA , fexA ) and decreased susceptibility towards last resort antibiotics such as linezolid and daptomycin . The combined data suggest that S. sciuri harbours a significant resistance gene pool that requires further attention. We hypothesise that members of this species, due to their flexible lifestyle, might contribute to the spread of such genes in livestock environments.", "source": "https://pubmed.ncbi.nlm.nih.gov/27185355/"}
{"doc_id": "6aa114c00b52be0ae72ee4e00cecdb8e", "sentence": "The results showed that chlorhexidine ( 0.5 mM ) was more effective than benzalkonium chloride ( 1 mM ) and piperazine ( 1 mM ) .", "spans": [{"span_id": 0, "text": "chlorhexidine", "start": 24, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "benzalkonium", "start": 73, "end": 85, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "piperazine", "start": 108, "end": 118, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "The effect of some cationic antiseptics on the acidogenicity of dental plaque in vivo. Two series of experiments were performed in order to compare the ability of different cationic antiseptics to inhibit the acid production in plaque. In addition an attempt was made to evaluate the influence of oral retention on the acid-inhibiting properties of these agents. In one series of experiments acid production, following sucrose applications on plaque, was measured in situ prior to and at given time intervals after rinsing with the individual agents. In a second series the effect of eluting the antiseptics retained in the oral cavity by means of 5 consecutive acetic acid (6 mM) rinses was evaluated. The results showed that chlorhexidine ( 0.5 mM ) was more effective than benzalkonium chloride ( 1 mM ) and piperazine ( 1 mM ) . cetylpyridinium chloride (1 mM) was the least effective. Acidic elution markedly reduced the inhibitory effect of single rinses of chlorhexidine (0.5 mM), benzalkonium chloride (1 mM) and the cetylpyridinium chloride (1 mM). This effect was less pronounced with a higher concentration (2.2 mM) of chlorhexidine. The results gave support to the view that retention of an agent in the mouth and in plaque is of significance for its ability to inhibit acid production of dental plaque.", "source": "https://pubmed.ncbi.nlm.nih.gov/6932161/"}
{"doc_id": "6ea354435c312ec5e44e62fe484b70f8", "sentence": "Finally , although anidulafungin ( as an echinocandin surrogate susceptibility marker ) and amphotericin B ECVs should identify Candida and Aspergillus isolates with reduced susceptibility to these agents using the Etest , these ECVs will not categorize a fungal isolate as susceptible or resistant , as breakpoints do .", "spans": [{"span_id": 0, "text": "anidulafungin", "start": 19, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "amphotericin", "start": 92, "end": 104, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Multicenter Study of Method-Dependent Epidemiological Cutoff Values for Detection of Resistance in Candida spp. and Aspergillus spp. to Amphotericin B and Echinocandins for the Etest Agar Diffusion Method. Method-dependent Etest epidemiological cutoff values (ECVs) are not available for susceptibility testing of either Candida or Aspergillus species with amphotericin B or echinocandins. In addition, reference caspofungin MICs for Candida spp. are unreliable. Candida and Aspergillus species wild-type (WT) Etest MIC distributions (microorganisms in a species-drug combination with no detectable phenotypic resistance) were established for 4,341 Candida albicans, 113 C. dubliniensis, 1,683 C. glabrata species complex (SC), 709 C. krusei, 767 C. parapsilosis SC, 796 C. tropicalis, 1,637 Aspergillus fumigatus SC, 238 A. flavus SC, 321 A. niger SC, and 247 A. terreus SC isolates. Etest MICs from 15 laboratories (in Argentina, Europe, Mexico, South Africa, and the United States) were pooled to establish Etest ECVs. anidulafungin, caspofungin, micafungin, and amphotericin B ECVs (in micrograms per milliliter) encompassing \u226597.5% of the statistically modeled population were 0.016, 0.5, 0.03, and 1 for C. albicans; 0.03, 1, 0.03, and 2 for C. glabrata SC; 0.06, 1, 0.25, and 4 for C. krusei; 8, 4, 2, and 2 for C. parapsilosis SC; and 0.03, 1, 0.12, and 2 for C. tropicalis The amphotericin B ECV was 0.25 \u03bcg/ml for C. dubliniensis and 2, 8, 2, and 16 \u03bcg/ml for the complexes of A. fumigatus, A. flavus, A. niger, and A. terreus, respectively. While anidulafungin Etest ECVs classified 92% of the Candida fks mutants evaluated as non-WT, the performance was lower for caspofungin (75%) and micafungin (84%) cutoffs. Finally , although anidulafungin ( as an echinocandin surrogate susceptibility marker ) and amphotericin B ECVs should identify Candida and Aspergillus isolates with reduced susceptibility to these agents using the Etest , these ECVs will not categorize a fungal isolate as susceptible or resistant , as breakpoints do .", "source": "https://pubmed.ncbi.nlm.nih.gov/27799206/"}
{"doc_id": "39b25cd9d4e2b993067672f328365fae", "sentence": "The method decision limits were determined to be 1.27 and 0.59 microg/kg for erythromycin and tylosin , respectively .", "spans": [{"span_id": 0, "text": "erythromycin", "start": 77, "end": 89, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "tylosin", "start": 94, "end": 101, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Determination of erythromycin and tylosin residues in honey by LC/MS/MS. Antibiotics are used in apiculture to protect bees against a variety of brood diseases. As a result of the development of resistance to oxytetracycline, erythromycin and tylosin are increasingly used for the prevention and treatment of these diseases. Therefore, Brazilian authorities have added these antibiotics to the National Regulatory Monitoring Program for the control of residues in honey. An analytical method has been developed for the determination of residues of erythromycin and tylosin in honey. The procedure involves solid-phase extraction of diluted honey samples with Bond Elut cartridges, followed by LC/MS with electrospray positive ionization in the multiple reaction monitoring mode. Two characteristic transitions were monitored for both drugs. Average analyte recoveries of erythromycin and tylosin ranged from 99 to 109% from sets of replicate honey samples fortified with drug concentrations of 5, 10, 15, and 20 microg/kg. The method decision limits were determined to be 1.27 and 0.59 microg/kg for erythromycin and tylosin , respectively . The detection capabilities were 5 and 5.2 microg/kg for erythromycin and tylosin, respectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/19610392/"}
{"doc_id": "92e3dc3dddb96036451c1e9b0f351877", "sentence": "Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer ( GERCOR DREAM ; OPTIMOX3 ): a randomised , open-label , phase 3 trial .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "erlotinib", "start": 28, "end": 37, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer ( GERCOR DREAM ; OPTIMOX3 ): a randomised , open-label , phase 3 trial . The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. ### methods This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7\u00b75 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. ### findings Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51\u00b70 months (IQR 36\u00b70-60\u00b70) in the bevacizumab group and 48\u00b73 months (31\u00b75-61\u00b70) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5\u00b71 months (95% CI 4\u00b71-5\u00b79) in the bevacizumab plus erlotinib group compared with 6\u00b70 months (4\u00b76-7\u00b79) in the bevacizumab group (stratified hazard ratio [HR] 0\u00b779 [95% CI 0\u00b760-1\u00b706]; p=0\u00b711; unstratified HR 0\u00b776 [0\u00b759-0\u00b799]; p=0\u00b7043). In the final analysis, median progression-free survival from randomisation was 5\u00b74 months (95% CI 4\u00b73-6\u00b72) in the bevacizumab plus erlotinib group compared with 4\u00b79 months (4\u00b71-5\u00b77) in the bevacizumab group (stratified HR 0\u00b781 [95% CI 0\u00b766-1\u00b701], p=0\u00b7059; unstratified HR 0\u00b778 [0\u00b768-0\u00b796], p=0\u00b7019). At the final analysis, median overall survival from maintenance was 24\u00b79 months (95% CI 21\u00b74-28\u00b79) in the bevacizumab plus erlotinib group and 22\u00b71 months (19\u00b76-26\u00b77) in the bevacizumab group (stratified HR 0\u00b779 [95% CI 0\u00b763-0\u00b799], p=0\u00b7036; unstratified HR 0\u00b779 [0\u00b764-0\u00b798], p=0\u00b7035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). ### interpretation Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. ### funding GERCOR and F Hoffmann-La Roche.", "source": "https://pubmed.ncbi.nlm.nih.gov/26474518/"}
{"doc_id": "8992547ade8ad225056deedabff483df", "sentence": "Eighteen patients with primary or recurrent ovarian cancer were treated with paclitaxel 150 or 110 mg/m2 , respectively , together with gemcitabine 800 mg/m2 and cisplatin 75 mg/m2 , 3 weekly for 6 cycles .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 77, "end": 87, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "gemcitabine", "start": 136, "end": 147, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Peripheral neuropathy due to therapy with paclitaxel, gemcitabine, and cisplatin in patients with advanced ovarian cancer. To evaluate the peripheral neuropathic changes induced by combination chemotherapy including paclitaxel (taxol), gemcitabine and cisplatin (TGC regimen). ### Patients And Methods Eighteen patients with primary or recurrent ovarian cancer were treated with paclitaxel 150 or 110 mg/m2 , respectively , together with gemcitabine 800 mg/m2 and cisplatin 75 mg/m2 , 3 weekly for 6 cycles . Neurologic evaluation and quantitative assessment by vibration perception threshold (VPT) and grip strength took place before therapy, after 3 and 6 cycles of chemotherapy, and thereafter when possible. ### results Both neuropathic symptoms and signs developed in all patients (100%), becoming most prominent 3 months after the last course of chemotherapy. Grade 3 peripheral neuropathy developed in one patient during chemotherapy, and in 3 additional patients after cessation of therapy. No significant differences were observed between chemo-naive patients and pretreated patients. ### conclusion This TGC combination is well tolerated in terms of peripheral neuropathy during therapy, although the off-therapy worsening caused by cisplatin remains a problem.", "source": "https://pubmed.ncbi.nlm.nih.gov/12825825/"}
{"doc_id": "8e02adf7ef7e1034f79edf03487bc95b", "sentence": "After pretreatment with warfarin ( 0.2 mg/kg/day ) , low-dose rivaroxaban ( 60 mg/kg/day ) , high-dose rivaroxaban ( 120 mg/kg/day ) , or vehicle for 14 days , transient middle cerebral artery occlusion was induced for 90 min , followed by reperfusion with tPA ( 10 mg/kg/10 ml ) .", "spans": [{"span_id": 0, "text": "warfarin", "start": 24, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "rivaroxaban", "start": 62, "end": 73, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "rivaroxaban", "start": 103, "end": 114, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2. This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin ( 0.2 mg/kg/day ) , low-dose rivaroxaban ( 60 mg/kg/day ) , high-dose rivaroxaban ( 120 mg/kg/day ) , or vehicle for 14 days , transient middle cerebral artery occlusion was induced for 90 min , followed by reperfusion with tPA ( 10 mg/kg/10 ml ) . Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. \u00a9 2016 Wiley Periodicals, Inc.", "source": "https://pubmed.ncbi.nlm.nih.gov/28035779/"}
{"doc_id": "20b7ca4fb30c58b4314d757911531693", "sentence": "The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine ( Pounds 2132 ) and tegafur with uracil ( Pounds 3385 ) were lower than costs for the intravenous Mayo regimen ( Pounds 3593 ) and infusional regimens on the de Gramont ( Pounds 6255 ) and Modified de Gramont ( Pounds 3485 ) schedules over the same treatment period .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 83, "end": 95, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "tegafur", "start": 116, "end": 123, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "uracil", "start": 129, "end": 135, "token_start": 20, "token_end": 21}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer. Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine ( Pounds 2132 ) and tegafur with uracil ( Pounds 3385 ) were lower than costs for the intravenous Mayo regimen ( Pounds 3593 ) and infusional regimens on the de Gramont ( Pounds 6255 ) and Modified de Gramont ( Pounds 3485 ) schedules over the same treatment period . Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/16804526/"}
{"doc_id": "07a90e10a5261b7008e02cead48838c6", "sentence": "However , the combination of clindamycin and ciprofloxacin increased mortality associated with B. anthracis Sterne infection , particularly in gamma-irradiated animals .", "spans": [{"span_id": 0, "text": "clindamycin", "start": 29, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "ciprofloxacin", "start": 45, "end": 58, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Clindamycin and quinolone therapy for Bacillus anthracis Sterne infection in 60Co-gamma-photon-irradiated and sham-irradiated mice. Sublethal ionizing doses of radiation increase the susceptibility of mice to Bacillus anthracis Sterne infection. In this study, we investigated the efficacy of clindamycin in 60Co-gamma-photon-irradiated and sham-irradiated mice after intratracheal challenge with B. anthracis Sterne spores. clindamycin has in vitro activity against B. anthracis and inhibits the production of toxin from other species, although no direct evidence exists that production of B. anthracis toxin is inhibited. ### methods Ten-week-old B6D2F1/J female mice were either sham-irradiated or given a sublethal 7 Gy dose of 60Co-gamma-photon radiation 4 days prior to an intratracheal challenge with toxigenic B. anthracis Sterne spores. Mice were treated twice daily with 200 mg/kg clindamycin (subcutaneous or oral), 100 mg/kg moxifloxacin (oral), 50 mg/kg ciprofloxacin (subcutaneous) or a combination therapy (clindamycin + ciprofloxacin). Bacteria were isolated and identified from lung, liver and heart blood at five timed intervals after irradiation. Survival was recorded twice daily following intratracheal challenge. ### results The use of clindamycin increased survival in gamma-irradiated and sham-irradiated animals challenged with B. anthracis Sterne in comparison with control mice (P < 0.001). ciprofloxacin-treated animals had higher survival compared with clindamycin-treated animals in two experiments, and less survival in a third experiment, although differences were not statistically significant. moxifloxacin was just as effective as clindamycin. Combination therapy did not improve survival of sham-irradiated animals and significantly decreased survival among gamma-irradiated animals (P = 0.01) in comparison with clindamycin-treated animals. B. anthracis Sterne was isolated from lung, liver and heart blood, irrespective of the antimicrobial treatment. ### conclusions Treatment with clindamycin, ciprofloxacin or moxifloxacin increased survival in sham-irradiated and gamma-irradiated animals challenged intratracheally with B. anthracis Sterne spores. However , the combination of clindamycin and ciprofloxacin increased mortality associated with B. anthracis Sterne infection , particularly in gamma-irradiated animals .", "source": "https://pubmed.ncbi.nlm.nih.gov/16239289/"}
{"doc_id": "f5a4e1a3a2fd7c354cb27e3be2de987c", "sentence": "We investigated the maximum tolerated dose , dose-limiting toxicities , and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan , cisplatin , and radiation therapy for patients with inoperable stage II-III non-small cell lung cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "celecoxib", "start": 136, "end": 145, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "irinotecan", "start": 169, "end": 179, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "cisplatin", "start": 182, "end": 191, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase I study of celecoxib with concurrent irinotecan, Cisplatin, and radiation therapy for patients with unresectable locally advanced non-small cell lung cancer. Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose , dose-limiting toxicities , and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan , cisplatin , and radiation therapy for patients with inoperable stage II-III non-small cell lung cancer ( NSCLC ) . ### Methods And Materials Eighteen patients were analyzed in a phase I clinical dose-escalation trial. celecoxib was given daily beginning 5\u2009days before radiation followed by maintenance doses for 12\u2009weeks. Toxicity was graded with the Common Terminology Criteria for Adverse Events V3.0 and response with the World Health Organization system. Primary endpoints were maximum tolerated dose of celecoxib and treatment toxicity; secondary endpoints were response and survival rates. ### results The maximum tolerated dose of celecoxib was not reached, in part owing to discontinuation of the drug supply. At doses of 200 or 400\u2009mg/day, no patients experienced any dose-limiting toxicity (acute grade \u22654 esophagitis or pneumonitis, neutropenic fever or thrombocytopenia requiring transfusion, or acute grade \u22653 diarrhea). Grade 3 toxicities were leukopenia (five patients), fatigue (3), pneumonitis (2), dyspnea (1), pain (1), and esophageal stricture (1). Interestingly, pulmonary fibrosis (a late toxicity) was no more severe in the higher-dose (400-mg) group and may have been less common than in the lower-dose group. The clinical response rate was 100% (8 complete, 10 partial). Two-year rates were: overall survival 65%; local-regional control 69%; distant metastasis-free survival 71%; and disease-free survival 64%. ### conclusion Although preliminary, our results suggest that adding celecoxib to concurrent chemoradiation for inoperable NSCLC is safe and can improve outcome without increasing normal tissue toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/22649768/"}
{"doc_id": "a928f7c6c1f1afb1f3997fc61a95654f", "sentence": "The combination of docetaxel and estramustine phosphate ( estramustine ) has been reported to be effective for HRPC .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "estramustine", "start": 33, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "estramustine", "start": 58, "end": 70, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Docetaxel, low-dose estramustine, and doxifluridine in hormone-refractory metastatic prostate cancer. Advanced prostate cancer, which is one of the most common cancers, usually progresses to hormone-refractory prostate cancer (HRPC). A recent randomized trial of treatment with docetaxel demonstrated improved survival for patients with HRPC. The combination of docetaxel and estramustine phosphate ( estramustine ) has been reported to be effective for HRPC . Low-dose estramustine suppresses the pituitary-gonadal axis. docetaxel plus 5-fluoro-5'-deoxyuridine (5'-dFUrd) had supra-additive cytotoxic effects on HRPC cells consistent with the molecular mechanism. Therefore, we examined the efficacy of adding 5'-dFUrd on the chemotherapy regimen, which consist docetaxel and estramustine. ### methods All of the HRPC patients were treated with estramustine 140 mg orally twice 5'-dFUrd 200 mg orally four times daily on days 1-21, and docetaxel 60 mg/m(2) was administered on day 1. We evaluated serum prostate-specific antigen (PSA) and measurable responses, the progression-free and overall survival, and the impact on adverse effects and the quality of life (QOL). ### results Of 34 patients with a median age of 72.3 years, 73% showed PSA responses and 70% showed measurable responses. The median progression-free survival was 18.0 and 5.8 months for PSA responders and non-responders and the overall survival was 19.4 months, respectively. There were few serious adverse effects. Grade 3/4 neutropenia occurred in 32.4% of the patients, and was easily managed with granulocyte colony-stimulating factor (G-CSF) injection. There was no significant change in the overall QOL scores serially. ### conclusions This study shows that the combined regimen is tolerable and effective in Japanese HRPC patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/17375305/"}
{"doc_id": "c46f91136c37afe4ed955420e39cc87a", "sentence": "Significant advances have been made in the last decade since the introduction of different tyrosine kinase inhibitors ( TKIs ) such as sunitinib , pazopanib , and sorafenib .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 135, "end": 144, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "pazopanib", "start": 147, "end": 156, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "sorafenib", "start": 163, "end": 172, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "First-line tyrosine kinase inhibitors in metastatic renal cell carcinoma: A regional cancer center experience. Renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy, and historically a poor prognosis for metastatic disease has been reported, with a 5-year survival rate of <10%. Significant advances have been made in the last decade since the introduction of different tyrosine kinase inhibitors ( TKIs ) such as sunitinib , pazopanib , and sorafenib . Unfortunately, even though the TKIs have been used for a long time, there are very few published data regarding the experience of TKI therapy in metastatic RCC (mRCC) from India. ### Materials And Methods This is a single institutional review of mRCC patients treated between January 2012 and July 2017. Patients who received at least 1 month of first-line TKIs were included for analysis of response rates, toxicity, survival outcomes, and prognostic factors. ### results Of the 40 mRCC patients, 31 (77.5%) were males. Median age at diagnosis was 58 years (range: 38-80 years). The most common site of metastasis was lungs (n = 24) followed by bone (n = 19) and liver (n = 7). Three patients had favorable risk disease, whereas 25 had intermediate risk and 12 had poor risk disease according to the MSKCC risk criteria. First-line TKI therapy used was sunitinib in 24, pazopanib in 11, and sorafenib in 5 patients. Toxicities of TKIs were Grade 1 or 2 in 13 patients and Grade 3 or 4 in 9 patients; the most common being fatigue, followed by hand-foot syndrome, skin rash, mucositis, and hypertension. Overall, 29 patients (72.5%) had disease control (complete responses in 1, partial responses in 10, and stable disease in 18 patients), whereas 11 had progression of disease at initial evaluation. At a median follow-up of 16 months (range: 2-38 months), median progression-free survival (PFS) was 10.8 months and median overall survival was 19.1 months. ### conclusions sunitinib and pazopanib are viable first-line options for mRCC and showed a comparable PFS in Indian patients. Careful patient selection, tailoring of TKI doses, and careful toxicity management are essential for optimum therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/30082547/"}
{"doc_id": "1d45a41a4087429135570126b747b54e", "sentence": "A fixed-dose combination of artesunate + amodiaquine ( ASAQ ) was recently developed .", "spans": [{"span_id": 0, "text": "artesunate", "start": 28, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "amodiaquine", "start": 41, "end": 52, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized, multicentre assessment of the efficacy and safety of ASAQ--a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. The use of artemisinin derivative-based combination therapy (ACT) such as artesunate plus amodiaquine is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. Fixed-dose combinations are more adapted to patients than regimens involving multiple tablets and improve treatment compliance. A fixed-dose combination of artesunate + amodiaquine ( ASAQ ) was recently developed . To assess the efficacy and safety of this new combination and to define its optimum dosage regimen (once or twice daily) in the treatment of uncomplicated P. falciparum malaria, a multicentre clinical study was conducted. ### methods A multicentre, randomized, controlled, investigator-blinded, parallel-group study was conducted in five African centers in Cameroon, Madagascar, Mali and Senegal from March to December 2006. Efficacy and safety of ASAQ were assessed compared to those of artemether + lumefantrine (AL). The WHO protocol with a 28-day follow-up for assessing the drug therapeutic efficacy was used. Patients suffering from uncomplicated P. falciparum malaria were randomized to receive ASAQ orally once daily (ASAQ1), ASAQ twice daily (ASAQ2) or AL twice daily (AL) for three days. The primary outcome was PCR-corrected parasitological cure rate and clinical response. ### results Of 941 patients initially randomized and stratified into two age groups (<5 years, and >or=5 years), 936 (99.5%) were retained for the intent to treat (ITT) analysis, and 859 (91.3%) patients for the per protocol (PP) analysis. Among ITT population, up to D28, PCR-corrected adequate parasitological and clinical response rates were 95.2% in the ASAQ1 group, 94.9% in the ASAQ2 group and 95.5% in the AL group. Moreover, the cure rate evaluated among PP population was >or=98.5% in both ASAQ therapeutic arms. Therapeutic response rates did not display any significant differences between age groups or between one geographical site and another. Altogether, this demonstrates the non-inferiority of ASAQ1 regimen compared to both ASAQ2 and AL regimens. During follow-up mild and moderate adverse events including gastrointestinal and/or nervous disorders were reported in 29.3% of patients, with no difference between groups in the nature, frequency or intensity of adverse events. ### conclusion The non-inferiority of ASAQ compared with AL was demonstrated. The fixed-dose combination artesunate + amodiaquine (ASAQ) is safe and efficacious even in young children under 5 years of age. Whilst administration on a twice-a-day basis does not improve the efficacy of ASAQ significantly, a once-a-day intake of this new combination clearly appears as an effective and safe therapy in the treatment of uncomplicated P. falciparum malaria both in adults and children. Implications of such findings are of primary importance in terms of public health especially in African countries. As most national policies plan to strengthen malaria control to reach the elimination of this disease, anti-malarial drugs such as the artesunate + amodiaquine fixed-dose ACT will play a pivotal role in this process. ### Trial Registration The protocol was registered with the www.clinicaltrials.gov open clinical trial registry under the identifier number NCT00316329.", "source": "https://pubmed.ncbi.nlm.nih.gov/19505304/"}
{"doc_id": "0da184f3d08d17f701d7a11270065b3e", "sentence": "All patients have received a median of four and half cycles ( range , 1 - 10 ) of 3-week ( 60 - 75 mg/m2 ) docetaxel regimens and 5 mg prednisone twice per day .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 107, "end": 116, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "prednisone", "start": 135, "end": 145, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy and safety of docetaxel and prednisolone chemotherapy in very elderly men with metastatic castration-resistant prostate cancer (mCRPC) in real world: a single institute experience. Prostate cancer is the most common type of malignancy in elderly men. Although elderly patients are commonly encountered in clinical practice, few studies have focused on the value of chemotherapy in elderly patients. In this study, we reviewed the use of docetaxel with prednisolone in elderly men (aged \u226580 years) with metastatic castration-resistant prostate cancer (mCRPC) at Ningbo First Hospital with a focus on efficacy and toxicity. ### methods A retrospective study including a series of men aged \u226580 years with mCRPC and received docetaxel plus prednisone chemotherapy between August 2011 and May 2019. All these cases were selected from the Ningbo First Hospital prostate cancer database located in Zhejiang Province, China. ### results Sixteen patients were identified, with a mean age of 82 years (range, 80 to 87 years). All patients have received a median of four and half cycles ( range , 1 - 10 ) of 3-week ( 60 - 75 mg/m2 ) docetaxel regimens and 5 mg prednisone twice per day . Seven (43.75%) patients completed more than six cycles. Ten (62.50%) patients had a good prostate-specific antigen (PSA) response of \u226550% decline. Eight (50.00%) patients had ostealgia before receiving docetaxel treatment and six of them (75.00%) experienced reduced pain after the treatment. Hematologic toxicity was observed in six (37.50%) patients with neutropenia, one of which was diagnosed with agranulocytosis and had to be admitted for the same reason. Other adverse reactions such as fever, debilitation, and alopecia were also observed. ### conclusions Very elderly patients (aged \u226580 years) with mCRPC are easy to be neglected and infrequently involved in clinical trials. Our study demonstrates that docetaxel chemotherapy plus prednisone is tolerable and effective among Chinese elderly patients (\u226580 years) with mCRPC. docetaxel chemotherapy may be given under careful surveillance even in frail elderly patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/33081478/"}
{"doc_id": "7ad567a67c448d2d87998e69080f20fb", "sentence": "Combination therapy with other agents including anticoagulants , antihypertensive , anti-inflammatory , oral hypoglycemic and antifungal agents as well as beta-blockers , H2 blockers , cyclosporine and digoxin has been also reviewed .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 185, "end": 197, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "digoxin", "start": 202, "end": 209, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In this article, de novo cholesterol synthesis, its inhibition by HMG-CoA reductase inhibitors (statins) and clinical pharmacology aspects of the statins have been reviewed. Statins are available in both active and pro-drug forms. Their affinity to bind and subsequently to inhibit HMG-CoA reductase activity is approximately 3 orders of magnitude higher than that of natural substrate (HMG-CoA). All members of this group of lipid-lowering agents are, to a varying degree, absorbed from the gut. However, their bioavailability depends on their lipophobicity and their concomitant use with meals. The interaction between HMG-CoA reductase inhibitors and other lipid-lowering agents has been reviewed in more detail. One major side-effect of lipid-lowering combination therapy is myopathy with or without rhabdomyolysis. Combination of statins with gemfibrozil seems to increase risk of this adverse event, particularly in patients with renal impairment, more than combination with other lipid-lowering agents. Combination therapy with other agents including anticoagulants , antihypertensive , anti-inflammatory , oral hypoglycemic and antifungal agents as well as beta-blockers , H2 blockers , cyclosporine and digoxin has been also reviewed . The pleiotropic non-lipid lowering properties of statins and their effects on the quality of lipoprotein particles, the activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase as well as their possible synergistic effects with n-3 fatty acids, phytosterols, vitamin E and aspirin in reducing cardiovascular events warrant further investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/10503952/"}
{"doc_id": "dc325ea5ead86b3a17c5f4b4f215509b", "sentence": "Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia .", "spans": [{"span_id": 0, "text": "tranexamic", "start": 21, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "norethisterone", "start": 41, "end": 55, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia . To compare the efficacy and safety of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. ### design A randomised, double-blind, placebo controlled study. ### setting University Department of Obstetrics and Gynaecology, Addenbrooke's Hospital, Cambridge. ### subjects One hundred and three women complaining of heavy periods with a regular cycle recruited directly from general practitioners within the hospital catchment area and from consultants' gynaecology clinics. ### interventions There were forty-six women on placebo with confirmed ovulatory menorrhagia, defined as menstrual blood loss greater than 80 ml/cycle and mid-luteal serum progesterone concentration greater than 9 nmol/l). Twenty-one received norethisterone (5 mg twice a day on days 19 and 26) and 25 received tranexamic acid (1 g four times daily on days 1 to 4) for two cycles. ### Main Outcome Measures Menstrual blood loss was measured using the alkaline haematin method. Haematological assessments were made both at the beginning and at the end of the study, questionnaires were given to assess subjective endpoints, and patients were asked to report any adverse events during all cycles. ### results tranexamic acid reduced mean menstrual blood loss by 45%, from 175 ml to 97 ml (95% CI for the difference in menstrual blood loss 52 to 108, P < 0.0001), norethisterone increased mean blood loss by 20% from 173 ml to 208 ml (95% CI for the difference in menstrual blood loss -64 to 2, P = 0.26). Fourteen (56%) women who received tranexamic acid achieved a mean menstrual loss of less than 80 ml per cycle during treatment, but only two (9.5%) who received norethisterone achieved this mean menstrual loss. There were no serious adverse events reported for either drug. ### conclusions tranexamic acid is a safe and effective form of medical therapy in women with menorrhagia and is highly likely to normalise blood loss in women losing 80 to 200 ml prior to treatment. norethisterone at this dose is not effective therapy for ovulatory menorrhagia.", "source": "https://pubmed.ncbi.nlm.nih.gov/7612535/"}
{"doc_id": "97e1c88327c1ea59d0837ea5a5433a97", "sentence": "The results of this work encourage the in vivo examination of the therapeutic potential of the combination of bortezomib and rapamycin in Mantle Cell Lymphoma patients .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 110, "end": 120, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "rapamycin", "start": 125, "end": 134, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The effect of Bortezomib and Rapamycin on Telomerase Activity in Mantle Cell Lymphoma. Mantle cell lymphoma (MCL) is a hematological malignancy with unfavorable prognosis. Novel therapeutic approaches for treating the disease are aimed at the mechanisms regulating growth signals, cellular proliferation, and survival pathways of the malignant clones. bortezomib (Brt), a proteasome inhibitor with pleiotropic activities was shown to be active in MCL and is currently implemented in therapeutic combinations for this disease. Telomerase activity is essential for survival of malignant cells and as such is considered a valid therapeutic target. This study evaluated the effects of bortezomib on telomerase activity and its regulation in MCL cells in vitro and ex vivo. Our study shows that bortezomib exerts a cytotoxic effect in a dose dependent manner in two MCL cell lines, with differential sensitivity. While the IC50 for HBL-2 cells ranged between 2.5 ng/ml to 1.5 ng/ml during 24-72 h respectively, the IC50 for the NCEB cells was twice. bortezomib differentially inhibited telomerase activity (TA): in HBL-2 cells there was a decline of 20%-55% during 24-72 h respectively. However in NCEB cells the decline was much smaller, and did not exceed 25%. Inhibition of telomerase activity is shown to be operated by two separate mechanisms: reduction of the hTERT mRNA expression (controlled by the binding of transcription factors) and reduction in phosphorylation of the catalytic subunit of hTERT by its kinases, AKT and PKC\u03b1. A decrease in telomerase activity was demonstrated also in mononuclear cells, isolated from three MCL patients following incubation of the cells in the presence of bortezomib for 24-72 h. In one patient the decrease in TA ranged between 17%-37% respectively, in the second patient between 63%-76% and in the third patient between 70-100% for 24-72 h respectively. The current study indicates that a combination of bortezomib and rapamycin, (an m-Tor pathway inhibitor used in MCL treatment) induced synergistic inhibition of telomerase activity. In HBL-2 cells, the combined treatment of bortezomib and rapamycin decreased TA by 80% compared to the expected value (40%) and for NCEB cells a similar trend was observed. In contrast, there was neither additive nor synergistic effect of this combination on cell proliferation. In the light of the crucial role of telomerase in cancer cells, it was important to characterize the possible relations between telomerase and bortezomib and to distinguish the biochemical mechanisms of its regulation and its interactions with other signal transduction inhibitors such as rapamycin. The results of this work encourage the in vivo examination of the therapeutic potential of the combination of bortezomib and rapamycin in Mantle Cell Lymphoma patients .", "source": "https://pubmed.ncbi.nlm.nih.gov/25500084/"}
{"doc_id": "3e99a850beac024e20cc6bb5376f01de", "sentence": "Additive effects of combined valsartan and spironolactone on cardiac aldosterone escape in spontaneously hypertensive rats .", "spans": [{"span_id": 0, "text": "valsartan", "start": 29, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "spironolactone", "start": 43, "end": 57, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Additive effects of combined valsartan and spironolactone on cardiac aldosterone escape in spontaneously hypertensive rats . The additive effects of combined valsartan and spironolactone on plasma and cardiac aldosterone escape were evaluated in spontaneously hypertensive rats (SHRs). Twenty-four SHRs were treated with valsartan (30 mg/kg body weight per day), spironolactone (20 mg/kg body weight per day) and a combination of both for 4 months. Blood was collected and plasma aldosterone (PA) was estimated with radioimmunoassay (RIA). Ex vivo heart perfusion was performed, the ex vivo cardiac aldosterone (EXCA) was assessed by RIA after high-performance liquid chromatography separation. PA and EXCA were significantly decreased after one month but increased after 4 months in valsartan administration group. The combined valsartan and spironolactone therapy normalized cardiac aldosterone levels. This study provides the first evidence that the long-term treatment with Angiotensin II type 1 receptor antagonist (AT1A) induces local aldosterone escape in cardiovascular tissue, whereas the combined AT1A and spironolactone therapy inhibits the escape in hypertensive rats.", "source": "https://pubmed.ncbi.nlm.nih.gov/15302230/"}
{"doc_id": "206efdfddbfc96d10d86fbfe7dea73ae", "sentence": "54 patients without distant metastases ( T2-T3b , N0-X , M0 ) received 3 cycles of neoadjuvant chemotherapy according to the MVAC protocol ( methotrexate , vinblastine , doxorubicin and cisplatin ) after transurethral resection ( TUR ) followed by cystectomy .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 141, "end": 153, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "vinblastine", "start": 156, "end": 167, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "doxorubicin", "start": 170, "end": 181, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "cisplatin", "start": 186, "end": 195, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Neoadjuvant chemotherapy (MVAC) in locally invasive bladder cancer. In order to evaluate the efficacy of neoadjuvant chemotherapy in invasive urothelial carcinoma of the bladder a retrospective analysis was performed. 54 patients without distant metastases ( T2-T3b , N0-X , M0 ) received 3 cycles of neoadjuvant chemotherapy according to the MVAC protocol ( methotrexate , vinblastine , doxorubicin and cisplatin ) after transurethral resection ( TUR ) followed by cystectomy . 52 patients had previously undergone cystectomy immediately after TUR. Complete histopathological remission was observed in 9 patients (17.3%) after TUR and in 17 patients (31.5%) after TUR+MVAC. Neoadjuvant MVAC resulted, therefore, in a 14% higher rate of complete remissions. The overall response to TUR was significantly improved by MVAC therapy. Downstaging by neoadjuvant chemotherapy was more readily achieved in initially low-stage tumours (T2: 44.4% and 30.8%, T3a: 47.1% and 19%, T3b: 5.3% and 5.5% in patients receiving TUR+MVAC and TUR alone, respectively). Overall survival did not differ significantly between both groups. Patients who were successfully downstaged to pT0 had a significantly better prognosis, and patients resistant to chemotherapy had the poorest prognosis, showing the shortest survival. In conclusion, histopathological response at cystectomy was improved by neoadjuvant MVAC chemotherapy after TUR and can be expected to be prognostically relevant in those patients who can be downstaged to T0, although overall survival failed to be significantly increased in this relatively small patient sample.", "source": "https://pubmed.ncbi.nlm.nih.gov/8869093/"}
{"doc_id": "82d01675243026c612a8cdb0a49b6a38", "sentence": "The objective of this study was to compare cycle control , efficacy and tolerance of an oral contraceptive containing 20 microg ethinylestradiol and 150 microg desogestrel with a preparation containing 30 microg ethinylestradiol combined with 75 microg gestodene .", "spans": [{"span_id": 0, "text": "ethinylestradiol", "start": 128, "end": 144, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "desogestrel", "start": 160, "end": 171, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "ethinylestradiol", "start": 212, "end": 228, "token_start": 32, "token_end": 33}, {"span_id": 3, "text": "gestodene", "start": 253, "end": 262, "token_start": 37, "token_end": 38}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Latin american experience with two low-dose oral contraceptives containing 30 microg ethinylestradiol/75 microg gestodene and 20 microg ethinylestradiol/150 microg desogestrel.  The objective of this study was to compare cycle control , efficacy and tolerance of an oral contraceptive containing 20 microg ethinylestradiol and 150 microg desogestrel with a preparation containing 30 microg ethinylestradiol combined with 75 microg gestodene . This study involved 342 women and 4104 cycles use in Argentina, Brazil, Chile, and Mexico. Contraceptive efficacy was good with both formulations. Two pregnancies occurred in the desogestrel group but were not due to method failure. With respect to cycle control, the incidence of intermenstrual bleeding was higher during the first 3 cycles in the desogestrel group; it was significant (p <0.01) during the first 3 days of the cycle for a normal or heavy bleeding only in the Mexican group. Amenorrhea was not reported for any group, but the incidence of dysmenorrhea was significantly higher (p <0.01) in the Brazilian desogestrel group (13.8%) and was significantly lower (p <0.01) in the Mexican gestodene group (8.5%). Adverse events were similar in all the countries with headache, breast tension, and nausea, the most frequently reported symptoms. The range of mean increase in body weight varied from 0.2 kg in the Argentine group to 2.6 kg in the Chilean group (95% confidence limit, +/- 2.51) in the gestodene group, and 0.2 kg in the Argentine group to 2.5 kg in Brazilian group (95% confidence limit, +/- 2.36) in the desogestrel group. Fifteen women discontinued because of headache, but there were no significant differences between the groups regarding discontinuation for this and other medical or non-medical reasons. Both oral contraceptive preparations are reliable and well tolerated, and both have favorable effects on control cycle.", "source": "https://pubmed.ncbi.nlm.nih.gov/11124360/"}
{"doc_id": "22442dbeede668f6698d00b04a0b5e72", "sentence": "They were assigned to either receiving a COCP containing 20 mcg ethinyl estradiol/150 mg desogestrel for two continuous cycle or NSAID ; mefenamic acid 500 mg TDS for 5 days , 21 days apart for two cycles .", "spans": [{"span_id": 0, "text": "ethinyl", "start": 64, "end": 71, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "desogestrel", "start": 89, "end": 100, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "mefenamic", "start": 137, "end": 146, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Management of bleeding irregularities among etonogestrel implant users: Is combined oral contraceptives pills or nonsteroidal anti-inflammatory drugs the better option? This study is to evaluate whether unacceptable bleeding among the etonogestrel implant user could be better alleviated using combined oral contraceptive pills (COCP) or nonsteroidal anti-inflammation drugs (NSAID). ### methods This is a prospective randomized study for evaluation of 84 etonogestrel implant (Implanon) users with prolonged or frequent bleeding. They were assigned to either receiving a COCP containing 20 mcg ethinyl estradiol/150 mg desogestrel for two continuous cycle or NSAID ; mefenamic acid 500 mg TDS for 5 days , 21 days apart for two cycles . Bleeding pattern during the treatment was recorded and analyzed. ### results A total of 32 women (76.2%) in COCP group and 15 women (35.7%) in NSAID group stop bleeding within 7\u2009days after the initiation of treatment which was statistically significant (P\u2009<\u20090.05). The mean duration of bleeding and spotting days in women treated with COCP was significantly lesser compared to NSAID group (7.29\u2009\u00b1\u20093.16 vs 10.57\u2009\u00b1\u20094.14\u2009days (P\u2009<\u20090.05). ### conclusion We conclude that COCP is more efficient compared to NSAID in managing bleeding irregularities among etonogestrel implant users.", "source": "https://pubmed.ncbi.nlm.nih.gov/31958877/"}
{"doc_id": "a5c80ba5bf5b384aa07401174cdc1726", "sentence": "Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis .", "spans": [{"span_id": 0, "text": "enzastaurin", "start": 30, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "bevacizumab", "start": 46, "end": 57, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Randomized, double-blinded, multicenter, phase II study of pemetrexed, carboplatin, and bevacizumab with enzastaurin or placebo in chemona\u00efve patients with stage IIIB/IV non-small cell lung cancer: Hoosier Oncology Group LUN06-116. : bevacizumab is approved in combination with chemotherapy as first-line treatment for non-small cell lung cancer (NSCLC). Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis . ### methods : ### Eligibility Criteria \u226518 years of age, chemona\u00efve, stage IIIB/IV nonsquamous NSCLC, and Eastern Cooperative Oncology Group performance status 0 to 1. Patients were randomized to placebo or enzastaurin 500 mg orally daily (after a loading dose), plus pemetrexed 500 mg/m, carboplatin area under the curve 6, and bevacizumab 15 mg/kg, intravenously, every 21 days for four cycles. Patients without progression received maintenance therapy with bevacizumab and placebo or enzastaurin. The primary objective was progression-free survival (PFS). Planned sample size was 90 patients, one-sided alpha of 0.20, with two interim analyses: one for safety and the second for futility, with a PFS hazard ratio of 0.8857. ### results : Forty patients were randomized. No unique safety concerns were noted at the first interim analysis. The early stopping rule for futility was met at the second interim analysis. Median PFS was 3.5 months and 4.3 months (hazard ratio: 1.04, 95% confidence interval: 0.49-2.21), and response rates were 20% and 30% (p = 0.462) for enzastaurin and placebo, respectively. Grade 3 or 4 toxicity was similar between the two arms. Two patients died on study because of respiratory arrest and pulmonary embolism. An additional patient died of sepsis secondary to a gastrointestinal perforation >30 days after study treatment discontinuation. ### conclusions : enzastaurin does not improve efficacy when combined with pemetrexed, carboplatin, and bevacizumab. This combination does not warrant further study in NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/20881647/"}
{"doc_id": "64476c3ec43afe5a97fb58f0c495f642", "sentence": "The PASI-75 , -90 and -100 were the highest in secukinumab ( 91.3 % , 82.6 % , 41.3 % , respectively ) , followed by ustekinumab ( 79.6 % , 44.9 % , 16.3 % ) , adalimumab ( 64.3 % , 28.6 % , 7.1 % ) and etanercept ( 50.0 % , 30.0 % , 0 % ) .", "spans": [{"span_id": 0, "text": "secukinumab", "start": 47, "end": 58, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "ustekinumab", "start": 117, "end": 128, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "adalimumab", "start": 160, "end": 170, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "etanercept", "start": 203, "end": 213, "token_start": 50, "token_end": 51}], "rels": [], "paragraph": "Real-world efficacy of biological agents in moderate-to-severe plaque psoriasis: An analysis of 75 patients in Taiwan. Real-world clinical data on psoriasis patients receiving different biological agents is needed, especially in Asian populations. ### objectives Our aim is to compare and analyze the efficacy and safety profile of four biological agents (etanercept, adalimumab, ustekinumab and secukinumab) in a real-world setting in Taiwan. ### methods We retrospectively analyzed the clinical data of all patients with moderate-to-severe plaque psoriasis (Psoriasis Area and Severity Index (PASI) \u2265 10) who received etanercept, adalimumab, ustekinumab or secukinumab between January 2011 and December 2018 in a tertiary hospital in Taiwan. ### results A total of 119 treatment episodes in 75 patients were included in this study. ustekinumab was used in 49 treatment episodes, followed by secukinumab in 46 treatment episodes, adalimumab in 14 treatment episodes and etanercept in 10 treatment episodes. The proportion of the biologic-na\u00efve was highest in etanercept (100%) and lowest in secukinumab (23.9%). The PASI-75 , -90 and -100 were the highest in secukinumab ( 91.3 % , 82.6 % , 41.3 % , respectively ) , followed by ustekinumab ( 79.6 % , 44.9 % , 16.3 % ) , adalimumab ( 64.3 % , 28.6 % , 7.1 % ) and etanercept ( 50.0 % , 30.0 % , 0 % ) . The rate of adverse events that required treatment was highest for secukinumab (15.2%), followed by adalimumab (14.3%), ustekinumab (8.2%), and etanercept (0%), including 4 cases of infections, 2 cases of cardiovascular diseases and 4 cases of cancers. ### conclusions This real world data showed differential efficacy and safety of the four biological agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/33373425/"}
{"doc_id": "502832b2d66be4f7c76573ad6f1b15dc", "sentence": "Trials have demonstrated decreased relapse with perioperative methotrexate , vinblastine , doxorubicin and cisplatin ( M-VAC ) chemotherapy in patients with muscle invasive bladder cancer .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 62, "end": 74, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "vinblastine", "start": 77, "end": 88, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "doxorubicin", "start": 91, "end": 102, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "cisplatin", "start": 107, "end": 116, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer.  Trials have demonstrated decreased relapse with perioperative methotrexate , vinblastine , doxorubicin and cisplatin ( M-VAC ) chemotherapy in patients with muscle invasive bladder cancer . We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. ### Materials And Methods We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. ### results Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). ### conclusions Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.", "source": "https://pubmed.ncbi.nlm.nih.gov/10751847/"}
{"doc_id": "2e405044ef34961a85c429587014c801", "sentence": "m2 on day 1 , oxaliplatin 85 mg/m\u00b2 day 1 and capecitabine twice-daily dose of 625 mg/ m2 , p.o . for 2 weeks ) every 3", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 14, "end": 25, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "capecitabine", "start": 45, "end": 57, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Modified Epirubicin and Oxaliplatin Plus Capecitabine (EOX) Regimen as a Second- Line Therapy in Patients with Advanced Gastric Cancer Objective: We aimed to evaluate the effectiveness of an mEOX (modified epirubicin, oxaliplatin plus capecitabine) regimen as second line therapy after failure of mDCF (modified docetaxel, cisplatin plus fluorouracil). Methods: Gastic cancer patients for whom first-line therapy was unsuccessful and who subsequently received mEOX (epirubicin 50 mg/ m2 on day 1 , oxaliplatin 85 mg/m\u00b2 day 1 and capecitabine twice-daily dose of 625 mg/ m2 , p.o . for 2 weeks ) every 3 weeks until disease progression or unacceptable toxicity, were retrospectively analyzed. Results: The study population comprised 129 cases with a median age of 55 years (range= 27-78), the majority being male (76 %). Most (75.2%) had \u2265 2 sites of metastasis. The median number of chemotherapy courses was five (range= 2\u20139). Forty-nine achieved a partial response and 33 showed stable disease, resulting in a ORR (overall response rate) of 38% and a DCR (disease control rate) of 63.6%. The most frequent features of grade 3-4 hematological and non-hematological toxicity were neutropenia (8.5%) and nausea/vomiting (5.4%). None of the patients suffered death due to toxicity. The median PFS was 4.7 months (95% CI, 4.1\u20135.3) and the OS was 7.4 months (95% CI, 6.3\u20138.5). On multivariate analysis, age \u2265 60 years and ECOG performance status (0-1) were independent prognostic factors affecting PFS and OS. Conslusions: In advanced gastric cancer patients, who progress after first line chemotherapy and have an ECOG performance status of 0-1, mEOX is a well tolerated triple regimen associated with a promising OS and PFS.", "source": "https://pubmed.ncbi.nlm.nih.gov/29374414/"}
{"doc_id": "60e477e5cd5aded203a0a848439207a0", "sentence": "The objective of this analysis was to assess the cost-effectiveness of risedronate compared to generic alendronate in Germany applying the REAL effectiveness data .", "spans": [{"span_id": 0, "text": "risedronate", "start": 71, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "alendronate", "start": 103, "end": 114, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "The impact of fewer hip fractures with risedronate versus alendronate in the first year of treatment: modeled German cost-effectiveness analysis. The risedronate and alendronate (REAL) cohort study provides unique comparative effectiveness data for real world bisphosphonate treatment of osteoporosis. ### objective The objective of this analysis was to assess the cost-effectiveness of risedronate compared to generic alendronate in Germany applying the REAL effectiveness data . ### Materials And Methods A validated Markov model of osteoporosis was populated with REAL effectiveness data and German epidemiological, cost, and utility data. To estimate the impact of therapy on hip fractures, costs, and quality adjusted life years (QALYs), the analysis included women>or=65 years, treated with risedronate or alendronate and followed for 4 additional years. Country-specific data included population mortality, fracture costs, and annual drug costs, using a German social insurance perspective. Costs and outcomes were discounted at 3%. A differential hip fracture relative risk reduction of 43% was applied to risedronate vs. alendronate. ### results The model predicted that treatment with risedronate would result in fewer hip fractures and more QALYs at a reduced cost (savings of euro278 per treated woman) compared to treatment with generic alendronate. Sensitivity analysis assuming 2 years of treatment and equivalence of effect after 1 year show cost savings as well (euro106 per treated woman). ### discussion Whereas previous economic evaluations involving bisphosphonates have mainly relied on efficacy data from noncomparative clinical trials, this study's strength is in the use of comparative effectiveness data from one data source. The magnitude of the cost savings observed were sensitive to alternative assumptions regarding treatment duration, therapy discontinuation and cost of generic alendronate. ### conclusions Based on \"real world\" data the analysis supports the first line use of risedronate for the treatment of osteoporotic women in Germany.", "source": "https://pubmed.ncbi.nlm.nih.gov/19883401/"}
{"doc_id": "5d8e94d769dadafed1e67a36606f7721", "sentence": "However , two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and , by contrast , increased toxicity .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 66, "end": 77, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "capecitabine", "start": 81, "end": 93, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The role of capecitabine in locally advanced rectal cancer treatment: an update. Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. oxaliplatin and irinotecan are therefore good candidates. However , two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and , by contrast , increased toxicity . capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational.", "source": "https://pubmed.ncbi.nlm.nih.gov/22621694/"}
{"doc_id": "677fdeeb41810fb495dcbcc5969fcc98", "sentence": "The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes .", "spans": [{"span_id": 0, "text": "everolimus", "start": 16, "end": 26, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bicalutamide", "start": 30, "end": 42, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR. To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. ### Experimental Design Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. ### results The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes . Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. ### conclusions This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/20842117/"}
{"doc_id": "503a43e79ed74f42ff3b6fe92e2e4472", "sentence": "Ropivacaine and bupivacaine were the common drugs used for RA , which were independent of RA utilization .", "spans": [{"span_id": 0, "text": "Ropivacaine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bupivacaine", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Regional anesthesia and lipid resuscitation for local anesthetic systemic toxicity in China: results of a survey by the orthopedic anesthesia group of the Chinese Society Of Anesthesiology. Intravenous lipid emulsions have been introduced for the management of patients with Local Anesthetic Systemic Toxicity (LAST). These emulsions have been stated as a first-line treatment in the guidelines of several international anesthesia organizations. Nevertheless, the adoption of lipid rescue therapy by Chinese practitioners remains unknown. We, therefore, evaluated the current approaches to treat LAST and the use of lipid rescue therapy among anesthesiologists in China. ### methods In September 2013, a 23-question survey on regional anesthesia practice and availability of lipid emulsions was sent by e-mail to directors or designated individuals at 41 academic anesthesiology departments listed by the orthopedic anesthesia group of the Chinese Society of Anesthesiology. ### results Responses were received from 36 of the 41 (88 %) anesthesiology departments. To simplify the analysis, responses were divided into two groups according to the annual percentage of patients who received regional anesthesia (RA) for orthopedic anesthesia: 14 departments (39%) with high-utilization (\u2265 50%) and 22 departments (61%) low-utilization (<50%) of RA. Ropivacaine and bupivacaine were the common drugs used for RA , which were independent of RA utilization . Interestingly, ultrasound-guided techniques were much more frequently used in low-utilization institutions than in high-utilization institutions (P = 0.025). Lipid emulsion was readily available in 8 of the 36 (22%) responding institutions, with 7 of the other 28 (25%) institutions planning to stock lipid emulsion. No differences in lipid availability and storage plans were observed between high- and low-utilization institutions. Lipid resuscitation was performed in five of the eight departments that had lipid emulsion. Eleven patients were successfully resuscitated and one was not. ### conclusion Lipid emulsion is not widely available in China to treat LAST resulted from RA for orthopedic patients. Efforts are required to promote lipid rescue therapy nationwide. ### Trial Registration Chinese Clinical Trail Registry (Registration number # ChiCTR-EOR-15006960; Date of Retrospective Registration on August 23rd, 2015) http://www.chictr.org.cn/showproj.aspx?proj=11703 .", "source": "https://pubmed.ncbi.nlm.nih.gov/26728368/"}
{"doc_id": "085af6dcbceb17f4d6d9007c05ca030d", "sentence": "In 13 patients treated with equivalent doses of rotigotine switched from other DAs ( pramipexole , ropinirole , and cabergoline ) , ESS did not increase after treatment ( 10.0 \u00b1 4.6 before and 8.6 \u00b1 4.5 after treatment ) and decreased without worsening of CGI-I in 54 % patients .", "spans": [{"span_id": 0, "text": "rotigotine", "start": 48, "end": 58, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "pramipexole", "start": 85, "end": 96, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "ropinirole", "start": 99, "end": 109, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "cabergoline", "start": 116, "end": 127, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Rotigotine Transdermal Patch Does Not Make Parkinson Disease Patients Sleepy During Daytime. To assess quantitatively the influence of rotigotine transdermal patch on daytime sleepiness, the most common adverse event by non-ergot dopamine agonists (DAs), in Parkinson disease (PD) patients. ### methods An open-label study enrolled PD patients with unsatisfactory control of motor symptoms. Treatment with rotigotine transdermal patch was titrated to optimal dose (4-8 mg/24 hours) over 2 to 4 weeks. Primary outcome was Epworth Sleepiness Scale (ESS) for daytime sleepiness. Secondary outcomes included Hoehn&Yahr stage, time spent with dyskinesia, Clinical Global Impression of Improvement (CGI-I) of motor symptoms, adverse events, and compliance. ### results The subjects were 31 PD patients (age 72 \u00b1 8, Hoehn &Yahr stage 2.7 \u00b1 0.9, mean \u00b1 SD). The ESS did not increase after rotigotine treatment (7.2 \u00b1 4.9 before treatment, 6.2 \u00b1 4.0 with 4 mg/24 hour, and 8.1 \u00b1 6.4 with 8 mg/24 hour). The CGI-I score improved after treatment; responder rate reached 88.9% with 8 mg/24 hours. No patients showed worsening in other secondary outcomes. In 13 patients treated with equivalent doses of rotigotine switched from other DAs ( pramipexole , ropinirole , and cabergoline ) , ESS did not increase after treatment ( 10.0 \u00b1 4.6 before and 8.6 \u00b1 4.5 after treatment ) and decreased without worsening of CGI-I in 54 % patients . Other secondary outcomes did not worsen after treatment. ### conclusions Twenty four-hour transdermal delivery of rotigotine at doses up to 8 mg/24 hours does not worsen the daytime sleepiness in PD patients and often improves it when switched from other non-ergot DAs. This is achieved together with satisfactory improvement in motor symptoms, demonstrating that this new modality of non-ergot DA is well tolerated and beneficial in PD patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/26536020/"}
{"doc_id": "2f80aa3ed0868deba396a0cbaf76b31f", "sentence": "To assess plasma steady-state pharmacokinetics ( PK ) of rifampicin , isoniazid , saquinavir and ritonavir in HIV and tuberculosis ( TB ) co-infected patients , and investigate potential interactions between TB drugs and protease inhibitors ( PIs ) .", "spans": [{"span_id": 0, "text": "isoniazid", "start": 70, "end": 79, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "saquinavir", "start": 82, "end": 92, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "ritonavir", "start": 97, "end": 106, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "rifampicin", "start": 57, "end": 67, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.  To assess plasma steady-state pharmacokinetics ( PK ) of rifampicin , isoniazid , saquinavir and ritonavir in HIV and tuberculosis ( TB ) co-infected patients , and investigate potential interactions between TB drugs and protease inhibitors ( PIs ) . ### methods Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. ### results Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. ### conclusions There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.", "source": "https://pubmed.ncbi.nlm.nih.gov/17307771/"}
{"doc_id": "08a35fc86bac0d38e3375f9b88b26dd4", "sentence": "We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 102, "end": 113, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "docetaxel", "start": 119, "end": 128, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "pertuzumab", "start": 150, "end": 160, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "trastuzumab", "start": 166, "end": 177, "token_start": 24, "token_end": 25}, {"span_id": 4, "text": "docetaxel", "start": 183, "end": 192, "token_start": 26, "token_end": 27}, {"span_id": 5, "text": "pertuzumab", "start": 195, "end": 205, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [2, 3, 4], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. ### methods We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel ( control group ) or pertuzumab plus trastuzumab plus docetaxel ( pertuzumab group ) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed . The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. ### results The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. ### conclusions The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).", "source": "https://pubmed.ncbi.nlm.nih.gov/22149875/"}
{"doc_id": "c2679a7e1f713326ad184919894b6e1c", "sentence": "Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg , and when combined with 140 mg/kg of aspirin , the LD50 was reduced to 900 mg/kg .", "spans": [{"span_id": 0, "text": "thiabendazole", "start": 54, "end": 67, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "aspirin", "start": 129, "end": 136, "token_start": 22, "token_end": 23}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The effect of thiabendazole on pain threshold. thiabendazole significantly increased the reaction time to thermal stimulus. However, in mice treated with morphine, the reaction time was not in any way different from those treated with combined doses of thiabendazole and morphine. thiabendazole was found to have an antinociceptive action. The protective dose for 50% of animal (ED50) against p-benzoquinone-induced writhing reflex was found to be 310 mg/kg. The ED50 for aspirin alone was 140 mg/kg. When the ED50 of aspirin was determined in combination with different dose levels of thiabendazole, it showed a marked reduction in the values reaching 50 mg/kg, when 300 mg of thiabendazole was used in combination. Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg , and when combined with 140 mg/kg of aspirin , the LD50 was reduced to 900 mg/kg . These findings indicate that thiabendazole possesses an analgesic activity which is potentiated by aspirin, though aspirin was found to significantly enhance its toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/4050451/"}
{"doc_id": "a9b18b3c6a9e25a33609280998e2412d", "sentence": "Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia ( AML ) , and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation .", "spans": [{"span_id": 0, "text": "Azacitidine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "enasidenib", "start": 16, "end": 26, "token_start": 2, "token_end": 3}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination of azacitidine and enasidenib enhances leukemic cell differentiation and cooperatively hypomethylates DNA.  Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia ( AML ) , and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation . We hypothesized that a combination of these agents could have interactive effects on DNA methylation and enhance differentiation in mIDH2 cells. Combination treatment enhanced cellular differentiation in TF-1 cells overexpressing IDJ2R140Q through increased hemoglobinization and increased hemoglobin \u03b3 RNA expression compared with the effects of single agents. Furthermore, in primary AML samples (IDH2R140Q or R172K), combination treatment reduced CD34+ cells and increased CD15+ cells to a greater extent than attained with single agents. To explore the mechanism of enhanced differentiation with combination treatment, the TF-1 epigenome was analyzed by profiling 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) DNA methylation changes. enasidenib treatment alone increased 5hmC, consistent with reactivation of ten-eleven-translocation (TET) enzyme activity. Compared with treatment with azacitidine alone, combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of ten-eleven-translocation enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation.", "source": "https://pubmed.ncbi.nlm.nih.gov/33794295/"}
{"doc_id": "8c910778beeef8e539f66fd377e27eeb", "sentence": "Good , moderate and mild pain relief were noted in 19 ( 41 % ) , six ( 13 % ) and seven ( 15 % ) patients on lamotrigine and 13 ( 28 % ) , five ( 11 % ) and 15 ( 33 % ) patients on amitriptyline , respectively , by patient 's global assessment of efficacy and safety .", "spans": [{"span_id": 0, "text": "lamotrigine", "start": 109, "end": 120, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "amitriptyline", "start": 181, "end": 194, "token_start": 50, "token_end": 51}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy. To compare the efficacy and safety of lamotrigine and amitriptyline in controlling chronic painful peripheral neuropathy in diabetic patients. ### methods A randomized, double-blind, crossover, active-control, clinical trial with variable dose titration was carried out (n = 53). amitriptyline orally, at doses of 10, 25 and 50 mg at night-time, each dose for 2 weeks, and lamotrigine orally, at doses of 25, 50 and 100 mg twice daily, each dose for 2 weeks, by optional titration were used. There was a placebo washout period for 2 weeks between the two drugs. Assessment for pain relief, overall improvement and adverse events were carried out. ### results Good , moderate and mild pain relief were noted in 19 ( 41 % ) , six ( 13 % ) and seven ( 15 % ) patients on lamotrigine and 13 ( 28 % ) , five ( 11 % ) and 15 ( 33 % ) patients on amitriptyline , respectively , by patient 's global assessment of efficacy and safety . Patient and physicians global assessment, McGill pain questionnaire and Likert pain scale showed no significant difference between the treatments, although improvement with both treatments was seen from 2 weeks. Of the 44 adverse events reported, 33 (75%) were with amitriptyline, sedation being the commonest [in 19 (43%) patients]. lamotrigine caused adverse events in 11 (25%), of which rash in three (7%) and elevations of creatinine in four (9%) were the most common. The preferred lamotrigine dose was 25 mg twice daily. ### conclusions As there are few differences between the two treatments in efficacy, lamotrigine 25 mg twice daily might be the first choice as it is associated with fewer adverse effects in our population.", "source": "https://pubmed.ncbi.nlm.nih.gov/17335465/"}
{"doc_id": "e3eaa19866764043fe913227f0c1329f", "sentence": "The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 51, "end": 62, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "triamcinolone", "start": 67, "end": 80, "token_start": 11, "token_end": 12}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema. The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. ### objectives To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. ### Search Methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. ### Selection Criteria We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. ### Data Collection And Analysis We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. ### Main Results There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 \u03bcm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 \u03bcm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 \u03bcm, 95% CI -39.87\u03bcm to 21.87\u03bcm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. ### Authors Conclusions Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO . There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.", "source": "https://pubmed.ncbi.nlm.nih.gov/29669176/"}
{"doc_id": "8d3aa3b09931b7d3aa9d1b62ecf79b24", "sentence": "Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults .", "spans": [{"span_id": 0, "text": "Doxorubicin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "ifosfamide", "start": 16, "end": 26, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Perspectives on anthracyclines plus ifosfamide in advanced soft tissue sarcomas.  Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults . Given in combination at full doses, with or without dacarbazine, these agents have induced higher response rates than were obtained with single-agent therapy. Because they involve considerable myelotoxicity, however, full-dose regimens should be reserved for patients with good performance status and without potential septic foci. Obviously, higher response rates do not automatically translate into improved survival. In soft tissue sarcomas, full-dose polychemotherapy will most probably provide a survival benefit only in selected patients in whom surgery can be performed in combination with chemotherapy. Prospective trials in such patients, although difficult to carry out, would be highly desirable. The information they would provide might help the clinician tailor treatment in a more rational way and improve chances of cure or long-term survival in at least some patient subgroups.", "source": "https://pubmed.ncbi.nlm.nih.gov/8453704/"}
{"doc_id": "dff2572ca5c7f865279efd425491fe4b", "sentence": "The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine .", "spans": [{"span_id": 0, "text": "methylprednisolone", "start": 83, "end": 101, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "prednisolone", "start": 145, "end": 157, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "cyclosporine", "start": 162, "end": 174, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Successful treatment of adolescent pemphigus vulgaris by immunoadsorption method. A 15-year-old girl with pemphigus vulgaris did not respond to oral administration of prednisolone at 45 mg/day. The skin and oral mucous membrane lesions recurred after effective treatments with methylprednisolone pulse therapy and combination therapy with prednisolone and cyclosporine . The finally successful treatment involved eleven cycles of immunoadsorption using a tryptophan column and administration of a moderate dose of prednisolone. Serum gamma-globulin level and anti-intercellular antibody titer decreased from 1.08 g/dl to 0.5 g/dl and 1:320 to 1:20, respectively. She has been well controlled with 21.5 mg/day prednisolone for 8 months after the final adsorption. Considering the physical, mental and social situation of adolescent student patients, immunoadsorption is a highly preferable choice among a variety of treatment modalities for pemphigus vulgaris because it makes the term of hospitalization shorter and avoids undesirable side effects from initial high dose corticosteroids.", "source": "https://pubmed.ncbi.nlm.nih.gov/10343469/"}
{"doc_id": "b9e3bc7f24bf72f23bc8e89b71cbd677", "sentence": "Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes .", "spans": [{"span_id": 0, "text": "colistin", "start": 17, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "ciprofloxacin", "start": 67, "end": 80, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Co-Delivery of Ciprofloxacin and Colistin in Liposomal Formulations with Enhanced In Vitro Antimicrobial Activities against Multidrug Resistant Pseudomonas aeruginosa. This study aims to develop liposomal formulations containing synergistic antibiotics of colistin and ciprofloxacin for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. ### methods colistin (Col) and ciprofloxacin (Cip) were co-encapsulated in anionic liposomes by ammonium sulfate gradient. Particle size, encapsulation efficiency, in vitro drug release and in vitro antibiotic activities were evaluated. ### results The optimized liposomal formulation has uniform sizes of approximately 100\u00a0nm, with encapsulation efficiency of 67.0% (for colistin) and 85.2% (for ciprofloxacin). Incorporation of anionic lipid (DMPG) markedly increased encapsulation efficiency of colistin (from 5.4 to 67.0%); however, the encapsulation efficiency of ciprofloxacin was independent of DMPG ratio. Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes . In vitro release of ciprofloxacin and colistin in the bovine serum for 2\u00a0h were above 70 and 50%. The cytotoxicity study using A549 cells showed the liposomal formulation is as non-toxic as the drug solutions. Liposomal formulations of combinations had enhanced in vitro antimicrobial activities against multidrug resistant P. aeruginosa than the monotherapies. ### conclusions Liposomal formulations of two synergistic antibiotics was promising against multidrug resistant P. aeruginosa infections.", "source": "https://pubmed.ncbi.nlm.nih.gov/30094660/"}
{"doc_id": "b0b756e4eaeb1d41e01248091673c2d5", "sentence": "MAB using flutamide as second-line hormonal therapy can give a comparatively favourable PSA response with no severe side-effects ; therefore , this therapy may be suitable for patients with HRPC after primary MAB using bicalutamide has failed , particularly in those with no bone metastases or whose disease has progressed for > 1 year after first-line therapy .", "spans": [{"span_id": 0, "text": "flutamide", "start": 10, "end": 19, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "bicalutamide", "start": 219, "end": 231, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "Clinical outcome of maximum androgen blockade using flutamide as second-line hormonal therapy for hormone-refractory prostate cancer. To investigate the efficacy of maximum androgen blockade (MAB) using flutamide as second-line hormonal therapy for advanced hormone-refractory prostate cancer (HRPC). ### Patients And Methods The study included 55 patients with HRPC who were treated with MAB using flutamide (375 mg daily) as second-line hormonal therapy. All patients had previously received bicalutamide combined with either surgical or medical castration as first-line hormonal therapy, which failed. The effect of the second-line therapy was evaluated by serum prostate-specific antigen (PSA) level alone, and the response defined as a decrease of >50% from the baseline PSA at the start of second-line therapy. ### results On initiating second-line hormonal therapy there was a reduction in the PSA level in 25 of the 55 patients (45%), among whom 12 (22%) were regarded as responders, while the PSA level continued to increase in the remaining 30 (55%). The median (range) duration of the PSA response was 6 (1-13) months. During the observation period there were no severe side-effects from the second-line MAB therapy. Patients without bone metastases or whose disease progressed >1 year after first-line therapy had a significantly higher incidence of PSA response to second-line therapy, despite no significant effect of other factors examined on the PSA response to second-line therapy. Furthermore, the cause-specific survival in responders to second-line therapy was significantly better than that in nonresponders; however, multivariate analysis showed that no factors, including response to second-line therapy, could be used as independent predictors of cause-specific survival. ### conclusions MAB using flutamide as second-line hormonal therapy can give a comparatively favourable PSA response with no severe side-effects ; therefore , this therapy may be suitable for patients with HRPC after primary MAB using bicalutamide has failed , particularly in those with no bone metastases or whose disease has progressed for > 1 year after first-line therapy .", "source": "https://pubmed.ncbi.nlm.nih.gov/16153202/"}
{"doc_id": "c5056778116a14b966bbe222b32e1acb", "sentence": "Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin 's lymphomas .", "spans": [{"span_id": 0, "text": "decitabine", "start": 17, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "vorinostat", "start": 48, "end": 58, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin 's lymphomas . PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat.  PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied.  RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common \u2265 grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for \u2265 4 cycles was observed in 11/38 (29%) evaluable patients.  CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.", "source": "https://pubmed.ncbi.nlm.nih.gov/21152384/"}
{"doc_id": "43af8a23a61c911f4823dbc4f666bac8", "sentence": "Epirubicin ( 35 mg/m(2 ) ) and cyclophosphamide ( 400 mg/m(2 ) ) were administered from day 2 to day 4 , every 4 weeks .", "spans": [{"span_id": 0, "text": "Epirubicin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cyclophosphamide", "start": 31, "end": 47, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer. 5-fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin ( 35 mg/m(2 ) ) and cyclophosphamide ( 400 mg/m(2 ) ) were administered from day 2 to day 4 , every 4 weeks . All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/11474271/"}
{"doc_id": "c4003c230fdd89dca38ff9d23a7fdbb1", "sentence": "Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty , use of cardiac resynchronization therapy , and taking carvedilol with spironolactone .", "spans": [{"span_id": 0, "text": "carvedilol", "start": 177, "end": 187, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "spironolactone", "start": 193, "end": 207, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Successful bridge to recovery with VAD implantation for anthracycline-induced cardiomyopathy. Anthracyclines are effective antineoplastic drugs, but they are known to be cardiotoxic. Recovery of cardiac function is rare. A few studies on implantation of a ventricular assist device (VAD) have been performed for anthracycline-induced cardiomyopathy. Recovery of left ventricular (LV) function with an LVAD is also rare. Recently, several adjunctive therapies were attempted to restore ventricular function. We report a successful bridge to recovery of ventricular function using VAD implantation for anthracycline-induced cardiomyopathy. The patient was a 57-year-old man who had been diagnosed with diffuse large B-cell lymphoma (DLBCL) at age 52. Combination chemotherapy including hydroxydaunorubicin was started. Complete remission was achieved after chemotherapy. Heart failure symptoms such as fatigue, dyspnea on exertion, and weight gain appeared 5\u00a0months later. A cardiac resynchronization device was implanted. His heart function deteriorated. He underwent implantation of a Toyobo LVAD and mitral annuloplasty. After implantation, he was prescribed carvedilol with spironolactone. He was weaned from the LVAD on postoperative day (POD) 239 and discharged on POD 37 after weaning. He remained in New York Heart Association classes within the first- to second-degree range, the LV dimention diastolic/systolic ratio was 56/46\u00a0mm, ejection fraction 38%, and mitral regurgitation mild at 3\u00a0years after weaning from the LVAD. Our patient could be weaned from LVAD probably due to the combination management strategy employing mitral valvuloplasty , use of cardiac resynchronization therapy , and taking carvedilol with spironolactone . Further studies will be needed to clarify the efficacy of these adjunctive therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/21534011/"}
{"doc_id": "8d4b14787de8987d0a9a17e167f7aeec", "sentence": "Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation ( 0.1 ng/ml ) of the assay", "spans": [{"span_id": 0, "text": "hydroxyzine", "start": 6, "end": 17, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "cetirizine", "start": 22, "end": 32, "token_start": 3, "token_end": 4}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pharmacokinetics of hydroxyzine and cetirizine following oral administration of hydroxyzine to exercised Thoroughbred horses. hydroxyzine is a first-generation antihistamine and cetirizine, a second-generation antihistamine and active metabolite of hydroxyzine. hydroxyzine is commonly used in performance horses and as such its use in closely regulated; however, there are no published studies suitable for establishing appropriate regulatory recommendations. In the current study, 12 exercised Thoroughbred research horses received a single oral administration of 500\u00a0mg of hydroxyzine. Blood and urine samples were collected prior to and up to 96\u00a0hr postdrug administration and concentrations of hydroxyzine and cetirizine determined using liquid chromatography-tandem mass spectrometry. A joint parent/metabolite population 2-compartment pharmacokinetic model with first-order absorption and elimination was utilized to describe the pharmacokinetics of both compounds. Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation ( 0.1 ng/ml ) of the assay at 96\u00a0hr (the last time point sampled). The terminal half-life was 7.41 and 7.13\u00a0hr for hydroxyzine and cetirizine, respectively. Findings from this study suggest that a prolonged withdrawal time should be observed if this compound is used in performance administered to performance horses and is classified as prohibited substance by the applicable regulatory body.", "source": "https://pubmed.ncbi.nlm.nih.gov/31490561/"}
{"doc_id": "9443916aa7d28a5adeec2d2386bee04d", "sentence": "Although well tolerated , the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy .", "spans": [{"span_id": 0, "text": "everolimus", "start": 42, "end": 52, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "vinorelbine", "start": 57, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "vinorelbine", "start": 109, "end": 120, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Improving the outcome of patients with HER2-negative metastatic breast cancer experiencing tumour progression following first-line chemotherapy remains an urgent medical need. The purpose of the VicTORia trial was to show superiority of everolimus in combination with vinorelbine versus vinorelbine monotherapy as second-line chemotherapy for patients with advanced HER2 negative breast cancer. ### methods In this randomised phase II trial, 133 patients were recruited in 32 centres in Germany. Patients were randomised 1:1 to second-line chemotherapy either with vinorelbine plus everolimus (arm1) or vinorelbine alone (arm2). Primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS rate at 6\u00a0months, overall survival (OS), overall response rate (ORR) and safety. Baseline PI3\u00a0K mutational status was determined in plasma samples. ### results Median progression-free survival was not different between arms (arm1 vs. arm2: 4.01\u00a0months, 95% CI 2.40-6.09 vs. 4.08, 95% CI 2.80-5.33). PFS rate at 6\u00a0months (arm1 vs. arm2: 39.4%, 95% CI 27.6-50.9% vs. 36.6%, 95% CI 24.6-48.6%), median OS (arm1 vs. arm2: 16.3\u00a0months, 95% CI 11.4-19.0 vs. 13.8\u00a0months, 95% CI 10.2-19.1) and ORR were not different between arms. Most frequent grade 3/4 adverse events were neutropenia (50% vs. 40%), gastrointestinal toxicities (19.1% vs. 6.1%), and infections (19.1% vs. 7.7%). PI3\u00a0K mutational status was neither associated with PFS nor with OS. ### conclusion Although well tolerated , the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy . There was no correlation between PI3\u00a0K mutational status and efficacy. EudracCT No 2011-001024-38, ClinicalTrials.gov No NCT01520103.", "source": "https://pubmed.ncbi.nlm.nih.gov/31115844/"}
{"doc_id": "eb3681c71c2520fe8ab1a0369e10b461", "sentence": "In addition , our results suggested that adalimumab , tocilizumab , rituximab and glucocorticoids may also have beneficial effects in restoring normal transcriptome , but not chloroquine , hydroxychloroquine or interferons .", "spans": [{"span_id": 0, "text": "adalimumab", "start": 41, "end": 51, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "tocilizumab", "start": 54, "end": 65, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "rituximab", "start": 68, "end": 77, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "chloroquine", "start": 175, "end": 186, "token_start": 26, "token_end": 27}, {"span_id": 4, "text": "hydroxychloroquine", "start": 189, "end": 207, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Transcriptomic signatures and repurposing drugs for COVID-19 patients: findings of bioinformatics analyses. The novel coronavirus SARS-CoV-2 is damaging the world's social and economic fabrics seriously. Effective drugs are urgently needed to decrease the high mortality rate of COVID-19 patients. Unfortunately, effective antiviral drugs or vaccines are currently unavailable. Herein, we systematically evaluated the effect of SARS-CoV-2 on gene expression of both lung tissue and blood from COVID-19 patients using transcriptome profiling. Differential gene expression analysis revealed potential core mechanism of COVID-19-induced pneumonia in which IFN-\u03b1, IFN-\u03b2, IFN-\u03b3, TNF and IL6 triggered cytokine storm mediated by neutrophil, macrophage, B and DC cells. Weighted gene correlation network analysis identified two gene modules that are highly correlated with clinical traits of COVID-19 patients, and confirmed that over-activation of immune system-mediated cytokine release syndrome is the underlying pathogenic mechanism for acute phase of COVID-19 infection. It suggested that anti-inflammatory therapies may be promising regimens for COVID-19 patients. Furthermore, drug repurposing analysis of thousands of drugs revealed that TNF\u03b1 inhibitor etanercept and \u03b3-aminobutyric acid-B receptor (GABABR) agonist baclofen showed most significant reversal power to COVID-19 gene signature, so we are highly optimistic about their clinical use for COVID-19 treatment. In addition , our results suggested that adalimumab , tocilizumab , rituximab and glucocorticoids may also have beneficial effects in restoring normal transcriptome , but not chloroquine , hydroxychloroquine or interferons . Controlled clinical trials of these candidate drugs are needed in search of effective COVID-19 treatment in current crisis.", "source": "https://pubmed.ncbi.nlm.nih.gov/33312453/"}
{"doc_id": "cfb44c26cc0a1b85c41cf38e39dac79a", "sentence": "In addition , biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1 , but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 53, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "doxorubicin", "start": 217, "end": 228, "token_start": 31, "token_end": 32}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "In vitro evaluation of schedule-dependent interactions between docetaxel and doxorubicin against human breast and ovarian cancer cells. docetaxel, a novel member of the taxoid family, has shown greater potency than paclitaxel in the treatment of advanced breast cancer and certain other solid tumors. The promising clinical activity of docetaxel has also promoted considerable interest in combining this drug with other antitumor agents. In this study, we assessed the cytotoxic interaction between docetaxel and doxorubicin administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including DNA fragmentation analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and flow cytometric analyses, we found that the antagonistic interaction occurred when tumor cells were exposed to the two drugs simultaneously or exposed to doxorubicin before docetaxel. However, no antagonism was observed when docetaxel was added before doxorubicin. Further analyses demonstrated that doxorubicin could interfere with the cytotoxic effect of docetaxel on both mitotic arrest and apoptotic cell death. In addition , biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1 , but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin . These results indicate that the interaction between docetaxel and doxorubicin is highly schedule dependent. Exposure of tumor cells to doxorubicin before docetaxel could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to docetaxel followed by doxorubicin.", "source": "https://pubmed.ncbi.nlm.nih.gov/10999771/"}
{"doc_id": "168b963c3be6ac1ded38c2d41bc9b197", "sentence": "Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 65, "end": 77, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "leucovorin", "start": 92, "end": 102, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy . To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. ### Patients And Methods For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. ### results Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. ### conclusions Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.", "source": "https://pubmed.ncbi.nlm.nih.gov/1727928/"}
{"doc_id": "121a385260e78585b9b54b3081ebe872", "sentence": "Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 38, "end": 47, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "ipilimumab", "start": 68, "end": 78, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma . nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open-label, uncontrolled phase II study that investigated the long-term efficacy and safety in treatment-naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1\u00a0mg/kg i.v.) in combination with ipilimumab (3\u00a0mg/kg i.v.) at 3-week intervals, followed by doses of nivolumab (3\u00a0mg/kg i.v.) at 2-week intervals. The median follow-up period was 20.8\u00a0months (range, 5.2-35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5-62.6). Median progression-free survival was not reached (95% CI, 3.02-not reached), and median overall survival was also not reached (95% CI, 19.52-not reached). The 30-month progression-free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune-related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long-term treatment-free survival (659 and 590\u00a0days, respectively). Long-term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.", "source": "https://pubmed.ncbi.nlm.nih.gov/32812243/"}
{"doc_id": "bfc860242fe9e9abc5f6ea5ffa6f1122", "sentence": "In some relatively developed regions in China , infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA .", "spans": [{"span_id": 0, "text": "infliximab", "start": 48, "end": 58, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "rituximab", "start": 63, "end": 72, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Cost effectiveness of different treatment strategies in the treatment of patients with moderate to severe rheumatoid arthritis in china. To analyse the cost-effectiveness of traditional disease-modifying anti-rheumatic drugs (tDMARDs) compared to biological therapies from the perspective of Chinese society. ### Methodology Principal Findings A mathematical model was developed by incorporating the clinical trial data and Chinese unit costs and treatment sequences from a lifetime perspective. Hypothetical cohorts with moderate to severe RA were simulated. The primary outcome measure-quality-adjusted life years (QALYs)-was derived from disease severity (HAQ scores). Primary analysis included drug costs, monitoring costs, and other costs. Probabilistic and one-way sensitivity analyses were performed. Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALYs than tDMARDs alone or TNF antagonists plus DMARDs. In comparison with tDMARDs, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab, and adalimumab without rituximab were $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, for etanercept, infliximab, and adalimumab with rituximab. No biotherapy was cost-effective under the willingness to pay threshold when the threshold was 3 times the per capita GDP of China. When 3 times the per capita GDP of Shanghai used as the threshold, infliximab and rituximab could yield nearly 90% cost-effective simulations in probabilistic sensitivity analysis. ### Conclusions Significance tDMARD was the most cost-effective option in the Chinese healthcare setting. In some relatively developed regions in China , infliximab and rituximab may be a favorable cost-effective alternative for moderate to severe RA .", "source": "https://pubmed.ncbi.nlm.nih.gov/23056637/"}
{"doc_id": "0b928797b63ebfe5e343e20167824e7c", "sentence": "Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin .", "spans": [{"span_id": 0, "text": "Topiramate", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "metformin", "start": 204, "end": 213, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. This is a randomized, placebo-controlled study of the weight-loss efficacy and safety of a controlled-release (CR) formulation of topiramate in overweight and obese patients with type 2 diabetes treated with diet and exercise alone or in combination with metformin. ### Research Design And Methods Patients with type 2 diabetes, BMI > or =27 kg/m2, A1C >6.5 and <11.0%, treated with diet and exercise alone or in combination with metformin monotherapy were enrolled. Patients were randomized to placebo or topiramate CR titrated up to 175 mg/day. Treatment consisted of a 7-week titration phase followed by a 9-week maintenance phase. ### results A total of 111 subjects were randomized and analyzed. By the end of week 16, patients in the placebo and topiramate groups lost 2.5 and 6.0 kg, which represented 2.3 and 5.8%, respectively, of their baseline body weight (P < 0.001 vs. placebo). A1C improved from a baseline of 7.4% in the placebo and 7.6% in the topiramate groups to 7.1 and 6.7%, respectively, representing a 0.4 and 0.9% reduction from baseline, respectively (P < 0.001 vs. placebo). topiramate also significantly reduced blood pressure and urinary albumin excretion. Adverse events were predominantly neuropsychiatric or central and peripheral nervous system related. ### conclusions Topiramate CR treatment produced significant weight loss and meaningful improvements in A1C and blood pressure in obese patients with type 2 diabetes treated with diet and exercise or in combination with metformin . However, the central nervous system and psychiatric adverse event profile of topiramate CR makes it unsuitable for the treatment of obesity and diabetes.", "source": "https://pubmed.ncbi.nlm.nih.gov/17363756/"}
{"doc_id": "b9dfb483cf8d157dbce9404de8005b7c", "sentence": "To compare efficacy and toxicity of bolus application of chemotherapy protocol , oxaliplatin , fluorouracil ( bolus ) , leucovorin ( folfox ) between two groups of patients in the therapy of metastatic colorectal carcinoma ( mCRC ) .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 81, "end": 92, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "fluorouracil", "start": 95, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "leucovorin", "start": 120, "end": 130, "token_start": 19, "token_end": 20}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer.  To compare efficacy and toxicity of bolus application of chemotherapy protocol , oxaliplatin , fluorouracil ( bolus ) , leucovorin ( folfox ) between two groups of patients in the therapy of metastatic colorectal carcinoma ( mCRC ) . ### methods A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Be\u017eanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . ### results Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. ### conclusion Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/26276661/"}
{"doc_id": "9075a075ca48e05ac8a70fe6bf5e903d", "sentence": "Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone .", "spans": [{"span_id": 0, "text": "Verapamil", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "quinine", "start": 14, "end": 21, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination chemotherapy with cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) plus oral quinine and verapamil in patients with advanced breast cancer. We evaluated the question of whether the chemosensitizers verapamil and quinine given orally to breast cancer patients failing combination chemotherapy alone would result in additional clinical responses. In vitro studies reported here showed verapamil sensitization of Adriamycin resistance in 18.8% of fresh human breast cancer specimens tested. Patients (27) were first treated with cyclophosphamide, vincristine, Adriamycin and dexamethasone (CVAD) alone. Verapamil and quinine were added in patients with tumors failing to respond or progressing on CVAD alone . Following treatment with CVAD alone there were no complete remissions and 3 patients (11%) developed partial remissions lasting 5.5, 8, 10.5 months. With the addition of verapamil and quinine to the CVAD regimen, one patient (4%) developed a complete remission of 11.8 months duration and 4 additional patients (15%) developed partial remissions lasting 2.8, 17.3, 19 and > 40 months. Thus, the overall rate of CVAD sensitization by verapamil and quinine was 19%. Treatment with CVAD plus verapamil and quinine was generally well tolerated with observed toxicities including: myelosuppression, neuropathy, Cushingoid symptoms and tinnitus and/or dizziness due to quinine. We conclude that addition of the non-cytotoxic chemosensitizers verapamil and quinine to CVAD in patients failing CVAD alone results in additional clinical responses in a small percentage of patients, some with long term durations. The results of this study lend credence to the notion that non-cytotoxic chemosensitizers can enhance the clinical activity of combination chemotherapy and the search for more effective and less toxic chemosensitizers continues.", "source": "https://pubmed.ncbi.nlm.nih.gov/9116320/"}
{"doc_id": "b01ddd458e6d0f844ef2a2dabc1e9c0d", "sentence": "However , dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells .", "spans": [{"span_id": 0, "text": "dipyridamole", "start": 10, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "epirubicin", "start": 70, "end": 80, "token_start": 13, "token_end": 14}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[Studies on reversing effect of multidrug resistance by dipyridamole. II. Inhibition of epirubicin efflux from resistant cells by dipyridamole and its pharmacological effect]. We have previously reported that dipyridamole increases the cytotoxicity of epirubicin and alters the cell cycle in doxorubicin-resistant (P388/DOX) cells, increasing the accumulation of G2/M phase by blocking the cell cycle. In cultured cells, dipyridamole increased dose-dependently the intracellular accumulation of epirubicin in the resistant cells. Simultaneous exposure of the resistant cells to epirubicin and 100 microM dipyridamole resulted in a 4.2-fold increase in proportion to the control level of epirubicin after 60 min. dipyridamole inhibited the enhanced efflux of epirubicin in doxorubicin-resistant cells. However , dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells . In mice, lethal and bone marrow toxicity induced by epirubicin were potentiated by administration of high-dose of dipyridamole. In addition, in vivo results also demonstrated that dipyridamole in combination with epirubicin produced a significant reversal of the in vivo antitumor activity of epirubicin in mice bearing P388/DOX cells. These data imply the enhancement effects of dipyridamole on the efficacy and toxicity of epirubicin.", "source": "https://pubmed.ncbi.nlm.nih.gov/8721351/"}
{"doc_id": "acbfe42000da2810b6325717404141e6", "sentence": "This study aims to evaluate the potential role of combination therapy with docetaxel , flavopiridol , or 5-FU in modulating chemosensitivity and better understand how they might be used clinically .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 75, "end": 84, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "flavopiridol", "start": 87, "end": 99, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil. Clinical treatment of solid tumors with docetaxel, flavopiridol, or 5-fluorouracil (5-FU) often encounters undesirable side effects and drug resistance. This study aims to evaluate the potential role of combination therapy with docetaxel , flavopiridol , or 5-FU in modulating chemosensitivity and better understand how they might be used clinically . ### methods HCT116 colon cancer cells were treated with docetaxel, flavopiridol, and 5-FU in several different administrative schedules in vitro, either sequentially or simultaneously. Cell survival was measured by MTT assay. The activity of caspase-3 was determined by caspase-3 assays and the soft agar colony assay was used to test the colony formation of HCT116 cells in soft agar. We also established xenograft models to extend in vitro observations to an in vivo system. ### results The maximum cytotoxicity was found when human colon cancer HCT116 cells were treated with docetaxel for 1 h followed by flavopiridol for 24 h and 5-FU for another 24 h. This sequential combination therapy not only inhibits tumor cell growth more strongly compared to other combination therapies but also significantly reduces colony formation in soft agar and augments apoptosis of HCT116 cells. Sequencing of docetaxel followed 1 h later by flavopiridol, followed 24 h later by 5-FU in xenograft models, also resulted in delayed tumor growth and higher survival rate. ### conclusion These results highlight the importance of an administrative schedule when combining docetaxel with flavopiridol and 5-FU, providing a rationale explanation for its development in clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/17007746/"}
{"doc_id": "caa3da2a86157dc41125f56205a1a5d4", "sentence": "Dipyridamole or dipyridamole and acetylsalicyclic acid were used in 22 pregnancies .", "spans": [{"span_id": 0, "text": "Dipyridamole", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "dipyridamole", "start": 16, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "acetylsalicyclic acid", "start": 33, "end": 54, "token_start": 4, "token_end": 6}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "The course of pregnancy in patients with artificial heart valves. Twenty-five women with prosthetic heart valves (PHV) became pregnant 28 times. Twenty-six of the pregnancies occurred while the patients were receiving oral anticoagulants and these were continued throughout in 25 pregnancies. Dipyridamole or dipyridamole and acetylsalicyclic acid were used in 22 pregnancies . Eighteen infants were delivered, one with a congenital corneal leukoma; none had hemorrhagic complications; their psychomotor development was normal. Nine women aborted 10 times, including patients with two PHV, pelvic trauma and self-induced abortion. We could not detect excess anticoagulation in eight of the nine who had spontaneous losses; excess anticoagulation occurred five weeks before an abortion. There were no maternal deaths despite numerous complications; in two women, brain embolism was related to short interruptions of anticoagulation. The details of management are mentioned. We lack enough evidence to suggest routine sterilization, routine interruption of coumarin therapy during pregnancy or routine interruption of pregnancy in women with certain types and models of PHV; however, pregnancy under such conditions, plus antithrombotic therapy, carries a high risk for the product and a potential teratogenic effect. Women with one or two PHV can have children if their management is closely supervised and if extreme care is taken with the use of oral anticoagulants.", "source": "https://pubmed.ncbi.nlm.nih.gov/973644/"}
{"doc_id": "ea455dd922639a395f7675d9beb480a2", "sentence": "Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer ; however , few data exist for this regimen in inflammatory breast cancer .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "trastuzumab", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study.  Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer ; however , few data exist for this regimen in inflammatory breast cancer . In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. ### methods In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged \u2265 18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00717405. ### findings Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63\u00b75%, 95% CI 49\u00b74-77\u00b75). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. ### interpretation Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed. ### funding Roche (France).", "source": "https://pubmed.ncbi.nlm.nih.gov/22377126/"}
{"doc_id": "17a298de5c61f56d978d1ac05164d0d5", "sentence": "The frequency of their resistance to penicillin and ampicillin was 76.8 % ( 159/207 ) , followed by erythromycin ( 56 % , 116/207 ) , trimethoprim-sulfamethoxazole ( 28.5 % , 59/207 ) , chloramphenicol ( 24.2 % , 50/207 ) , kanamycin ( 19.8 % , 41/207 ) , and doxycycline ( 1.4 % , 3/207 ) .", "spans": [{"span_id": 0, "text": "ampicillin", "start": 52, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "erythromycin", "start": 100, "end": 112, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "chloramphenicol", "start": 186, "end": 201, "token_start": 34, "token_end": 35}, {"span_id": 3, "text": "kanamycin", "start": 224, "end": 233, "token_start": 42, "token_end": 43}, {"span_id": 4, "text": "doxycycline", "start": 260, "end": 271, "token_start": 51, "token_end": 52}], "rels": [], "paragraph": "Antimicrobial susceptibilities of exfoliative toxigenic and non-toxigenic Staphylococcus hyicus strains in Japan. Staphylococcus hyicus isolates (n=207), including 150 exfolitative toxigenic and 57 non-toxigenic strains, were examined for their susceptibility to 13 antimicrobial agents by using the dehydrated 96-well MIC panel system. The frequency of their resistance to penicillin and ampicillin was 76.8 % ( 159/207 ) , followed by erythromycin ( 56 % , 116/207 ) , trimethoprim-sulfamethoxazole ( 28.5 % , 59/207 ) , chloramphenicol ( 24.2 % , 50/207 ) , kanamycin ( 19.8 % , 41/207 ) , and doxycycline ( 1.4 % , 3/207 ) . Resistance to chloramphenicol and trimethoprim-sulfamethoxazole was significantly higher in toxigenic strains than non-toxigenic strains (p<0.01), whereas kanamycin and erythromycin resistance was significantly higher in non-toxigenic strains (p<0.01 and <0.05, respectively). Resistance to two or more antimicrobials was observed in 85.5% (177/207) of total strains, with a significantly higher occurrence in toxigenic strains (89.3%, 134/150 vs. 75.4%, 43/57; p<0.05).", "source": "https://pubmed.ncbi.nlm.nih.gov/19498301/"}
{"doc_id": "7a43db7cf232e74d3891f1026462d914", "sentence": "Rats were distributed into three groups ( n = 5 ) according to the drug studied namely , 50 % enantiomeric excess bupivacaine mixture ( 5 \u03bcg/mL ) ; pancuronium ( 2 \u03bcg/mL ) ; 50 % enantiomeric excess bupivacaine mixture + pancuronium .", "spans": [{"span_id": 0, "text": "bupivacaine", "start": 114, "end": 125, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "pancuronium", "start": 148, "end": 159, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "bupivacaine", "start": 199, "end": 210, "token_start": 39, "token_end": 40}, {"span_id": 3, "text": "pancuronium", "start": 221, "end": 232, "token_start": 42, "token_end": 43}], "rels": [{"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Effect of 50% enantiomeric excess bupivacaine mixture combined with pancuronium on neuromuscular transmission in rat phrenic nerve-diaphragm preparation; a pilot study. Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium. ### methods Rats were distributed into three groups ( n = 5 ) according to the drug studied namely , 50 % enantiomeric excess bupivacaine mixture ( 5 \u03bcg/mL ) ; pancuronium ( 2 \u03bcg/mL ) ; 50 % enantiomeric excess bupivacaine mixture + pancuronium . The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture. ### results A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture. ### conclusion A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action.", "source": "https://pubmed.ncbi.nlm.nih.gov/26755834/"}
{"doc_id": "fff07e1e94c80840f59c9458ee5f7de2", "sentence": "Blood was sampled immediately prior to premedication ( temazepam ) , after induction of anaesthesia ( fentanyl and thiopentone ) and at 10-minute intervals until the end of the procedure ( N2O maintenance , vecuronium relaxation ) .", "spans": [{"span_id": 0, "text": "temazepam", "start": 55, "end": 64, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "fentanyl", "start": 102, "end": 110, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "thiopentone", "start": 115, "end": 126, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "vecuronium", "start": 207, "end": 217, "token_start": 34, "token_end": 35}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "The plasma ACTH, AVP, CRH and catecholamine responses to conventional and laparoscopic cholecystectomy. We compared the responses of the stress hormones, cortisol, ACTH, vasopressin (AVP), corticotrophin releasing hormone (CRH) and catecholamines to elective conventional and laparoscopic cholecystectomy. ### design A right upper quadrant transverse incision was used for conventional cholecystectomy, and four 1-2-cm incisions for the laparoscopic procedure (for insertion of surgical instruments, diathermy, fibreoptic telescope and light source, and carbon dioxide insufflation). Blood was sampled immediately prior to premedication ( temazepam ) , after induction of anaesthesia ( fentanyl and thiopentone ) and at 10-minute intervals until the end of the procedure ( N2O maintenance , vecuronium relaxation ) . A blood sample was taken after reversal, and then at 10-minute intervals for 50 minutes. Plasma sodium and blood pressure were measured at similar intervals. Results are expressed as mean +/- standard error. ### patients Twelve patients were studied (six in each group). ### measurements Peptide hormones were measured by radioimmunoassay, cortisol by ELISA and catecholamines by HPLC. ### results The mean premedication hormone values for the conventional and laparoscopic procedures did not increase significantly after induction of anaesthesia. Within 10 minutes of the first incision, however, there was a marked concordant rise in mean plasma ACTH and AVP levels for both procedures (conventional: ACTH, from a premedication value of 10.2 +/- 1.7 to 80.1 +/- 14.3 pmol/l, AVP from 1.2 +/- 0.4 to 117 +/- 24 pmol/l, P < 0.01 for both hormones; laparoscopic: ACTH from 5.8 +/- 2.6 to 55.1 +/- 26.0 pmol/l, AVP from 1.6 +/- 0.11 to 49.2 +/- 27.09 pmol/l). At the end of both types of operation mean levels of ACTH and AVP were still elevated, although the ACTH: AVP ratio had increased. Greater variability in ACTH and AVP responses was seen in the laparoscopic than in the conventional procedure, three patients showing a relatively small response to surgery. Total secretion of ACTH during both types of surgery was not significantly less both during (P < 0.05), and after (P < 0.01) laparoscopic surgery. For both procedures, the timing of AVP and ACTH peaks was significantly related (P < 0.002). A small but significant rise in CRH was observed 30 minutes after the start of surgery for both procedures P < 0.05). The timing of CRH and ACTH peaks was unrelated. The maximum mean plasma cortisol level for the conventional procedure (1268 +/- 147 nmol/l) was reached 20 minutes after reversal of anaesthesia and remained at this level until the end of sampling. The cortisol response was comparable during the laparoscopic procedure but was beginning to fall at 60 minutes post-operatively. Plasma adrenaline responses to the two types of surgery were not significantly different, but the plasma total noradrenaline response to laparoscopic surgery as indicated by the response area during the first 20 minutes was significantly increased (P < 0.02). Plasma sodium, renin activity and initial systolic blood pressure fall were not significantly different during the two procedures. ### conclusions For both procedures, the peak of ACTH secretion after incision is likely to be AVP dependent, and the timing of peak levels of these two hormones was significantly related. Subsequent ACTH secretion may be the result of an interaction between AVP and CRH. Laparoscopic cholecystectomy results in a smaller AVP rise than does the conventional procedure, and plasma AVP falls more rapidly post-operatively. During the period of observation, ACTH, CRH, cortisol and adrenaline responses were not significantly lessened by the laparoscopic approach, but there was a significant increase in the noradrenaline response. Stress hormone monitoring may assist further improvements in surgical technique.", "source": "https://pubmed.ncbi.nlm.nih.gov/8392916/"}
{"doc_id": "f953f0ee4e567cff2bf69362b2ed6d37", "sentence": "This study was performed to compare the efficacy of peritonsillar infiltration of bupivacaine , tramadol and combination of bupivacaine-tramadol in post-tonsillectomy pain .", "spans": [{"span_id": 0, "text": "bupivacaine", "start": 82, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "tramadol", "start": 96, "end": 104, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Preemptive peritonsillar infiltration with bupivacaine in combination with tramadol improves pediatric post-tonsillectomy pain better than using bupivacaine or tramadol alone: A randomized, placebo-controlled, double blind clinical trial. Post-tonsillectomy pain is one of the most common problems after anesthesia, therefore use of a good anesthesia technique with minimum side effect is an important aim. This study was performed to compare the efficacy of peritonsillar infiltration of bupivacaine , tramadol and combination of bupivacaine-tramadol in post-tonsillectomy pain . ### Materials And Methods In a double blind trial 120 ASA I and II children condidated for tonsillectomy were randomized into four groups: Peritonsillar infiltration with bupivacaine 1 mg/kg in Group B, tramadol 2 mg/kg in Group T, combination of bupivacaine-tramadol in Group BT and saline in Group C was done. ### results Until 60 minutes in the recovery room, control of pain in the first three groups were better than Group C (P < 0.05) and in the third group it was better than others. Four hours after surgery, control of pain was better in the second and third groups in comparison to Groups B and Group C (P <0.05) and was better in the third group in comparison to the second group. Then, 24 hours after that, only in the group III the control of pain was effective (P < 0.05). ### conclusions In this study we showed that peritonsillar infiltration with combination of bupivacain-tramadol provided less post surgery pain compared with infiltration of bupivacaine and tramadol alone in adenotonsillectomy of children.", "source": "https://pubmed.ncbi.nlm.nih.gov/26322280/"}
{"doc_id": "4dd39ba2d55cff79d702f364d08a7ac0", "sentence": "The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 51, "end": 60, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "mitomycin", "start": 112, "end": 121, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report. To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone. ### Methods And Materials Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66-70 Gy. The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol. Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients. ### results Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%-80%). DFS at the median follow-up of 14 months was 60% (95% CI 43-77%) and OS 58% (95% CI 42-74%). ### conclusion From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/9719123/"}
{"doc_id": "85888116da06bb6c9a2ad7c9e1ea3c18", "sentence": "The study objectives were to evaluate the safety , tolerability , and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced , recurrent , or metastatic colorectal cancer .", "spans": [{"span_id": 0, "text": "dulanermin", "start": 112, "end": 122, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "FOLFOX6", "start": 152, "end": 159, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "bevacizumab", "start": 164, "end": 175, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.  The study objectives were to evaluate the safety , tolerability , and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced , recurrent , or metastatic colorectal cancer . ### Patients And Methods A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. ### results In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). ### conclusions Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.", "source": "https://pubmed.ncbi.nlm.nih.gov/24075777/"}
{"doc_id": "cdca7eda69e96a52d1fdd56e49cf9261", "sentence": "Inhalatory beta2-mimetics with long-term action ( LABA ) , formoterol and salmeterol , possess a period of action longer than 12 hours .", "spans": [{"span_id": 0, "text": "formoterol", "start": 59, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "salmeterol", "start": 74, "end": 84, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "[A comparison of inhalatory beta2-mimetics with long-term action (formoterol vs. salmeterol)]. Asthma is a serious global health problem. People of all age groups in all countries of the world suffer from this chronic disease of the respiratory tract, which may have a very serious and sometimes fatal course. Most beta2-mimetics with a rapid onset of effect act for 4 to 6 hours. Inhalatory beta2-mimetics with long-term action ( LABA ) , formoterol and salmeterol , possess a period of action longer than 12 hours . formoterol and salmeterol represent great progress in asthma management, particularly in combination with inhalatory corticosteroids (IKS). Their effective bronchodilatory properties and long-term improvement of pulmonary functions are a great clinical contribution for the patients. Both formoterol and salmeterol are strong and effective beta2-agonists, but their different chemical structures produce different pharmacological properties. Due to the fact that the onset of the effect of salmeterol is slower, it should not be used to treat acute symptoms or quickly deteriorating asthma. formoterol exerts a rapid onset of the effect and high internal activity, thanks to which it can be used for relieving treatment. The present paper aims to characterize and compare the properties of long-term acting beta2-mimetics, with detailed focus on their two representatives, formoterol and salmeterol.", "source": "https://pubmed.ncbi.nlm.nih.gov/17128593/"}
{"doc_id": "82bcf2ff9f17f26be78f8edd00b37e44", "sentence": "This study evaluates the possible protective effects of the calcium channel blocker amlodipine , the angiotensin converting enzyme inhibitor lisinopril , and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity , aiming to understand its underlying hepatotoxic mechanisms .", "spans": [{"span_id": 0, "text": "amlodipine", "start": 84, "end": 94, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "lisinopril", "start": 141, "end": 151, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "allopurinol", "start": 189, "end": 200, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats. Exposure to chemotherapeutic agents such as acetaminophen may lead to serious liver injury. Calcium deregulation, angiotensin II production and xanthine oxidase activity are suggested to play mechanistic roles in such injury. ### objective This study evaluates the possible protective effects of the calcium channel blocker amlodipine , the angiotensin converting enzyme inhibitor lisinopril , and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity , aiming to understand its underlying hepatotoxic mechanisms . ### Material And Methods Animals were allocated into a normal control group, a acetaminophen hepatotoxicity control group (receiving a single oral dose of acetaminophen; 750\u00a0mg/kg/day), and four treatment groups receive N-acetylcysteine (300\u00a0mg/kg/day; a reference standard), amlodipine (10\u00a0mg/kg/day), lisinopril (20\u00a0mg/kg/day) and allopurinol (50\u00a0mg/kg/day) orally for 14 consecutive days prior to acetaminophen administration. Evaluation of hepatotoxicity was performed by the assessment of hepatocyte integrity markers (serum transaminases), oxidative stress markers (hepatic malondialdehyde, glutathione and catalase), and inflammatory markers (hepatic myeloperoxidase and nitrate/nitrite), in addition to a histopathological study. ### results Rats pre-treated with amlodipine, lisinopril or allopurinol showed significantly lower serum transaminases, significantly lower hepatic malondialdehyde, myeloperoxidase and nitrate/nitrite, as well as significantly higher hepatic glutathione and catalase levels, compared with acetaminophen control rats. Serum transaminases were normalized in the lisinopril treatment group, while hepatic myeloperoxidase was normalized in the all treatment groups. Histopathological evaluation strongly supported the results of biochemical estimations. ### conclusion amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.", "source": "https://pubmed.ncbi.nlm.nih.gov/27829805/"}
{"doc_id": "ae3ea590e974f8fa2cf4dadd985b54a2", "sentence": "The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) every three weeks , or no further treatment .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 146, "end": 162, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "methotrexate", "start": 165, "end": 177, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "fluorouracil", "start": 182, "end": 194, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results. Node-negative breast cancers are considered to comprise a subgroup which is amenable to cure with local-regional therapy alone. However, approximately 30% of affected patients present new disease manifestations within 10 years after surgery. To test the hypothesis that node-negative and estrogen receptor-negative breast cancer patients can benefit from adjuvant chemotherapy, a prospective randomized study was activated at the Istituto Nazionale Tumori of Milan in 1980. ### Patients And Methods The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) every three weeks , or no further treatment . Adjuvant chemotherapy was administered in the outpatient clinic of the Division of Medical Oncology. Patient characteristics were fairly well balanced between the two treatment groups except for primary tumor size: 58% of those with a primary tumor measuring > 2 cm in its largest diameter were randomized in the control group compared with 38% in the CMF regimen (P = 0.06). ### results At 12 years after surgery treatment outcome was significantly superior for patients given adjuvant CMF. The relapse-free survival rate was 71% (95% confidence limits (CL): 56-86) versus 43% (95% CL: 28-58), and total survival was 80% (95% CL: 68-92) versus 50% (95% CL: 34-66), respectively. The benefit from the administration of CMF was evident in all patient subsets and was not influenced by menopausal status. ### conclusions The long-term results of this trial of adjuvant combination chemotherapy confirm our previous observations on the efficacy of adjuvant chemotherapy in node-negative breast cancer patients at high risk of early disease relapse.", "source": "https://pubmed.ncbi.nlm.nih.gov/8839902/"}
{"doc_id": "28dd79429e758bc58daa73abfa6f418a", "sentence": "This study compared the efficacy of topical emedastine 0.05 % ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis .", "spans": [{"span_id": 0, "text": "emedastine", "start": 44, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "loratadine", "start": 100, "end": 110, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A randomized, double-blind, placebo-controlled comparison of emedastine 0.05% ophthalmic solution with loratadine 10 mg and their combination in the human conjunctival allergen challenge model. When selecting treatment for allergic conjunctivitis, a primary concern is whether to choose local or systemic therapy. ### objective This study compared the efficacy of topical emedastine 0.05 % ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis . ### methods This was a single-center, randomized, double-masked, placebo-controlled, parallel-group study. At visit 1, eligible subjects underwent conjunctival allergen challenge to identify the dose required to elicit a positive allergic reaction. After 7 days, subjects returned for visit 2, at which the allergen dose was confirmed. At visit 3, which took place 2 weeks later, subjects were randomized to receive either emedastine plus placebo capsules, loratadine plus placebo eyedrops, or both emedastine and loratadine. One hour after receiving study drug, subjects were challenged with allergen in both eyes. Allergic signs and symptoms were graded using standardized 5-point scales. The primary efficacy variables were itching and conjunctival hyperemia. Secondary efficacy variables were ciliary and episcleral hyperemia, chemosis, lid swelling, and tearing. Itching was graded subjectively at 3, 5, and 10 minutes after challenge. All other variables were assessed at 5, 10, and 20 minutes after challenge. ### results Eighty subjects (mean age, 43.68 years) were randomized to receive study treatment. Forty subjects (20 men, 20 women) received emedastine plus placebo capsules, 20 (7 men, 13 women) received loratadine plus placebo eyedrops, and 20 (12 men, 8 women) received both active treatments. In the between-group efficacy comparison at visit 3, the difference in itching and hyperemia scores between emedastine and loratadine was statistically significant at all time points (all, P < 0.05). Efficacy scores for the combination of emedastine and loratadine were significantly better than those for loratadine alone at 2 of 3 time points for itching and all time points for hyperemia (P < 0.05). The combination was significantly better than emedastine alone at I of 3 time points for itching and 6 of 9 time points for hyperemia (P < 0.05). ### conclusion In this study, emedastine was more efficacious than loratadine for reducing the itching and redness associated with allergic conjunctivitis in the human conjunctival allergen challenge model.", "source": "https://pubmed.ncbi.nlm.nih.gov/11952027/"}
{"doc_id": "0c769f1d92ebcf03959b819c250c55aa", "sentence": "Erythromycin , clindamycin and carbenicillin suppressed the donor flora permanently , as could be seen by the reduced colonization resistance .", "spans": [{"span_id": 0, "text": "Erythromycin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "clindamycin", "start": 15, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "carbenicillin", "start": 31, "end": 44, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Recontamination after gastrointestinal decontamination with non-absorbable antibiotics. In an attempt to restore the colonization resistance we administered anaerobic microflora to prevent an abnormal colonization of the intestine after antibiotic treatment had been discontinued. After the antibiotics had been discontinued and before the donor flora had been administered and had colonized the intestine, microorganisms present were \"unopposed\" and expanded to a high density. A mouse model was used to investigate which antibiotics negatively influenced the donor flora and reduced the colonization resistance when administered intraperitoneally. Erythromycin , clindamycin and carbenicillin suppressed the donor flora permanently , as could be seen by the reduced colonization resistance . benzylpenicillin, ampicillin, doxycycline and the combination gentamicin-cephalothin affected the colonization resistance as long as these agents were present. gentamicin alone and cephalothin and oxytetracycline had no effect on the colonization resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/6795128/"}
{"doc_id": "a44bb4123bef8777f41094293cb87a41", "sentence": "Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis , induced by nivolumab plus ipilimumab .", "spans": [{"span_id": 0, "text": "Mycophenolate", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "nivolumab", "start": 126, "end": 135, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "ipilimumab", "start": 141, "end": 151, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Successful mycophenolate mofetil treatment of a patient with severe steroid-refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer.  Mycophenolate mofetil resulted in rapid improvement of steroid-refractory immune-related adverse event hepatitis , induced by nivolumab plus ipilimumab .", "source": "https://pubmed.ncbi.nlm.nih.gov/33598220/"}
{"doc_id": "9a000d387e6e636fdacb29a6195a8626", "sentence": "The mannose-linked prodrugs of saquinavir and indinavir display therefore a most promising therapeutic potential provided that bioavailability , penetration into the HIV infected macrophages , and HIV-reservoirs of these PIs are improved .", "spans": [{"span_id": 0, "text": "saquinavir", "start": 31, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "indinavir", "start": 46, "end": 55, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Synthesis and in vitro biological evaluation of mannose-containing prodrugs derived from clinically used HIV-protease inhibitors with improved transepithelial transport. In an approach to improve the pharmacological properties, safety and pharmacokinetic profiles, and their penetration into HIV reservoirs or sanctuaries, and consequently, the therapeutic potential of the current protease inhibitors (PIs) used in clinics, we investigated the synthesis of various mannose-substituted saquinavir, nelfinavir, and indinavir prodrugs, their in vitro stability with respect to hydrolysis, anti-HIV activity, cytotoxicity, and permeation through a monolayer of Caco-2 cells used as a model of the intestinal barrier. Mannose-derived conjugates were prepared in two steps, in good yields, by condensing an acid derivative of a protected mannose with the PIs, followed by deprotection of the sugar protecting group. With respect to hydrolysis, these PI prodrugs are chemically stable with half-life times in the 50-60 h range that are compatible with an in vivo utilization aimed at improving the absorption/penetration or accumulation of the prodrug in specific cells/tissues and liberation of the active free drug inside HIV-infected cells. These stabilities correlate closely with the low in vitro anti-HIV activity measured for those prodrugs wherein the coupling of mannose to the PIs was performed through the peptidomimetic PI's hydroxyl. Importantly, mannose conjugation to the PIs was further found to improve the absorptive transepithelial transport of saquinavir and indinavir but not of nelfinavir across Caco-2 cell monolayers, by contrast to glucose conjugation which had the opposite effect. The mannose-linked prodrugs of saquinavir and indinavir display therefore a most promising therapeutic potential provided that bioavailability , penetration into the HIV infected macrophages , and HIV-reservoirs of these PIs are improved .", "source": "https://pubmed.ncbi.nlm.nih.gov/17105238/"}
{"doc_id": "1082f766cc489eaa697664eb74af0378", "sentence": "Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine ( AZT ) .", "spans": [{"span_id": 0, "text": "nevirapine", "start": 78, "end": 88, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "zidovudine", "start": 134, "end": 144, "token_start": 18, "token_end": 19}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. Drug susceptibility and mutations in the reverse transcriptase (RT) gene were analyzed with 167 virus isolates from 38 patients treated with nevirapine, a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) RT. Resistant isolates emerged quickly and uniformly in all patients administered nevirapine either as monotherapy or in combination with zidovudine ( AZT ) . Resistance developed as early as 1 week, indicating rapid turnover of the virus population. The development of resistance was associated with the loss of antiviral drug activity as measured by CD4 lymphocyte counts and levels of HIV p24 antigen and RNA in serum. In addition to mutations at amino acid residues 103, 106, and 181 that had been identified by selection in cell culture, mutations at residues 108, 188, and 190 were also found in the patient isolates. Sequences from patient clones documented cocirculating mixtures of populations of different mutants. The most common mutation with monotherapy, tyrosine to cysteine at residue 181, was prevented from emerging by coadministration of AZT, which resulted in the selection of alternative mutations. The observations documented that, under selective drug pressure, the circulating virus population can change rapidly, and many alternative mutants can emerge, often in complex mixtures. The addition of a second RT inhibitor, AZT, significantly altered the pattern of mutations in the circulating population of HIV.", "source": "https://pubmed.ncbi.nlm.nih.gov/7509000/"}
{"doc_id": "250d6ed126d0eaf8fc10454a26a19069", "sentence": "Postoperative combination chemotherapy for six cycles with cisplatin ( 100 mg/m2 per day for 1 day every 3 weeks ) , bleomycin ( 15 units intravenously weekly for 18 weeks ) and etoposide ( 100 mg/m2 per day for 3 days every 3 weeks ) were given and the tumor responded dramatically .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 59, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "bleomycin", "start": 117, "end": 126, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "etoposide", "start": 178, "end": 187, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Huge retroperitoneal germinoma presenting with pathological fracture of the spine. Primary retroperitoneal germ cell tumors are extremely rare neoplasms. The most common presenting features are abdominal pain and palpable abdominal masses. Pathological fractures of the spine presenting as bilateral lower leg weakness are exceptionally rare. We describe a 16-year-old girl who developed progressive paraplegia after a minor falling injury. Radiological study demonstrated a huge retroperitoneal tumor with invasion of the T12 vertebral body and spinal canal. A posterior surgical approach was used to perform laminectomy (T12, L1), removal of the intraspinal tumor and internal fixation with transpedical screws (T10, T11 to L2,3), and posterolateral fusion. Postoperative combination chemotherapy for six cycles with cisplatin ( 100 mg/m2 per day for 1 day every 3 weeks ) , bleomycin ( 15 units intravenously weekly for 18 weeks ) and etoposide ( 100 mg/m2 per day for 3 days every 3 weeks ) were given and the tumor responded dramatically . The patient had fully recovered without evidence of sequelae or recurrence at 2 years after operation. To the authors' knowledge, this is the first case in which a huge retroperitoneal germinoma presented as pathological fracture of the spine and spinal cord compression. The effectiveness of the postoperative cisplatin-based chemotherapy against this tumor made major retroperitoneal surgery to remove the main tumor mass unnecessary is also demonstrated.", "source": "https://pubmed.ncbi.nlm.nih.gov/12635842/"}
{"doc_id": "9238a8d50acf022196b0df5ab094dc79", "sentence": "The other received chemotherapy including prednisone , vincristine , cytarabine and L-asparaginase , combined with intrathecal injections of methotrexate , dexamethasone and Ara-C and supporting treatment .", "spans": [{"span_id": 0, "text": "prednisone", "start": 42, "end": 52, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "vincristine", "start": 55, "end": 66, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "cytarabine", "start": 69, "end": 79, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "L-asparaginase", "start": 84, "end": 98, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "methotrexate", "start": 141, "end": 153, "token_start": 18, "token_end": 19}, {"span_id": 5, "text": "dexamethasone", "start": 156, "end": 169, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "[Renal tubular acidosis as an initial manifestation in children with malignant lymphoma]. Primary renal lymphoma is one of the malignant lymphomas that initially presents in the extra lymphonode, which is rarely seen in children. This study reported two cases of primary renal lymphoma in children who were definitively diagnosed by renal biopsy. Renal tubular acidosis was the initial manifestation in both cases. They were referred to the hospital with chief complaints of polydipsia, polyuria, debilitation, vomiting and anemia. Imaging and laboratory examinations showed bilateral renomegaly, hypocalcemia, hypophosphatemia, and metabolic acidosis. One of the patients discontinued therapy. The other received chemotherapy including prednisone , vincristine , cytarabine and L-asparaginase , combined with intrathecal injections of methotrexate , dexamethasone and Ara-C and supporting treatment . Twenty-three days after treatment, polydipsia and polyuria were relieved, and acidosis, kaliopenia and anemia were improved in the patient. There were no abnormal findings in the renal B-ultrasound re-examination. It was concluded that when a patient is suspected of renal lymphoma, diagnostic puncture and renal biopsy should be performed early. Early combined therapeutics including chemotherapy, radiation therapy, surgery and supporting treatments may result in a favorable prognosis in patients with this disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/18706173/"}
{"doc_id": "6ed6398f293569b074c6a6cdf21d3160", "sentence": "Then , neoadjuvant chemotherapy ( NAC ) consisting of a combination of 5-fluorouracil ( 5-FU ) , oxaliplatin , irinotecan , and leucovorin ( FOLFOXIRI ) was planned , followed by primary tumor resection .", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 71, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "oxaliplatin", "start": 97, "end": 108, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "irinotecan", "start": 111, "end": 121, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "leucovorin", "start": 128, "end": 138, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "A pathological complete response after neoadjuvant triplet chemotherapy for locally advanced transverse colon cancer. Perioperative chemotherapy could improve oncological outcomes for patients with advanced colon cancer. However, the effectiveness of triplet chemotherapy in the neoadjuvant setting is still unknown. ### Presentation Of Case A 61-year-old man was referred to our hospital due to abdominal distention. Abdominal computed tomography showed a huge, 18-cm mass in the right upper abdomen. Biopsy showed well-differentiated adenocarcinoma. Locally advanced transverse colon cancer T4b N2a M0 Stage IIIC was diagnosed. Considering the extensive invasion to surrounding organs and difficulties in achieving margin-negative surgery, an emergency ileostomy was performed first. Then , neoadjuvant chemotherapy ( NAC ) consisting of a combination of 5-fluorouracil ( 5-FU ) , oxaliplatin , irinotecan , and leucovorin ( FOLFOXIRI ) was planned , followed by primary tumor resection . After 6 courses of treatment, the primary tumor shrank remarkably. Finally, laparoscopic radical extended right hemi-colectomy was performed. There were no residual tumor cells in resected specimens, including the primary tumor and surrounding lymph nodes. The pathological diagnosis was complete response. ### conclusion A case of pathological complete response after neoadjuvant treatment followed by radical resection was reported. Further research is needed to confirm the appropriate indications for neoadjuvant FOLFOXIRI therapy for patients with LACC.", "source": "https://pubmed.ncbi.nlm.nih.gov/32535526/"}
{"doc_id": "893a4fe9446abfbc8679233b84a42857", "sentence": "Interestingly , aspirin not only significantly inhibited the growth of TNBC cells , but also attenuated YAP and \u03b2-catenin expression by upregulating the E3 ubiquitin ligase \u03b2-TrCP to abolished docetaxel and vinorelbine resistance .", "spans": [{"span_id": 0, "text": "aspirin", "start": 16, "end": 23, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "docetaxel", "start": 193, "end": 202, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "vinorelbine", "start": 207, "end": 218, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Aspirin attenuates YAP and \u03b2-catenin expression by promoting \u03b2-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer. The use of aspirin has been associated with reduced breast cancer risk, but it is litter known if aspirin overcomes chemoresistance in triple-negative breast cancer (TNBC). Herein, we demonstrated that changes in the expression of Yes-associated protein (YAP) and \u03b2-catenin might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity in TNBC patients. Inhibition of YAP or \u03b2-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against drug-resistant TNBC cells as well as the sensitivity of these cells to the agents in vitro and in vivo. Interestingly , aspirin not only significantly inhibited the growth of TNBC cells , but also attenuated YAP and \u03b2-catenin expression by upregulating the E3 ubiquitin ligase \u03b2-TrCP to abolished docetaxel and vinorelbine resistance . The combination of aspirin and docetaxel or vinorelbine remarkably inhibited the growth of drug-resistant TNBC cells in vitro and in vivo. Moreover, TNBC patients with high YAP and/or \u03b2-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or \u03b2-catenin expression. Collectively, our study discovered a novel role of aspirin based on its anticancer effect, and put forward some possible mechanisms of chemoresistance in TNBC. The combined use of aspirin and anti-microtubule drugs presented several promising therapeutic approaches for TNBC treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/32661222/"}
{"doc_id": "933527b89d2e939d859d3827c6181476", "sentence": "No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 18, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxorubicin", "start": 32, "end": 43, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination paclitaxel (Taxol) and doxorubicin therapy for metastatic breast cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a very active agent for the treatment of breast cancer, with associated complete response rates of 12% in patients with minimally pretreated metastatic disease. Simultaneous paclitaxel and doxorubicin administration by 72-hour continuous infusion in patients with previously untreated metastatic breast cancer has yielded an overall response rate of 72% with 8% complete responses. No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination . Two phase I studies from the M.D. Anderson Cancer Center (Houston, TX) and the University of Indiana (Indianapolis, IN) have shown that administration of a 24-hour paclitaxel infusion prior to doxorubicin results in a significantly higher incidence of mucositis than the reverse sequence. Preliminary pharmacokinetic studies from M.D. Anderson suggest that peak plasma concentration and clearance of doxorubicin are altered by pretreatment with 24-hour paclitaxel. In contrast, in an ongoing phase I study at the Istituto Nazionale Tumori in Milan, Italy, no differences in toxicities have been observed with the combination of intravenous bolus doxorubicin and 3-hour infusional paclitaxel administered by either sequence. Preclinical in vitro and in vivo studies suggest that the combination of paclitaxel and doxorubicin is associated with no or minimal additive antitumor effects. The modest complete response rates that have been observed in patients with metastatic breast cancer to date are in agreement with these observations. A randomized study of paclitaxel versus doxorubicin versus intravenous bolus doxorubicin followed by 24-hour paclitaxel is now being conducted by the Eastern Cooperative Oncology Group.", "source": "https://pubmed.ncbi.nlm.nih.gov/7939757/"}
{"doc_id": "24dcd3973e994e04cedf76aea5968ffc", "sentence": "Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide ( n = 18 ) and/or ifosfamide , carboplatin , and etoposide ( n = 7 ) .", "spans": [{"span_id": 0, "text": "rituximab", "start": 22, "end": 31, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "cytarabine", "start": 64, "end": 74, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "etoposide", "start": 79, "end": 88, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "ifosfamide", "start": 107, "end": 117, "token_start": 17, "token_end": 18}, {"span_id": 4, "text": "carboplatin", "start": 120, "end": 131, "token_start": 19, "token_end": 20}, {"span_id": 5, "text": "etoposide", "start": 138, "end": 147, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study. In order to describe relapsed B-cell non-Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the rituximab era, relapses in the French LMB2001 study were reviewed. ### methods Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B-cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C. ### results Median time to relapse after diagnosis was 4.5 months (range 2.4-13.6). Thirty-two patients received salvage therapy. Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide ( n = 18 ) and/or ifosfamide , carboplatin , and etoposide ( n = 7 ) . First-line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty-one patients received high-dose chemotherapy (HDC) followed by autologous (n\u00a0=\u00a013) or allogeneic (n\u00a0=\u00a08) transplant. With a median follow-up of 6.8 years, the 5-year survival rate after relapse was 36.4% (95% confidence interval [CI] 22-53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5-year survival rate of 75% (95% CI 46.8-91.1%) for patients in CR before HDC, 33% (95% CI 9.7-70%) for patients in partial remission, and 0% for nonresponders (P\u00a0=\u00a0.033). ### conclusion Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control.", "source": "https://pubmed.ncbi.nlm.nih.gov/31207026/"}
{"doc_id": "d1b822405fac9b02cb1858fa96693979", "sentence": "A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [ by 10 % , 8 % and 6 % ( p < 0.05 compared with baseline ) and 41 % , 40 % and 39 % ( p < 0.001 compared with baseline ) in simvastatin , simvastatin/ezetimibe and rosuvastatin groups , respectively ] .", "spans": [{"span_id": 0, "text": "simvastatin", "start": 227, "end": 238, "token_start": 51, "token_end": 52}, {"span_id": 1, "text": "rosuvastatin", "start": 267, "end": 279, "token_start": 55, "token_end": 56}], "rels": [], "paragraph": "Comparison of the effect of simvastatin versus simvastatin/ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia. Statins may exhibit anti-inflammatory and antioxidant effects. Whether different statins at equivalent doses or the combination of low-dose statin with ezetimibe have comparable anti-inflammatory and antioxidant effects is unknown. The aim of this study was to compare the effects of simvastatin, simvastatin/ezetimibe or rosuvastatin at equivalent low-density lipoprotein cholesterol lowering doses on inflammation and oxidative stress indices in subjects with hypercholesterolemia. ### methods This was a pre-specified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study. We enrolled one hundred and fifty three (n = 153) hypercholesterolemic subjects who were randomized to receive simvastatin 40 mg or simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg daily. Plasma 8-Epi prostaglandin F2 alpha (8-epiPGF2a), oxidized LDL (oxLDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass were measured at baseline and following 12 weeks of treatment. ### results A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [ by 10 % , 8 % and 6 % ( p < 0.05 compared with baseline ) and 41 % , 40 % and 39 % ( p < 0.001 compared with baseline ) in simvastatin , simvastatin/ezetimibe and rosuvastatin groups , respectively ] . In all treatment groups a significant reduction in total plasma Lp-PLA2 activity and mass was observed (by 36%, 31% and 38% and 36%, 32% and 32% for simvastatin, simvastatin/ezetimibe and rosuvastatin, respectively, p < 0.001 compared with baseline). No intergroup differences were observed. ### conclusions simvastatin 40 mg, simvastatin/ezetimibe 10/10 mg and rosuvastatin 10 mg significantly reduced 8-epiPGF2a, oxLDL and Lp-PLA2 activity and mass to a similar extent.", "source": "https://pubmed.ncbi.nlm.nih.gov/24125402/"}
{"doc_id": "780f78a0170826430ef2034760acb82d", "sentence": "Both mono and combination therapies achieved the primary efficacy parameters : lowered diastolic blood pressure ( at trough ) more than placebo , p < 01 ( except the 120 mg verapamil SR , NS , 0.5 mg trandolapril , 0.5/180 and 2/120 combinations , p < 05 ) , yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo .", "spans": [{"span_id": 0, "text": "verapamil", "start": 173, "end": 182, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "trandolapril", "start": 200, "end": 212, "token_start": 38, "token_end": 39}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Efficacy of combination therapy with trandolapril and verapamil sr in primary hypertension: a 4 x 4 trial design. The Trandolapril Study Group. The Joint National Committee V suggested that combination therapy can provide effective blood pressure control in patients with stage I-IV hypertension. This 4 x 4 factorial trial design assessed the efficacy of monotherapy with trandolapril-an ACE inhibitor, and verapamil SR-a calcium antagonist, each in a range of 3 doses as monotherapy, and in combination therapy in patients with stage I-III diastolic hypertension. After a 4-week, single-blind placebo treatment period, 746 patients in 39 study centers were randomized to 1 of the 16 double-blind treatments for 6 weeks (placebo, verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono and combination therapies achieved the primary efficacy parameters : lowered diastolic blood pressure ( at trough ) more than placebo , p < 01 ( except the 120 mg verapamil SR , NS , 0.5 mg trandolapril , 0.5/180 and 2/120 combinations , p < 05 ) , yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo . Combination therapy was more effective than monotherapy for sitting diastolic blood pressure 2/180, p < 01; 2/240 and 8/240, p < 05. There were no differences between active treatment groups and placebo as a percentage of patients having adverse reactions. trandolapril, 2 and 8 mg, appeared to have a greater incremental effect on the systolic blood pressure reduction of the combination than verapamil SR 180 and 240 mg.", "source": "https://pubmed.ncbi.nlm.nih.gov/9107443/"}
{"doc_id": "2b6693d5c27ba14a8015f09d746854cd", "sentence": "In metastastic patients , the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 45, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "methotrexate", "start": 167, "end": 179, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "vinblastine", "start": 182, "end": 193, "token_start": 29, "token_end": 30}, {"span_id": 3, "text": "doxorubicin", "start": 196, "end": 207, "token_start": 31, "token_end": 32}, {"span_id": 4, "text": "cisplatin", "start": 61, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 4], "is_context_needed": false}, {"class": "COMB", "spans": [1, 2, 3], "is_context_needed": true}], "paragraph": "[Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?]. Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients , the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) . For second-line treatment, vinflunine is the only approved therapeutic agent.", "source": "https://pubmed.ncbi.nlm.nih.gov/26077309/"}
{"doc_id": "d5d8fcd01d8db1d9d3739da1219f562a", "sentence": "In the last few years , a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC , including ceritinib ( LDK378 ) , alectinib ( RO5424802/CH5424802 ) , AP26113 , ASP3026 , TSR-011 , PF-06463922 , RXDX-101 , X-396 , and CEP-37440 .", "spans": [{"span_id": 0, "text": "ceritinib", "start": 135, "end": 144, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "alectinib", "start": 158, "end": 167, "token_start": 30, "token_end": 31}], "rels": [], "paragraph": "ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years , a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC , including ceritinib ( LDK378 ) , alectinib ( RO5424802/CH5424802 ) , AP26113 , ASP3026 , TSR-011 , PF-06463922 , RXDX-101 , X-396 , and CEP-37440 . Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.", "source": "https://pubmed.ncbi.nlm.nih.gov/25322323/"}
{"doc_id": "b5a06ce3b2c6a8e918a9ac3c2ff81e10", "sentence": "A randomized clinical trial of adjuvant chemotherapy with doxorubicin , ifosfamide , and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas ( SARCGYN study ) .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 58, "end": 69, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "ifosfamide", "start": 72, "end": 82, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "cisplatin", "start": 89, "end": 98, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A randomized clinical trial of adjuvant chemotherapy with doxorubicin , ifosfamide , and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas ( SARCGYN study ) . There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase \u2265 20% of 3-year PFS. ### methods Patients with FIGO stage \u2264 III US, physiological age \u2264 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m&sup2; d1, ifosfamide 3 g/m&sup2;/day d1-2, cisplatin 75 mg/m&sup2; d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment. ### results Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41). ### conclusion API adjuvant CT statistically increases the 3 year-DFS of patients with US.", "source": "https://pubmed.ncbi.nlm.nih.gov/23139262/"}
{"doc_id": "3af3c8177f3067d578e6e60e026f8a52", "sentence": "Combination therapy with irinotecan ( CPT-11 ) , 5-fluorouracil ( 5-FU ) and leucovorin is widely used for the treatment of metastatic colorectal cancer .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 25, "end": 35, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "leucovorin", "start": 77, "end": 87, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "5-fluorouracil", "start": 49, "end": 63, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Pharmacodynamic study of the Saltz regimen for metastatic colorectal cancer in a hemodialyzed patient.  Combination therapy with irinotecan ( CPT-11 ) , 5-fluorouracil ( 5-FU ) and leucovorin is widely used for the treatment of metastatic colorectal cancer . However, little is known about the safety of chemotherapy of malignancies in hemodialysis (HD) patients. We encountered a patient with colorectal carcinoma on HD. We decided to administer combination chemotherapy while monitoring the pharmacodynamics of the patient. ### Case Report A 74-year-old male received regular HD 3 times a week because of type 1 diabetes mellitus. He was diagnosed with stage IV colorectal cancer in November 2004. After sigmoidectomy, the patient received chemotherapy: a weekly schedule of CPT-11 (50 mg/m(2)) was administered followed by l-leucovorin (10 mg/m(2)) and 5-FU (400 mg/m(2)) just after HD. During the course, the plasma concentrations of both SN-38, an active metabolite of CPT-11, and 5-FU were not increased compared with those of patients with normal renal function. Our patient presented with grade III hematological toxicity that was easily recovered by granulocyte colony-stimulating factor. ### conclusion These data suggest that the dose-reduced Saltz regimen can be feasible for colorectal cancer patients receiving dialysis as postoperative adjuvant chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/17952001/"}
{"doc_id": "0b47114f991a5b292f543492d5a64fad", "sentence": "Long-term safety and outcome of fludarabine , cyclophosphamide and mitoxantrone ( FCM ) regimen in previously untreated patients with advanced follicular lymphoma : 12 years follow-up of a phase 2 trial .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 32, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "cyclophosphamide", "start": 46, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "mitoxantrone", "start": 67, "end": 79, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Long-term safety and outcome of fludarabine , cyclophosphamide and mitoxantrone ( FCM ) regimen in previously untreated patients with advanced follicular lymphoma : 12 years follow-up of a phase 2 trial . fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12\u00a0years, 52 patients eventually relapsed/progressed with 10\u00a0year progression-free survival (PFS) of 46\u00a0%. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9\u00a0% at 5 and 10\u00a0years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8\u00a0% at 5 and 10\u00a0years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10\u00a0years was 83\u00a0%. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.", "source": "https://pubmed.ncbi.nlm.nih.gov/28101592/"}
{"doc_id": "faf925d887ed6a4e48d9695fbf094b0e", "sentence": "After clinical improvement under vemurafenib monotherapy , four cycles of ipilimumab were additionally administered .", "spans": [{"span_id": 0, "text": "vemurafenib", "start": 33, "end": 44, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "ipilimumab", "start": 74, "end": 84, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "18F-FDG PET/CT longitudinal studies in patients with advanced metastatic melanoma for response evaluation of combination treatment with vemurafenib and ipilimumab. Sixteen BRAF-mutation positive, metastatic melanoma patients with highly advanced disease received combination therapy of vemurafenib and ipilimumab as an individual treatment decision. Our aim was to assess the role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (PET/CT) in the evaluation of the clinical benefit (CB) of this combination treatment. After clinical improvement under vemurafenib monotherapy , four cycles of ipilimumab were additionally administered . F-FDG PET/CT was performed before the start, after two cycles and after completion of the combined ipilimumab/vemurafenib treatment. PET-based patient response evaluation to treatment was based on the European Organization for Research and Treatment of Cancer and the PET Response Evaluation Criteria for Immunotherapy criteria. Progression-free survival (PFS) from the end of combination treatment was calculated. According to their best clinical response at the end of combination treatment, eight patients showed CB and eight patients had no-CB. Two patients revealed extraordinary good clinical outcome with PFS of more than 5 years. Overall, 13 out of 16 patients were correctly classified by the European Organization for Research and Treatment of Cancer and 15 out of 16 by the PET Response Evaluation Criteria for Immunotherapy criteria. Median PFS was 8.8 months among PET-responders and 3.6 months among nonresponders. During immunotherapy administration seven patients developed radiologic signs of immune-related adverse events (irAEs), with colitis and arthritis being the most frequent ones; these patients had a significantly longer PFS than those without irAEs (P=0.036). F-FDG PET/CT is a valuable tool for the evaluation of patients receiving a combination of targeted treatment and immunotherapy. The appearance of irAEs on PET/CT might correlate with benefit to immunotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/30653029/"}
{"doc_id": "2280600696c1c1d4dfb49c7feb372ecd", "sentence": "Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer ( TURANDOT ): primary endpoint results of a randomised , open-label , non-inferiority , phase 3 trial .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 17, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "bevacizumab", "start": 35, "end": 46, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "capecitabine", "start": 52, "end": 64, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer ( TURANDOT ): primary endpoint results of a randomised , open-label , non-inferiority , phase 3 trial . The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1\u00b704; 97\u00b75% repeated CI [RCI] -\u221e to 1\u00b769). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. ### methods In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR \u22651\u00b733) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. ### findings Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30\u00b72 months (95% CI 25\u00b76-32\u00b76 months) versus 26\u00b71 months (22\u00b73-29\u00b70), respectively. The stratified HR was 1\u00b702 (97\u00b75% RCI -\u221e to 1\u00b726; repeated p=0\u00b70070), indicating non-inferiority. The unstratified Cox model (HR 1\u00b713 [97\u00b75% RCI -\u221e to 1\u00b739]; repeated p=0\u00b7061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. ### interpretation bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. ### funding Roche.", "source": "https://pubmed.ncbi.nlm.nih.gov/27501767/"}
{"doc_id": "bd92e7ffac8bd34d9b66848f322ec216", "sentence": "She underwent rectectomy and adjuvant chemotherapy with fluorouracil , leucovorin plus oxaliplatin for stage IIIB rectal cancer .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 56, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "leucovorin", "start": 71, "end": 81, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "oxaliplatin", "start": 87, "end": 98, "token_start": 11, "token_end": 12}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Esophageal Metastasis from Rectal Cancer Successfully Treated with Fluorouracil-Based Chemotherapy with Bevacizumab: A Case Report and Review of the Literature. Esophageal metastasis from colorectal carcinoma is uncommon, and diagnosis of esophageal metastasis is difficult. We report a case of a 54-year-old woman with postoperative recurrence of rectal cancer metastasizing to the esophagus. She underwent rectectomy and adjuvant chemotherapy with fluorouracil , leucovorin plus oxaliplatin for stage IIIB rectal cancer . Three years later, she presented with dysphagia and cough. Computed tomography showed thickening of the esophagus wall, enlargement of the lymph nodes in the mediastinum and abdomen, and ground-glass opacities in the right lung. Endoscopy revealed a submucosal tumor of the midthoracic esophagus. Histopathological analysis of the tumor biopsy showed infiltration of adenocarcinoma cells into the stroma of the esophagus; tumor cells were positive for caudal type homeobox 2 and negative for thyroid transcription factor 1. A transbronchial biopsy indicated pulmonary lymphangitic carcinomatosis of rectal adenocarcinoma. Based on those findings, she was diagnosed with recurrent rectal cancer. She received fluorouracil-based chemotherapy plus bevacizumab, which ameliorated her symptoms and induced a durable response without severe adverse events. Diagnosis of esophageal metastasis from rectal cancer can thus be made by repeated biopsy. Furthermore, aggressive systemic treatment with fluorouracil-containing chemotherapy and bevacizumab is a treatment option for colorectal cancer patients with esophageal metastasis.", "source": "https://pubmed.ncbi.nlm.nih.gov/28626398/"}
{"doc_id": "b3a8d61ce1a9282b5cf5c5a4d0f54a18", "sentence": "We designed this phase II trial to evaluate the safety , tolerability , and efficacy of the combination of carboplatin , paclitaxel , cetuximab , and bevacizumab in chemotherapy-naive patients with advanced , nonsquamous NSCLC .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 107, "end": 118, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "paclitaxel", "start": 121, "end": 131, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "cetuximab", "start": 134, "end": 143, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "bevacizumab", "start": 150, "end": 161, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Phase II trial of carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab in advanced nonsquamous non-small-cell lung cancer: SWOG S0536. cetuximab and bevacizumab have each been demonstrated to prolong survival when added to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). However, the potential benefit of combining cetuximab and bevacizumab together with a platinum-based doublet had not been explored. We designed this phase II trial to evaluate the safety , tolerability , and efficacy of the combination of carboplatin , paclitaxel , cetuximab , and bevacizumab in chemotherapy-naive patients with advanced , nonsquamous NSCLC . ### methods Patients received with up to six cycles of carboplatin (area under curve 6), paclitaxel (200 mg/m(2)), cetuximab (400 mg/m(2) day 1 then 250 mg/m(2) weekly), and bevacizumab (15 mg/kg) every 21 days. Patients with an objective response or stable disease received maintenance cetuximab (250 mg/m(2) weekly) and bevacizumab (15 mg/kg every 21 days) until disease progression. The primary endpoint was safety as defined by the frequency and severity of hemorrhagic toxicities. Secondary endpoints included response rate, progression-free survival, overall survival, and toxicity. Molecular biomarkers were assessed in an exploratory manner. ### results The primary endpoint of grade 4 or higher hemorrhage of 2% (95% confidence interval: 0%-7%) met prespecified criteria for safety. One hundred ten patients were enrolled. There were four treatment-related deaths including lung hemorrhage (2), infection (1), and unknown (1). Median progression-free survival was 7 months and median overall survival was 15 months. The response rate was 56% with an overall disease control rate of 77%. ### conclusion This regimen was safe, feasible, and effective as a frontline treatment of advanced NSCLC, providing the basis for the ongoing phase III trial S0819.", "source": "https://pubmed.ncbi.nlm.nih.gov/24189513/"}
{"doc_id": "5f47b0d8abbede477b693d64fb8dd329", "sentence": "All patients underwent mexiletine monotherapy ( M-mono ) , propafenone monotherapy ( P-mono ) , low dose combination therapy ( low M+P ) , and full dose combination therapy ( full M+P ) .", "spans": [{"span_id": 0, "text": "mexiletine", "start": 23, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "propafenone", "start": 59, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Mexiletine and propafenone: a comparative study of monotherapy, low, and full dose combination therapy. The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-lead electrocardiogram (standard ECG), signal-averaged ECG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy ( M-mono ) , propafenone monotherapy ( P-mono ) , low dose combination therapy ( low M+P ) , and full dose combination therapy ( full M+P ) . Full M+P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M+P increased PQ interval and QRS duration to a lesser extent than P-mono and full M+P did. P-mono and full M+P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M+P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M+P, and 14 on full M+P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M+P, and full M+P were 46.4 +/- 9.0, 56.6 +/- 10.4, 64.4 +/- 9.2, and 71.4 +/- 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 +/- 17.7, 62.6 +/- 23.6, 87.5 +/- 6.2, and 92.1 +/- 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/1279613/"}
{"doc_id": "d531c7b35a8bc9c67dad085ae9b7d352", "sentence": "Cephalexin , 500 mg 4 times daily , plus trimethoprim-sulfamethoxazole , 320 mg/1600 mg twice daily , for 7 days ( n = 248 participants ) or cephalexin plus placebo for 7 days ( n = 248 participants ) .", "spans": [{"span_id": 0, "text": "Cephalexin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cephalexin", "start": 141, "end": 151, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "trimethoprim-sulfamethoxazole", "start": 41, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, \u03b2-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity. ### objective To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone. ### Design Setting And Participants Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012. ### interventions Cephalexin , 500 mg 4 times daily , plus trimethoprim-sulfamethoxazole , 320 mg/1600 mg twice daily , for 7 days ( n = 248 participants ) or cephalexin plus placebo for 7 days ( n = 248 participants ) . ### Main Outcomes And Measures The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%. ### results Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P\u2009=\u2009.50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, -1.0% to 15.5%; P\u2009=\u2009.07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly. ### Conclusions And Relevance Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed. ### Trial Registration clinicaltrials.gov Identifier: NCT00729937.", "source": "https://pubmed.ncbi.nlm.nih.gov/28535235/"}
{"doc_id": "77e0b10b4077f694602171ec11b8fbad", "sentence": "In the NALA trial , neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine .", "spans": [{"span_id": 0, "text": "neratinib", "start": 20, "end": 29, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "capecitabine", "start": 35, "end": 47, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "lapatinib", "start": 158, "end": 167, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "capecitabine", "start": 173, "end": 185, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "Neratinib plus capecitabine for the treatment of advanced HER2-positive breast cancer. Several agents are being developed for advanced HER2-positive breast cancer, such as potent tyrosine kinase inhibitors (TKI) targeting ErbB family receptors, novel antibody-drug conjugates, higher affinity anti-HER2 antibodies, among others. neratinib is an irreversible pan-HER (EGFR, ERBB2, and ERBB4) TKI being tested in early and advanced HER2-positive breast cancer. In the NALA trial , neratinib plus capecitabine led to increased PFS and time to intervention for central nervous system disease over the standard regimen of lapatinib plus capecitabine . The main adverse event in the neratinib arm was diarrhea, which mandates for prophylactic treatment with loperamide. ### Areas Covered In this review, we analyze and discuss preclinical and clinical data with neratinib plus capecitabine. We summarize efficacy and safety results from phase I/II and III trials, and discuss this regimen within the landscape of treatment for patients with HER2-positive metastatic breast cancer progressing after two lines of HER2-directed treatment. ### Expert Opinion neratinib plus capecitabine is a valid treatment option for patients with advanced HER2-positive breast cancer, after progression to at least two anti-HER2-based regimens. Given the multiple options that are being developed in this context, efforts should be employed to establish strong predictive biomarkers of efficacy to each drug and combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/32862744/"}
{"doc_id": "4a18483d052bd05090b82ed366d8e395", "sentence": "Since the patient had anemia , aspirin and cilostazol were discontinued after diagnosis .", "spans": [{"span_id": 0, "text": "aspirin", "start": 31, "end": 38, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "cilostazol", "start": 43, "end": 53, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[A Case of Ascending Colon Cancer with Essential Thrombocythemia]. Essential thrombocythemia(ET)is a rare myeloproliferative disorder characterized by thrombocytosis and a risk of thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Including our case, only 5 cases of c o l orectal cancer with ET have been reported in Japan. Herein, we report a case of colon cancer in an ET patient who underwent laparoscopic right hemicolectomy. Our perioperative management avoided complications such as thrombosis or bleeding. An 81-year-old woman developed bloody stools. She was previously diagnosed with ET 9 years ago. aspirin, cilostazol, and hydroxyurea(HU)were prescribed. Colonoscopy revealed a tumor at the ascending colon. Histopathological examination showed a well-differentiated tubular adenocarcinoma. Since the patient had anemia , aspirin and cilostazol were discontinued after diagnosis . HU was discontinued from the day before surgery to 2 days after surgery. enoxaparin was subcutaneously administered for 1 to 3 days after surgery. aspirin and cilostazol were resumed on the fourth day post-surgery. The patient could be discharged when her condition stabilizes with no thrombosis and bleeding after 8 days.", "source": "https://pubmed.ncbi.nlm.nih.gov/33468948/"}
{"doc_id": "f53ebc5049fa66cd3aa251a61ce9a16d", "sentence": "This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 96, "end": 108, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "etanercept", "start": 113, "end": 123, "token_start": 18, "token_end": 19}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Oral non-Hodgkin's lymphoma in a patient with rheumatoid arthritis treated with etanercept and methotrexate. Oral non-Hodgkin's lymphomas (O-NHLs) are a rare group of diverse lymphoid tissue malignancies and represent less than 5% of the oral cavity malignancies and 2% of all extra-nodal NHLs. Oral-NHLs affect the Waldeyer's-ring, the salivary glands, the bone of the jaws and the oral mucosa, their clinical appearance is very heterogeneous. Among the risk factors for NHLs are immunosuppression (primary or secondary), autoimmunity and inflammation. O-NHLs share the same risk factors. This case report describes a patient with O-NHL which was possibly linked to the combination of methotrexate and etanercept for the treatment of her rheumatoid arthritis . To our knowledge this is probably among the first cases of O-NHL with possible relation to the use of a Tumor Necrosis Factor (TNF) antagonist biological agent (etanercept). This case could contribute to the sensitization of the dentists for the signs and symptoms of this rare malignancy. It also underlines the need for thorough medical history and medication recording for all the dental patients. Key words:Lymphoma (oral) methotrexate, etanercept.", "source": "https://pubmed.ncbi.nlm.nih.gov/25810835/"}
{"doc_id": "2385bbe94c2fcb3c8d02c68a6e685707", "sentence": "In a prospective , pragmatic , randomised , parallel group study , 170 patients of mean ( SD ) age 37 ( 12 ) years with acute asthma ( peak expiratory flow ( PEF ) 212 ( 80 ) l/min ) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS .", "spans": [{"span_id": 0, "text": "prednisolone", "start": 247, "end": 259, "token_start": 50, "token_end": 51}, {"span_id": 1, "text": "salbutamol", "start": 285, "end": 295, "token_start": 54, "token_end": 55}, {"span_id": 2, "text": "prednisolone", "start": 335, "end": 347, "token_start": 63, "token_end": 64}, {"span_id": 3, "text": "salbutamol", "start": 368, "end": 378, "token_start": 67, "token_end": 68}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomised pragmatic comparison of UK and US treatment of acute asthma presenting to hospital. Systemic corticosteroids and inhaled beta(2) agonists are accepted first line treatments for acute severe asthma, but there is no consensus on their optimum dosage and frequency of administration. American regimens include higher initial dosages of beta(2) agonists and corticosteroids than UK regimens. ### methods In a prospective , pragmatic , randomised , parallel group study , 170 patients of mean ( SD ) age 37 ( 12 ) years with acute asthma ( peak expiratory flow ( PEF ) 212 ( 80 ) l/min ) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS . ### results Outcome measures were: deltaPEF at 1 hour (BTS 89 l/min, US 106 l/min, p=0.2, CI -8 to 41) and at 2 hours (BTS 49 l/min, US 101 l/min, p<0.0001, CI 28 to 77); time to discharge if admitted (BTS 4 days, US 4 days); rates of achieving discharge PEF (>60%) at 2 hours (BTS 64%, US 78%, p=0.04); time to regain control of asthma as measured by PEF >/=80% best with salbutamol leads to a greater immediate improvement in PEF but the degree of recovery at 24 hours and speed of recovery thereafter is achieved as effectively with lower corticosteroid doses as recommended in the British guidelines.", "source": "https://pubmed.ncbi.nlm.nih.gov/12454298/"}
{"doc_id": "e4e7a7e096b8a824afdb91ec6603eba7", "sentence": "We report a case of a 78-year-old white male ( weight , 90 kg ) presented to the Department of Medical Oncology and Hematology , Istituto Clinico Humanitas , Rozzano , Milan , Italy , with refractory MM immunoglobulin G kappa ( IgGkappa ) , Durie-Salmon Stage IIA , with progressive renal failure after an oral melphalan , prednisone , and thalidomide regimen ( 4 mg/m2.d , 40 mg/m2.d for 7 days every 6 weeks , and 100 mg/d , respectively ) .", "spans": [{"span_id": 0, "text": "melphalan", "start": 311, "end": 320, "token_start": 56, "token_end": 57}, {"span_id": 1, "text": "prednisone", "start": 323, "end": 333, "token_start": 58, "token_end": 59}, {"span_id": 2, "text": "thalidomide", "start": 340, "end": 351, "token_start": 61, "token_end": 62}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function. Multiple myeloma (MM) is a hematologic neoplasia characterized by the monoclonal proliferation of bone marrow plasma cells. Renal failure occurs in 20% to 30% of MM patients at diagnosis and in >50% with an advanced form of the disease. For those with advanced MM, often a high-risk group of patients with poor prognosis, salvage treatment for renal failure needs to avoid nephrotoxic drugs. ### Case Summary We report a case of a 78-year-old white male ( weight , 90 kg ) presented to the Department of Medical Oncology and Hematology , Istituto Clinico Humanitas , Rozzano , Milan , Italy , with refractory MM immunoglobulin G kappa ( IgGkappa ) , Durie-Salmon Stage IIA , with progressive renal failure after an oral melphalan , prednisone , and thalidomide regimen ( 4 mg/m2.d , 40 mg/m2.d for 7 days every 6 weeks , and 100 mg/d , respectively ) . The patient had documented increments of serum monoclonal component (M-protein), anemia, and renal failure with Bence Jones proteinuria (serum creatinine, 2.9 mg/dL; creatinine clearance, 30 mL/min; hemoglobin, 10.9 g/dL; serum IgGkappa M-protein, 3.9 g/dL; proteinuria 3.5 g/d;light-chain level in urine, 1.2 g/L). After 2 cycles with bortezomib at a reduced dose (1.0 mg/m2 twice weekly for 2 weeks followed by a 10-day rest period) to evaluate tolerability and renal toxicity, the patient completed another 3 cycles at the standard dose (1.3 mg/m2) in combination with dexamethasone (20 mg on the day of bortezomib administration and the day after). This led to an improvement of the renal function with a reduction of serum and urinary M-protein (serum creatinine 1.4 mg/dL; serum IgGkappa M-protein, 2.9 g/dL; proteinuria, 2 g/d; kappa light-chain level in urine, 0.7 g/L). The patient developed thrombocytopenia but did not suffer from some of the more severe adverse events associated with bortezomib, such as infection or peripheral neuropathy, even at full dose. ### conclusion We report an elderly patient with refractory MM and progression with renal failure who responded to bortezomib treatment. bortezomib was well tolerated in this patient.", "source": "https://pubmed.ncbi.nlm.nih.gov/16860177/"}
{"doc_id": "15b396da057bf3eb9a6ad966cb34cf79", "sentence": "Following an intravitreal injection of ranibizumab , off-label administration of intravitreal dexamethasone was considered to reduce the edema .", "spans": [{"span_id": 0, "text": "ranibizumab", "start": 39, "end": 50, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "dexamethasone", "start": 94, "end": 107, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Effect of intravitreal dexamethasone on macular edema in von Hippel-Lindau disease assessed using swept-source optical coherence tomography: a case report. Von Hippel-Lindau disease is a rare hereditary syndrome caused by germinal mutations in a von Hippel-Lindau tumor-suppressing gene. Retinal hemangioblastoma is the ocular hallmark lesion of von Hippel-Lindau disease. ### Case Presentation A 20-year-old Caucasian woman presented to our institution with painless visual impairment in the right eye. A fundus ophthalmoscopic evaluation and swept-source optical coherence tomographic examination revealed a retinal hemangioblastoma associated with cystoid macular edema. On the basis of the clinical ocular findings and genetic analysis, von Hippel-Lindau disease was diagnosed. Following an intravitreal injection of ranibizumab , off-label administration of intravitreal dexamethasone was considered to reduce the edema . An almost complete resolution of the edema in the macular area was observed 1 week after the injection. Finally, laser photocoagulation and transconjunctival cryotherapy were performed; the patient developed \"ablatio fugax\" after cryotherapy. ### conclusions In our experience, intravitreal dexamethasone administration has proven to be a useful tool for reducing retinal hemangioblastoma-related macular edema in von Hippel-Lindau disease and may be considered a potentially valuable treatment that can be used in combination with other therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/30185211/"}
{"doc_id": "39c5dd43cb040ee8f6350c3f2071e992", "sentence": "Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies .", "spans": [{"span_id": 0, "text": "Rabeprazole", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "omeprazole", "start": 27, "end": 37, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Rabeprazole: a review of its use in acid-related gastrointestinal disorders. rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies . One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.", "source": "https://pubmed.ncbi.nlm.nih.gov/10551440/"}
{"doc_id": "aea6e5bbd17d903de73866d5840bb07f", "sentence": "We performed a prospective , preplanned , pooled analysis of six randomized , phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) or CAPOX ( capecitabine and oxaliplatin ) administered for 3 months , as compared with 6 months .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 198, "end": 210, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "leucovorin", "start": 213, "end": 223, "token_start": 33, "token_end": 34}, {"span_id": 2, "text": "oxaliplatin", "start": 230, "end": 241, "token_start": 36, "token_end": 37}, {"span_id": 3, "text": "capecitabine", "start": 255, "end": 267, "token_start": 41, "token_end": 42}, {"span_id": 4, "text": "oxaliplatin", "start": 272, "end": 283, "token_start": 43, "token_end": 44}], "rels": [{"class": "POS", "spans": [3, 4], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. ### methods We performed a prospective , preplanned , pooled analysis of six randomized , phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) or CAPOX ( capecitabine and oxaliplatin ) administered for 3 months , as compared with 6 months . The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. ### results After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). ### conclusions Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).", "source": "https://pubmed.ncbi.nlm.nih.gov/29590544/"}
{"doc_id": "c2b21e29d41a7690c76cf73efa04e478", "sentence": "Growth inhibition and apoptosis were significantly ( P < 0.05 ) higher in BxPC-3 , HPAC , and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib .", "spans": [{"span_id": 0, "text": "celecoxib", "start": 120, "end": 129, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "erlotinib", "start": 134, "end": 143, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "celecoxib", "start": 175, "end": 184, "token_start": 30, "token_end": 31}, {"span_id": 3, "text": "erlotinib", "start": 188, "end": 197, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy. The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 micromol/L), celecoxib (1 and 10 micromol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-kappaB activation. Growth inhibition and apoptosis were significantly ( P < 0.05 ) higher in BxPC-3 , HPAC , and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib . However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 micromol/L) and celecoxib (10 micromol/L) compared with celecoxib- or erlotinib-treated cells. celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-kappaB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-kappaB inactivation contributes to the potentiation of erlotinib by celecoxib.", "source": "https://pubmed.ncbi.nlm.nih.gov/16373709/"}
{"doc_id": "d85f44a5e953a3b8e43b5bf99e30a3b5", "sentence": "Subcutaneous aspirin , 100 mg/kg , which reduced duodenal PGE2 generation to a greater degree than either ulcerogen , given in conjunction with pentagastrin , did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS )", "spans": [{"span_id": 0, "text": "aspirin", "start": 13, "end": 20, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "pentagastrin", "start": 144, "end": 156, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Role of prostanoids in experimental duodenal ulcer in rat. The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation was 235 +/- 25 and 832 +/- 40 ng/g/min, respectively, whereas full-thickness duodenal PGE2 and PGI2 generation was 665 +/- 46 and 662 +/- 49 ng/g/min, respectively. Over an intraperitoneal dose range of 0-25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm2) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE2 generation, while having no effect on PGI2 generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE2 generation 39% compared to control values. In fed male rats, gastric mucosal PGE2 and PGI2 generation was 179 +/- 18 and 813 +/- 61 ng/g/min, respectively, whereas duodenal PGE2 and PGI2 generation was 321 +/- 27 and 454 +/- 38 ng/g/min, respectively. Duodenal ulceration (7.7 +/- 2.3 mm2) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE2 generation compared to control values, while having no effect on PGI2 generation. Subcutaneous aspirin , 100 mg/kg , which reduced duodenal PGE2 generation to a greater degree than either ulcerogen , given in conjunction with pentagastrin , did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS )", "source": "https://pubmed.ncbi.nlm.nih.gov/3131076/"}
{"doc_id": "4c286a03b81e5883cc213110576889fa", "sentence": "Prevalence of metronidazole , clarithromycin , and amoxicillin resistance is high in developing world including Africa .", "spans": [{"span_id": 0, "text": "metronidazole", "start": 14, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "clarithromycin", "start": 30, "end": 44, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "amoxicillin", "start": 51, "end": 62, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "The magnitude of antibiotic resistance to Helicobacter pylori in Africa and identified mutations which confer resistance to antibiotics: systematic review and meta-analysis. Worldwide Helicobacter pylori (H.pylori) treatment is of great challenge due to increased antibiotic resistance. The burden of H. pylori antibiotic resistance in Africa is high with unclear information regarding the real magnitude. This systematic review and meta-analysis was conducted to investigate the magnitude of H.pylori antibiotic resistance in Africa to gain insight of the extent of the problem among H.pylori na\u00efve treatment patients. ### method The search was performed in the academic databases, Embase, PubMed, Web of Science and Africa Wide Information. ProQuest Dissertation and Theses, Scopus, Ethos, Africa Index Medicus (WHO), BioMed Central Proceedings, BASE, British Library, Open grey, Library of Congress and the New York Academy of Grey Literature Report were additionally searched for grey literature. Published articles from Africa on H.pylori antibiotic resistance between 1986 and June 2017 were systematically reviewed to estimate the H. pylori extent of resistance to macrolides, quinolones, amoxicillin, tetracycline and metronidazole. ### results In 26 articles a total of 2085 isolates were tested for metronidazole, 1530 for amoxicillin, 1277 for tetracycline, 1752 for clarithromycin and 823 for quinolones.The overall pooled proportion of H.pylori resistance to quinolones, clarithromycin, tetracycline, metronidazole and amoxicillin were: (17.4%, 95%CI 12.8 - 21.9), (29.2%, 95%CI:26.7-31.8), (48.7%, 95%CI: 44.5-52.9), (75.8%, 95% CI: 74.1-.77.4) and (72.6%, 95% CI: 68.6-76.6), respectively. The commonest mutation detected were A2143G (49/97) for clarithromycin, RdxA (41/56) for metronidazole and D87I (16/40) for quinolones. ### conclusion Prevalence of metronidazole , clarithromycin , and amoxicillin resistance is high in developing world including Africa . This could impair the first line triple therapy of the H.pylori infection. There is a need of conducting surveillance of H.pylori susceptibility pattern in Africa for dual and triple resistance which can be used for the empirical treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/29699490/"}
{"doc_id": "c17fc0df1fea762c276a5d2457332e93", "sentence": "These results indicate that low-dose 100 microg levonorgestrel and 20 microg ethinyl estradiol given for 21 days is effective in suppressing ovarian activity and they confirm the contraceptive efficacy observed in clinical trials ( Pearl index of 0.8 ) .", "spans": [{"span_id": 0, "text": "levonorgestrel", "start": 48, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ethinyl", "start": 77, "end": 84, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The effects on ovarian activity of a monophasic oral contraceptive with 100 microg levonorgestrel and 20 microg ethinyl estradiol. An open-label, single-center, noncomparative study was conducted to determine the effects of a monophasic oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol on ovarian activity. The subjects were 26 healthy women 20 to 35 years of age who had normal ovulatory cycles and were not at risk for becoming pregnant. For 3 treatment cycles, they took 1 tablet of active drug daily for 21 days followed by placebo tablets for 7 days. Follicle diameters and serum progesterone and 17beta-estradiol levels were measured before, during, and after treatment. In 2 (2.7%) of 73 cycles, luteinized unruptured follicles were present and in another 2 (2.7%) cycles, ovulation was confirmed by the disappearance of the enlarged follicle. Ovarian activity, as reflected by mean serum progesterone levels, was restored after treatment. The results of this study are in agreement with those of other studies that showed suppression of ovarian activity in women treated with a monophasic oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol. These results indicate that low-dose 100 microg levonorgestrel and 20 microg ethinyl estradiol given for 21 days is effective in suppressing ovarian activity and they confirm the contraceptive efficacy observed in clinical trials ( Pearl index of 0.8 ) .", "source": "https://pubmed.ncbi.nlm.nih.gov/10561676/"}
{"doc_id": "f5280bfb01586dd9949743d020881015", "sentence": "The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23 % in triple-negative patients .", "spans": [{"span_id": 0, "text": "ixabepilone", "start": 19, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "capecitabine", "start": 35, "end": 47, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer. Patients with ER/PR/HER2-negative (triple negative) breast cancer are not candidates for hormonal therapy or HER2-targeted agents. Ongoing research is aimed at identifying and understanding the benefit of established and emerging therapies in this disease setting. Triple-negative patients may achieve early responses to anthracyclines and taxanes, but novel strategies are also eagerly sought. The epothilone B analog ixabepilone acts to stabilize microtubules and demonstrates antitumor activity in recent breast cancer studies. Herein, we have analyzed efficacy and safety data of ixabepilone specifically for the treatment of women with triple-negative disease. A retrospective analysis was completed using activity and toxicity data in the triple-negative subsets from 5 phase II studies. In addition, a prospective pooled analysis of triple-negative patients from 2 phase III trials is also reviewed. Of 2,261 patients evaluated in these trials, 556 (24.5%) had triple-negative tumors. In the neoadjuvant setting, ixabepilone produced a pathologic complete response rate in the breast of 26% in triple-negative patients (vs. 15% in the non-triple-negative population). In patients with metastatic breast cancer whose pretreatment status ranged from no prior therapy to progression on several classes of agents, overall response rates (ORR) in the phase II ixabepilone monotherapy trials ranged from 6 to 55%, comparable to rates seen in patients with non-triple-negative tumors. The combination of ixabepilone and capecitabine in the phase II study resulted in an ORR of 23 % in triple-negative patients . A similar ORR (31%) was observed for a preplanned pooled analysis of triple-negative patients in the phase III trials of ixabepilone plus capecitabine. The median progression-free survival (PFS) was significantly longer for triple-negative patients treated with ixabepilone plus capecitabine (4.2 months) compared with treatment with capecitabine alone (1.7 months). No increase in toxicity was noted in the triple-negative subgroup compared with other patients. ixabepilone shows notable antitumor activity in patients with triple-negative breast cancer when used in a variety of settings. The addition of ixabepilone to capecitabine results in an approximately twofold increase in median PFS for triple-negative patients versus capecitabine alone and responses to ixabepilone in triple-negative disease are comparable to those seen in patients with non-triple-negative tumors.", "source": "https://pubmed.ncbi.nlm.nih.gov/20229176/"}
{"doc_id": "f1876516f12f16458a9741e1e09fd6e9", "sentence": "We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 182, "end": 193, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "paclitaxel", "start": 198, "end": 208, "token_start": 30, "token_end": 31}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Rapid tumor necrosis and massive hemorrhage induced by bevacizumab and paclitaxel combination therapy in a case of advanced breast cancer. bevacizumab when combined with chemotherapy exerts significant activity against many solid tumors through tumor angiogenesis inhibition; however, it can induce severe side effects. We report the rare case of a 27-year-old premenopausal woman with locally advanced breast cancer that was marked by rapid tumor necrosis followed by massive hemorrhage shortly after bevacizumab and paclitaxel administration . On the basis of histopathological examination of a biopsy specimen and computed tomography findings, she was diagnosed with stage IV estrogen and progesterone receptor-negative and human epidermal growth factor receptor type 2-positive breast cancer with multiple organ metastases when she had entered gestational week 24. cyclophosphamide, Adriamycin\u00ae, fluorouracil therapy was initiated, but multiple liver metastases continued to progress. A healthy fetus was delivered by induced delivery and trastuzumab-based treatment was initiated. Although the multiple liver metastases were controlled successfully by trastuzumab combined with paclitaxel, the primary tumor continued to expand even after subsequent administration of three other treatment regimens including anti-human epidermal growth factor receptor type 2 agents and cytotoxic drugs. To inhibit primary tumor growth, a combination therapy with paclitaxel and bevacizumab was subsequently initiated. Following therapy initiation, however, the large tumor occupying the patient's entire left breast became necrotic and ulcerated rapidly. Furthermore, massive hemorrhage from the tumor occurred 5 weeks after bevacizumab-based therapy initiation. Although hemostasis was achieved by manual compression, the patient required blood transfusion for the massive blood loss. She eventually succumbed to respiratory failure. This case report demonstrates that primary breast cancer lesions with skin involvement have the potential to cause massive hemorrhage after bevacizumab-based treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/24124381/"}
{"doc_id": "5b276187d854e37f1e11f2a96b3f7f34", "sentence": "More recently , paclitaxel plus carboplatin also has been evaluated in previously untreated patients .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 16, "end": 26, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "carboplatin", "start": 32, "end": 43, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Current status of chemotherapy for ovarian cancer. Standard treatment for patients with advanced ovarian cancer has been cytoreductive surgery followed by combination chemotherapy. Until recently, platinum-based chemotherapy was considered optimal and patients were treated with regimens built around either cisplatin or carboplatin. Recently, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to be a highly active agent in refractory ovarian cancer patients. Subsequently, the Gynecologic Oncology Group performed a prospective randomized trial of paclitaxel plus cisplatin compared with cisplatin plus cyclophosphamide in suboptimal stage III and IV ovarian cancer patients. Based on higher response rates, longer time to progression, and marked improvement in median survival (37.5 months compared with 24.4 months), the Gynecologic Oncology Group currently considers paclitaxel plus cisplatin to be the new standard regimen for patients with advanced disease. More recently , paclitaxel plus carboplatin also has been evaluated in previously untreated patients . Using area under the curve dosing for carboplatin, it was demonstrated that this agent could be combined with paclitaxel (175 mg/m2 in a 3-hour infusion) with acceptable toxicity. All current Gynecologic Oncology Group protocols for untreated patients with ovarian cancer use a paclitaxel-based regimen. These clinical trials are evaluating the relative efficacy of carboplatin plus paclitaxel versus cisplatin plus paclitaxel as well as differences in dose and schedule and number of cycles of treatment. Investigational studies are continuing with high-dose chemotherapy that requires hematologic support as well as with intraperitoneal therapy (cisplatin or paclitaxel).", "source": "https://pubmed.ncbi.nlm.nih.gov/7481863/"}
{"doc_id": "a29a75ad6709d12bac212da17d06c3d6", "sentence": "Mitoxantrone and cyclophosphamide in advanced breast cancer : a pilot study .", "spans": [{"span_id": 0, "text": "Mitoxantrone", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cyclophosphamide", "start": 17, "end": 33, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Mitoxantrone and cyclophosphamide in advanced breast cancer : a pilot study . A trial of combination chemotherapy using mitoxantrone-cyclophosphamide was started in 1983. Sixteen patients with widely metastatic cancer of the breast, including one man, received mitoxantrone, 10 mg/m2 intravenously (IV) over 30 minutes on day 1, followed by cyclophosphamide, 200 mg/m2 by mouth (PO) daily in divided doses on days 3 to 6. It is too early to evaluate four patients at present. The remaining 12 received three or more courses of treatment, and three of these patients achieved a complete response. Another four patients went into partial remission, amounting to an overall response rate of 58%. The other evaluable patients showed stable disease with improved symptoms. Hematologic toxicity was mainly granulocytopenia, but thrombocytopenia occurred in two patients. Alopecia, nausea, and vomiting were attributed to the cyclophosphamide component of the therapy. mitoxantrone appeared to have no cardiac toxicity. It was concluded that mitoxantrone-cyclophosphamide is an effective chemotherapeutic combination with minimal toxicity and should be further studied in larger controlled trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/6385260/"}
{"doc_id": "1106afc2c9fb4c7a9ae5de454d4c4e8e", "sentence": "We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia ( \u226510.0 mmol/L ) with BOT ( long-acting insulin plus glimepiride ) with their insulin titrated enough to keep preprandial glycemia < 7.2 mmol/L , and who had their treatment changed to liraglutide monotherapy , with the subsequent addition of glimepiride , when required .", "spans": [{"span_id": 0, "text": "glimepiride", "start": 140, "end": 151, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "liraglutide", "start": 272, "end": 283, "token_start": 44, "token_end": 45}, {"span_id": 2, "text": "glimepiride", "start": 330, "end": 341, "token_start": 52, "token_end": 53}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Efficacy of liraglutide therapy in Japanese type 2 diabetic patients insufficiently controlled with basal-supported oral therapy. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00223.x, 2012) Aims/Introduction:\u2002 We assessed the efficacy of liraglutide therapy in Japanese type\u20032 diabetic patients insufficiently controlled with basal-supported oral therapy (BOT). ### Materials And Methods We retrospectively analyzed the data of 37 patients who had postprandial hyperglycemia ( \u226510.0 mmol/L ) with BOT ( long-acting insulin plus glimepiride ) with their insulin titrated enough to keep preprandial glycemia < 7.2 mmol/L , and who had their treatment changed to liraglutide monotherapy , with the subsequent addition of glimepiride , when required . Those who achieved the glycemic target at all points (preprandial glycemia <7.2\u2003mmol/L and postprandial glycemia <10.0\u2003mmol/L) were regarded as responders and the efficacy of liraglutide therapy was assessed. We also explored the predictive clinical characteristics associated with its efficacy. ### results Daily doses of insulin and glimepiride with BOT were 14\u2003\u00b1\u20039\u2003units and 1.5\u2003\u00b1\u20030.9\u2003mg, respectively. After the change to liraglutide therapy, 37% of the patients appeared to be responders to the therapy, whereas 12% had their glycemic control rather deteriorated. Efficacy of liraglutide therapy was significantly associated with baseline insulin dosage and post-breakfast glycemia with BOT. The C-statistic of the model was calculated to be 0.90. ### conclusions There were responders and non-responders to liraglutide therapy in Japanese BOT failures. It is likely that baseline insulin dosage and post-breakfast glycemia with BOT are clinically useful indicators for the efficacy of liraglutide therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/24843616/"}
{"doc_id": "be5a1c925d0cb0e6d439ac0b5e827128", "sentence": "It was shown that the H2 receptor antagonist cimetidine when combined with N , N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl ( DPPE ) , a tamoxifen derivate , inhibits the proliferation of HT168 cells .", "spans": [{"span_id": 0, "text": "cimetidine", "start": 45, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "DPPE", "start": 134, "end": 138, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "tamoxifen", "start": 145, "end": 154, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl", "start": 79, "end": 131, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 3], "is_context_needed": false}], "paragraph": "Cimetidine and a tamoxifen derivate reduce tumour formation in SCID mice xenotransplanted with a human melanoma cell line. Histamine is produced by many cells expressing histidine decarboxylase (HDC), the enzyme responsible for the synthesis of histamine. Since melanoma cells and tissue contain relatively large amounts of histamine, the functional significance of histamine was examined using specific antihistamines in vitro and in vivo in the human melanoma cell line HT168 and severe combined immunodeficiency (SCID) mice. It was shown that the H2 receptor antagonist cimetidine when combined with N , N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine-HCl ( DPPE ) , a tamoxifen derivate , inhibits the proliferation of HT168 cells . Furthermore, it is suggested that there is a factor(s) that interferes with the exponential growth of HT168 cells xenografted to immunodeficient mice, and cimetidine and DPPE together significantly influence this factor(s). This combination of antihistamines also increases the survival of human melanoma-grafted mice. These changes are accompanied by enhanced infiltration of interferon-gamma- producing mouse macrophages into the tumour tissue. These findings suggest that two different mechanisms are probably acting concordantly: direct inhibition of tumour cell proliferation by the H2 receptor antagonists, and activation of the local immune response characterized by interferon-gamma production. These findings may help to elucidate the possibility of a rationally designed antihistamine strategy in melanoma therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/12140379/"}
{"doc_id": "371012fb02d83cd72167038138c75fc9", "sentence": "We report here on a case of successful treatment of a patient suffering with severe liver dysfunction and metastatic gastric cancer ; the patient was treated with a combination of capecitabine and oxaliplatin ( XELOX ) .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 180, "end": 192, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "oxaliplatin", "start": 197, "end": 208, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Capecitabine and oxaliplatin (XELOX) for the treatment of patients with metastatic gastric cancer and severe liver dysfunction. Gastric cancer patients with severe liver dysfunction secondary to hepatic metastases have limited treatment options. Most cytotoxic drugs have a narrow therapeutic index. Although both capecitabine and oxaliplatin have been well tolerated as single agents for patients with severe hepatic dysfunction, the combination of these drugs has not been investigated. We report here on a case of successful treatment of a patient suffering with severe liver dysfunction and metastatic gastric cancer ; the patient was treated with a combination of capecitabine and oxaliplatin ( XELOX ) . The initial bilirubin level of the patient was 10.9 mg/dL. After two cycles of treatment, his bilirubin level decreased to 2.1 mg/dL. He has experienced an excellent radiological response and he has received six cycles of XELOX chemotherapy. XELOX chemotherapy is feasible and it can be associated with positive outcomes for the patients suffering with metastatic gastric cancer and severe liver dysfunction.", "source": "https://pubmed.ncbi.nlm.nih.gov/17249509/"}
{"doc_id": "866cea479a93e1b7b5b53f5813e3c8af", "sentence": "From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years .", "spans": [{"span_id": 0, "text": "vincristine", "start": 63, "end": 74, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "ifosfamide", "start": 79, "end": 89, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "dactinomycin", "start": 95, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "etoposide", "start": 111, "end": 120, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "NEG", "spans": [0, 1, 3], "is_context_needed": true}], "paragraph": "Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor. The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma. ### Patients And Methods From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years . ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate, or 9 g/m2 of ifosfamide per course. The three-drug regimen was repeated every 3-4 weeks. ### results Twenty-eight patients (14%) developed renal toxicity: 19 had renal tubular dysfunction (RTD) characterized by low serum phosphate (< or = 3 mg/dl) or bicarbonate (< 20 or = mEq/L) levels, five had decreased glomerular function (DGF), and four had both RTD and DGF. When nine or more courses of ifosfamide (> 72 g/m2) were given, children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age (34% versus 6%; p < 0.001). A similar age difference was observed even when eight or fewer courses (< or = 72 g/m2) were given (p = 0.03). A matched case-control comparison showed that renal abnormalities at diagnosis, chiefly hydronephrosis, also increased the risk of renal tubular injury by ifosfamide by a factor of 13 (p < 0.001). Patients with DGF tended to be older than those with RTD, and all but one received > 72 g/m2 of ifosfamide. ### conclusions Patients who are < 3 years of age who receive more than eight courses (> 72 g/m2) of ifosfamide and who have a preexisting renal abnormality have an increased risk of RTD and DGF. The renal function of patients being considered for ifosfamide treatment must be carefully monitored. ifosfamide should be avoided in patients with renal abnormalities at diagnosis unless the potential benefit clearly exceeds the risk of further renal impairment.", "source": "https://pubmed.ncbi.nlm.nih.gov/7978043/"}
{"doc_id": "8e992315910c8453b24e152e7b079ea9", "sentence": "This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance , to evaluate the vascular benefits of coadministered therapy .", "spans": [{"span_id": 0, "text": "amlodipine", "start": 80, "end": 90, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "atorvastatin", "start": 95, "end": 107, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Coadministered amlodipine and atorvastatin produces early improvements in arterial wall compliance in hypertensive patients with dyslipidemia. Combining statins with antihypertensive therapy has been demonstrated to provide an early reduction in cardiovascular events. This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance , to evaluate the vascular benefits of coadministered therapy . ### methods During an initial 8-week, double-blind phase, patients with concomitant hypertension and dyslipidemia were randomized into four treatment groups (placebo, amlodipine 5 mg, atorvastatin 10 mg, or coadministered amlodipine 5 mg and atorvastatin 10 mg). The sustained effect of combined therapy was evaluated during subsequent 8-week, single-blind, and 12-week, open-label periods. In the single-blind phase, all patients were coadministered amlodipine 5 mg and atorvastatin 10 mg, which were then titrated to optimize blood pressure and low-density lipoprotein cholesterol control during the open-label phase. Arterial compliance was assessed every 4 weeks using the HDI/Pulsewave CR-2000. ### results Overall, 668 patients (61% male, mean age 55 years) were randomized to treatment. A 19% improvement in small artery compliance (C2) was observed with coadministered amlodipine and atorvastatin from baseline to week 8, which was significantly greater than with either treatment alone or with placebo (P = 0.03 to 0.0001). After 28 weeks, C2 was increased from baseline in all groups, but the overall improvement was greatest in the group receiving coadministered drugs for the entire study period (P < 0.05). ### conclusions Early and sustained improvement in small artery compliance was observed following coadministration of amlodipine and atorvastatin, thus demonstrating a vascular benefit with simultaneous treatment of hypertension and dyslipidemia.", "source": "https://pubmed.ncbi.nlm.nih.gov/19057518/"}
{"doc_id": "e925c82c9d2d2338c659d275057e5ecd", "sentence": "We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies ( selective BRAF-inhibitor monotherapy , dabrafenib combined with trametinib [ D&T ] , anti-programmed cell death protein 1 [ anti-PD1 ] therapies , and anti-PD1 combined with ipilimumab ) seen from February 2013 to May 2016 .", "spans": [{"span_id": 0, "text": "dabrafenib", "start": 213, "end": 223, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "trametinib", "start": 238, "end": 248, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "anti-PD1", "start": 325, "end": 333, "token_start": 46, "token_end": 47}, {"span_id": 3, "text": "ipilimumab", "start": 348, "end": 358, "token_start": 49, "token_end": 50}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: An observational study. Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies. ### methods We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies ( selective BRAF-inhibitor monotherapy , dabrafenib combined with trametinib [ D&T ] , anti-programmed cell death protein 1 [ anti-PD1 ] therapies , and anti-PD1 combined with ipilimumab ) seen from February 2013 to May 2016 . We compared these changes with the melanocytic lesions of 10 control patients. ### results In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P\u00a0<\u00a00.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P\u00a0<\u00a00.001) as well as the anti-PD1 and ipilimumab groups (59%, P\u00a0<\u00a00.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant. ### conclusions Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls. The findings emphasise the importance of regular dermatological monitoring in specialised clinics for patients on anti-melanoma systemic therapy. Clinicians should expect changes in the global pigmentation of melanocytic lesions but be suspicious of lesions with structural changes.", "source": "https://pubmed.ncbi.nlm.nih.gov/28707403/"}
{"doc_id": "05b1012375dc91d3f46f44b59e1fd1fb", "sentence": "He received six cycles MOPP-induction therapy followed by a chlorambucil maintenance therapy with procarbazine and prednisone reinforcements .", "spans": [{"span_id": 0, "text": "chlorambucil", "start": 60, "end": 72, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "procarbazine", "start": 98, "end": 110, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "prednisone", "start": 115, "end": 125, "token_start": 15, "token_end": 16}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Acute erythroleukemia following chemotherapy for Hodgkin's disease. A case of erythroleukemia developing in a patient 6.5 years after therapy for Hodgkin's disease (HD) is described. The patient had chemotherapy alone for a stage III B lymphocyte-predominant HD. He received six cycles MOPP-induction therapy followed by a chlorambucil maintenance therapy with procarbazine and prednisone reinforcements . To our knowledge this is the first case of erythroleukemia following HD treated with chemotherapy alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/6932816/"}
{"doc_id": "a361c296e0a5fe7615178d1738c3cc72", "sentence": "The introduction of rituximab , alemtuzumab , and bendamustine has improved the current outlook for patients with CLL .", "spans": [{"span_id": 0, "text": "rituximab", "start": 20, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "alemtuzumab", "start": 32, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "bendamustine", "start": 50, "end": 62, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Standard of care and novel treatments for chronic lymphocytic leukemia. The standard of care and novel treatments for chronic lymphocytic leukemia (CLL) are reviewed. ### summary Recent advances in the treatment of CLL have dramatically changed the therapeutic landscape for both patients and health care professionals. The majority of conventional first-line therapies are noncurative and are only used to treat disease that is symptomatic or progressive and include chlorambucil, monotherapy with purine analogues, and combination chemotherapy. Immunotherapeutic agents such as rituximab and alemtuzumab may be indicated in select patient populations. However, because clinical trials have found that overall survival does not depend on the initial therapy, selection of first-line therapy should be based on patient-specific factors and the patient's goals for therapy with respect to response, survival, and symptom palliation. Progression-free survival time and time to treatment are critical endpoints for CLL treatment. An increasingly important endpoint is minimal residual disease (MRD), as it is considered to be the major cause of relapse in CLL. Finally, comparison of toxicities between different therapies is critical in CLL, as it is in other disease states. Several new agents are currently being evaluated for use in CLL, including alvocidib, oblimersen, and lumiliximab. ### conclusion Chemotherapy remains the mainstay of treatment for the majority of patients with CLL. The introduction of rituximab , alemtuzumab , and bendamustine has improved the current outlook for patients with CLL . As overall survival does not appear to depend on the initial therapy, treatment should be selected based on patient-specific factors and goals. Challenges in CLL include determining when to initiate therapy, eradicating MRD, and managing therapeutic resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/20966144/"}
{"doc_id": "4459519c47bc0fd3fbadcc6fff8f621d", "sentence": "Ten patients were treated with pirfenidone ( 2403 mg/die ) and 1 with nintedanib", "spans": [{"span_id": 0, "text": "pirfenidone", "start": 31, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "nintedanib", "start": 70, "end": 80, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Possible value of antifibrotic drugs in patients with progressive fibrosing non-IPF interstitial lung diseases. Fibrosing, non-idiopathic pulmonary fibrosis (non-IPF) interstitial lung diseases (fILDs) are a heterogeneous group of diseases characterized by a different amount of inflammation and fibrosis. Therapy is currently based on corticosteroids and/or immunomodulators. However, response to these therapies is highly variable, sometimes without meaningful improvement, especially in more fibrosing forms. pirfenidone and nintedanib have recently demonstrated to reduce functional decline in patients with IPF. However, their antifibrotic mechanism makes these two drugs an interesting approach for treatment of fibrosing ILDs other than IPF. ### objectives We here report our experience with antifibrotic drugs in fibrosing non-IPF ILDs patients having a progressive phenotype during immunosuppressive therapy. ### methods Patients with a multidisciplinary team diagnosis of fibrosing non-IPF ILDs experiencing a progressive phenotype during treatment with corticosteroids and/or immunomodulators between October-2014 and January-2018 at our tertiary referral Center for ILDs were retrospectively analyzed. Antifibrotic therapy was administered after application with the respective health insurance company and after consent by the patient. Pulmonary-function-tests and follow-up visits were performed every 6\u2009\u00b1\u20091\u2009months. ### results Eleven patients were treated with antifibrotic drugs (8 males, mean age 62\u2009\u00b1\u200912.8\u2009years, mean FVC% 62.8\u2009\u00b1\u200922.3, mean DLCO% 35.5\u2009\u00b1\u200910.7, median follow-up under antifibrotic treatment 11.1\u2009months). Patients had a diagnosis of unclassifiable ILD in 6 cases, pleuroparenchymal fibroelastosis in 2 cases, idiopathic-NSIP in 1 case, asbestos-related ILD in 1 case and Hermansky-Pudlak syndrome in 1 case. Treatment before antifibrotics consisted of corticosteroids in all patients: 5 combined with Azathioprin, 1 with either methotrexate or cyclophosphamide (i.v.). Ten patients were treated with pirfenidone ( 2403 mg/die ) and 1 with nintedanib (300\u2009mg/die). Median FVC was 56, 56, 50%, at time points\u2009-\u200924, -\u200912, -\u20096 before initiation, 44% at time of initiation and 46.5% at 6\u2009months after initiation of antifibrotic treatment. Antifibrotic treatment was generally well tolerated with a need of dose reduction in 2 cases (rash and nausea) and early termination in 3 cases. ### conclusions Antifibrotic treatment may be a valuable treatment option in patients with progressive fibrosing non-IPF ILD if currently no other treatment options exist. However, prospective, randomized clinical trials are urgently needed to assess the real impact of antifibrotic therapy in these patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/31718637/"}
{"doc_id": "aca07ce099defc39959faeabed961a9a", "sentence": "More recently , case-control and cohort studies and well-conceived , phase II/III clinical trials have been done or are under way to evaluate putative chemopreventive agents including established drugs like aspirin and non-steroidal anti-inflammatory drugs ( NSAIDs ) , 5-aminosalicylates and statins ; more controversial drugs like cyclo-oxygenase-2 ( COX-2 ) inhibitors , ursodeoxycholic acid ; various vitamins and micronutrients including calcium , selenium , folic acid , and dietary fibre , fat and protein content .", "spans": [{"span_id": 0, "text": "aspirin", "start": 207, "end": 214, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "5-aminosalicylates", "start": 270, "end": 288, "token_start": 39, "token_end": 40}, {"span_id": 2, "text": "cyclo-oxygenase-2", "start": 333, "end": 350, "token_start": 47, "token_end": 48}, {"span_id": 3, "text": "COX-2", "start": 353, "end": 358, "token_start": 49, "token_end": 50}, {"span_id": 4, "text": "ursodeoxycholic acid", "start": 374, "end": 394, "token_start": 53, "token_end": 55}], "rels": [], "paragraph": "Chemoprevention of colorectal cancer. Colorectal cancer is a major cause of mortality and treatment costs are considerable. Advocating lifestyle modification, faecal occult blood testing and surveillance colonoscopy in appropriate populations are already in practice. A developing concept is chemoprevention. Several models of carcinogenesis in colorectal cancer have been developed and there is an increasing database on the major molecular mechanisms involved in carcinogenesis mainly from preclinical experiments and phase I trials. There have been several large epidemiological and observational studies to evaluate possible protective effects of >200 agents. More recently , case-control and cohort studies and well-conceived , phase II/III clinical trials have been done or are under way to evaluate putative chemopreventive agents including established drugs like aspirin and non-steroidal anti-inflammatory drugs ( NSAIDs ) , 5-aminosalicylates and statins ; more controversial drugs like cyclo-oxygenase-2 ( COX-2 ) inhibitors , ursodeoxycholic acid ; various vitamins and micronutrients including calcium , selenium , folic acid , and dietary fibre , fat and protein content . Despite promising outcome in preclinical studies, there is currently very limited data from well-controlled and appropriately powered clinical studies. The most promising agents currently are aspirin, traditional NSAIDs and COX-2 inhibitors. The recent reports of cardiovascular risks of the COX-2 inhibitors and some traditional NSAIDs have resulted in stagnation of the field. Pending the expected release of results from several phase III trials in the near future, chemoprevention for colorectal cancer can only be practically considered in the very-high-risk population like those with familial adenomatous polyposis and ulcerative colitis, in conjunction with surveillance colonoscopy. This article reviews the major models of colorectal carcinogenesis, the concept of chemoprevention with special reference to colorectal cancer and the current state of clinical literature and the future direction of colorectal cancer chemoprevention for both researcher and clinician alike.", "source": "https://pubmed.ncbi.nlm.nih.gov/17947819/"}
{"doc_id": "121cc940e6c7801b8ef91dd420bbcd5a", "sentence": "Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma : a multicentre phase II study .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 10, "end": 20, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "rituximab", "start": 25, "end": 34, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma : a multicentre phase II study . There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non-Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty-two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n\u00a0=\u00a033, 79%). Patient characteristics included median age 62\u00a0years (40-86); 38% bulky disease; 19% malignant effusions; 91% advanced-stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0-2 vs. 3-5 was 60% vs. 26% respectively (P\u00a0=\u00a00\u00b702), with corresponding OS rates of 92% and 81% respectively (P\u00a0=\u00a00\u00b716). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL.", "source": "https://pubmed.ncbi.nlm.nih.gov/24761968/"}
{"doc_id": "2a53d260b295d78e2f2e900107f15b71", "sentence": "The ifosfamide , carboplatin and etoposide ( ICE ) regimen was developed to address these challenges .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 4, "end": 14, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "carboplatin", "start": 17, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "etoposide", "start": 33, "end": 42, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Despite advances in the management of aggressive non-Hodgkin's lymphoma, the treatment of relapsed and primary refractory disease remains a major challenge. High-dose chemotherapy or radio-chemotherapy followed by autologous or allogeneic stem cell transplantation (SCT) is a potentially curative treatment approach; however, the applicability of this approach is restricted to patients responding to second-line chemotherapy. Thus, second-line therapy must be both efficacious and without stem cell or organ toxicity that would compromise the ability to proceed to SCT. The ifosfamide , carboplatin and etoposide ( ICE ) regimen was developed to address these challenges . In a series of prospective clinical trials, 222 patients were treated with the ICE regimen. with an overall response rate of 72%. The mobilization of stem cells with this regimen was excellent,with 86% of patients mobilizing at least 2.0 x 10(6) CD34+ cells/kg. The incidence of treatment-related toxicity precluding SCT after ICE is very low. Herein, we report the clinical results of this treatment program for 222 patients with 5-year median follow-up for surviving patients. rituximab was subsequently added to the ICE regimen for patients with diffuse large B-cell lymphoma (DLBCL) to improve upon these favorable results. This resulted in an increased complete remission rate. Additional follow-up is necessary to determine if this improvement in the complete remission rate will confer an increase in the overall survival following SCT.", "source": "https://pubmed.ncbi.nlm.nih.gov/12736224/"}
{"doc_id": "b740d6e2917c26c5d772eb2155529a4f", "sentence": "Tofacitinib combination therapy was also associated with the lower PMPM cost compared with adalimumab combination therapy in the TNF-IR analysis .", "spans": [{"span_id": 0, "text": "Tofacitinib", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "adalimumab", "start": 91, "end": 101, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "An Economic Evaluation of Tofacitinib Treatment in Rheumatoid Arthritis: Modeling the Cost of Treatment Strategies in the United States. tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). tofacitinib is approved in the United States for use in adults with moderately to severely active RA and an inadequate response or intolerance to methotrexate. ### objectives To (a) evaluate, using an economic model, the treatment costs of an RA strategy including tofacitinib, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic RA treatment strategies, which are commonly prescribed in the United States, and (b) assess the economic impact of monotherapy and combination therapy in patients who had an inadequate response to methotrexate therapy (MTX-IR analysis) and to combination therapy in patients who had an inadequate response to a tumor necrosis factor inhibitor (TNF-IR analysis). ### methods A transparent, Excel-based economic model with a decision-tree approach was developed to evaluate costs over a 1- and 2-year time horizon. The model compared tofacitinib 5 mg twice a day (BID) either as monotherapy or in combination with MTX with similarly labeled biologic therapies. Response to treatment was modeled as American College of Rheumatology (ACR) 20/50/70 response. ACR20 represented clinical response and determined whether patients continued therapy. ACR response rates at 6-month intervals were sourced from prescribing information and safety event rates from a published meta-analysis. Following an adverse event or a lack of response to treatment, it was assumed that 75% of patients switched to the next line of treatment (first to abatacept and then to rituximab). The perspective was that of a U.S. payer. Costs were reported in 2015 U.S. dollars and included drug wholesale acquisition costs, monitoring, drug administration, and treatment for minor and serious adverse events. The patient population eligible for treatment was based on the total number of members (i.e., RA and non-RA) in a payer organization; members with RA treated with biologic therapies were estimated using epidemiological data. Sensitivity analyses were conducted to explore the impact of varying key parameters, including treatment-switching probability, product rebate, major rates of adverse drug reaction, and ACR20 rates, on the model outcomes. ### results tofacitinib combination therapy after MTX failure was associated with the lowest cost per member per month (PMPM) over a 2-year time frame at $5.53, compared with $6.49 for adalimumab, $6.43 for etanercept, $5.95 for certolizumab, and $5.89 for tocilizumab. Similar savings were observed when all biologics were administered as monotherapy. Tofacitinib combination therapy was also associated with the lower PMPM cost compared with adalimumab combination therapy in the TNF-IR analysis . tofacitinib was also among the lowest cost per ACR20 responder in each analysis. Sensitivity analyses demonstrated that tofacitinib would potentially be cost saving even in the least optimistic scenarios. ### conclusions This analysis suggests that tofacitinib 5 mg BID following MTX failure is a lower cost per patient treatment option when used either as monotherapy or combination therapy, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic regimens. tofacitinib + MTX in TNF-IR patients was also predicted to be a lower-cost treatment option compared with adalimumab+MTX and was associated with the lowest cost per ACR 20/50/70 responder. ### disclosures This study was funded by Pfizer, which determined the research topic and paid York Health Economics Consortium to develop the analysis and conduct the research. York Health Economics Consortium has received consultancy fees from Pfizer. Gerber, Wallenstein, Mendelsohn, Bourret, Singh, and Moynagh are employees and shareholders of Pfizer. Editorial support was funded by Pfizer and was provided by Claxton, Jenks, and Taylor, who are employees of York Health Economics Consortium. Study concept and design were contributed primarily by Taylor, Jenks, Gerber, and Singh, along with the other authors. Gerber, Moynagh, and Singh collected the data, assisted by Bouret and Mendelsohn; data interpretation was performed by Claxton, Gerber, Bouret, and Mendelsohn. The manuscript was written primarily by Claxton, with assistance from the other authors, and revised by Claxton, Gerber, Bouret, and Mendelsohn, with assistance from the other authors.", "source": "https://pubmed.ncbi.nlm.nih.gov/27579831/"}
{"doc_id": "aa7244029b3ff67b517ef6f9a89e4e34", "sentence": "Effect of sequential treatments with alendronate , parathyroid hormone ( 1 - 34 ) and raloxifene on cortical bone mass and strength in ovariectomized rats .", "spans": [{"span_id": 0, "text": "alendronate", "start": 37, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "parathyroid hormone", "start": 51, "end": 70, "token_start": 7, "token_end": 9}, {"span_id": 2, "text": "raloxifene", "start": 86, "end": 96, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effect of sequential treatments with alendronate , parathyroid hormone ( 1 - 34 ) and raloxifene on cortical bone mass and strength in ovariectomized rats . Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear. ### methods Six-month old female rats were either sham operated or ovariectomized (OVX). OVX rats were left untreated for two months and then were treated with vehicle (Veh), hPTH (1-34) (PTH), alendronate (Aln), or raloxifene (Ral) sequentially for three month intervals, for a total of three periods. Mid-tibial cortical bone architecture, mass, mineralization, and strength were measured on necropsy samples obtained after each period. Bone indentation properties were measured on proximal femur necropsy samples. ### results Eight or more months of estrogen deficiency in rats resulted in decreased cortical bone area and thickness. Treatment with PTH for 3months caused the deposition of endocortical lamellar bone that increased cortical bone area, thickness, and strength. These improvements were lost when PTH was withdrawn without followup treatment, but were maintained for the maximum times tested, six months with Ral and three months with Aln. Pre-treatment with anti-resorptives was also somewhat successful in ultimately preserving the additional endocortical lamellar bone formed under PTH treatment. These treatments did not affect bone indentation properties. ### summary Sequential therapy that involved both PTH and anti-resorptive agents was required to achieve lasting improvements in cortical area, thickness, and strength in OVX rats. Anti-resorptive therapy, either prior to or following PTH, was required to preserve gains attributable to an anabolic agent.", "source": "https://pubmed.ncbi.nlm.nih.gov/25016965/"}
{"doc_id": "b701ddeb0bd97b91f62fe6b654023d06", "sentence": "Atorvastatin and metformin both have pleiotropic effects .", "spans": [{"span_id": 0, "text": "Atorvastatin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "metformin", "start": 17, "end": 26, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Atorvastatin Plus Metformin Confer Additive Benefits on Subjects with Dyslipidemia and Overweight/Obese via Reducing ROCK2 Concentration.  Atorvastatin and metformin both have pleiotropic effects . Whether atorvastatin combined with metformin could provide additive benefits on subjects with dyslipidemia and overweight/obese is unknown. And the mechanism is also not fully clear yet. ### methods A cross-sectional research was performed and 130 subjects with dyslipidemia and overweight/obese were enrolled and randomly assigned into combined group (20\u2009mg of atorvastatin daily plus 500\u2009mg of metformin twice daily) and control group (20\u2009mg of atorvastatin daily). At baseline and 8 weeks later, parameters of interest were recorded and fasting venous blood was drawn for laboratory examination. ### results The rates of overweight (76.9% vs. 73.8%) and obese (23.1% vs. 26.2%) in both group were comparable. Dyslipidemia in both groups were featured by increased serum levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Serum level of high sensitivity C-reactive protein (Hs-CRP) was comparably elevated in both groups at baseline, and leukocyte rho-associated kinase 2 (ROCK2) and serum nitric oxide (NO) concentrations were also comparable. Generally, the baseline characteristics between these 2 groups were no significant differences. 8 weeks later, compared to baseline, body mass index (BMI), the rates of overweight and obese, daily exercise time, smoking status, lipid profiles, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations in both groups were improved. Notably, compared to control group, the rate of obese, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations were improved more profoundly in the combined group (p<0.05). After adjusted for age, gender, BMI, TG, LDL-C, Hs-CRP and exercise time, atorvastatin plus metformin was positively associated with serum NO concentration, with odds ratio (OR) of 1.146 (95% confidence interval (CI) 1.089-1.164, combined group vs. control group, p<0.05), and inversely associated with leukocyte ROCK2 concentration, with OR of 0.853 (95% CI 0.834-0.872, combined group vs. control group, p<0.05). ### conclusion In subjects with dyslipidemia and overweight/obese, atorvastatin plus metformin may confer additive benefits through reducing leukocyte ROCK2 concentration.", "source": "https://pubmed.ncbi.nlm.nih.gov/27123784/"}
{"doc_id": "3ddf01008a6da5a27b7b3ed32a532cba", "sentence": "Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "irinotecan", "start": 172, "end": 182, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "oxaliplatin", "start": 187, "end": 198, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Targeted agents for adjuvant therapy of colon cancer. Among patients with colorectal cancer (CRC) diagnosed in the United States, 37.2% are diagnosed with stage III and 27.9% with stage II disease. In locoregionally advanced CRC, surgery is the primary treatment modality and has a curative intent. The survival depends on the pathologic stage and varies from 30%-60% for stage III to 60%-80% for stage II. However, as much as 40%-50% of patients will relapse and require additional treatment of the disease. Clinical failure after resection of CRC is predominantly secondary to the clinical progression of previously undetected distant metastatic disease. Until very recently, the absolute benefit for survival obtained with adjuvant therapy compared with control was about 6%. Introduction of oxaliplatin in the adjuvant setting has shown a reduction of 23% in the risk of relapse when compared with 5-fluorouracil alone (MOSAIC). Recent phase III studies have shown that targeted agents improved survival in patients with advanced-stage CRC. Bevacizumab , a monoclonal antibody targeting vascular endothelial growth factor , is the first antiangiogenic drug to show improved efficacy when used in combination with irinotecan and oxaliplatin for first- and second-line treatment of CRC . cetuximab, another monoclonal antibody targeting epidermal growth factor receptor, has shown efficacy in third-line therapy and promising results in first-line phase II studies. There is great interest in whether the biologic agents bevacizumab and cetuximab can improve survival in the adjuvant-therapy setting. This article reviews the adjuvant therapy for colon cancer and discusses the potential role and current trials involving the targeted agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/16796791/"}
{"doc_id": "f53a76b0f77943392506a7584cb6fb49", "sentence": "Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function , dyspnea , exacerbations , and health status .", "spans": [{"span_id": 0, "text": "GLY", "start": 29, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "aclidinium", "start": 37, "end": 47, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "tiotropium", "start": 73, "end": 83, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Practical considerations when prescribing a long-acting muscarinic antagonist for patients with COPD. COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of the recommended first-choice therapeutic options for patients with COPD, and several new agents have been developed in recent years. A literature search identified 14 published randomized, placebo-controlled studies of the efficacy and safety of LAMAs in patients with COPD, with improvements seen in lung function, exacerbations, breathlessness, and health status. A greater weight of evidence currently exists for glycopyrronium (GLY) and tiotropium than for umeclidinium and aclidinium, especially in terms of exacerbation reductions. To date, there have been few head-to-head clinical studies of the different LAMAs. Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function , dyspnea , exacerbations , and health status . Overall, evidence demonstrates that currently available LAMAs provide effective and generally well-tolerated therapy for patients with COPD. Delivery devices for the different LAMAs vary, which may affect individual patient's adherence to and preference for treatment. Subtle differences between individual therapeutic options may be important to individual patients and the final treatment choice should involve physician's and patient's experiences and preferences.", "source": "https://pubmed.ncbi.nlm.nih.gov/29670345/"}
{"doc_id": "3d0d59d4e485f6a55293b551396a97b1", "sentence": "Between Oct 24 , 2016 , and Jan 24 , 2018 , 861 patients were randomly assigned to receive pembrolizumab plus axitinib ( n=432 ) or sunitinib monotherapy ( n=429 ) .", "spans": [{"span_id": 0, "text": "pembrolizumab", "start": 91, "end": 104, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "axitinib", "start": 110, "end": 118, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "sunitinib", "start": 132, "end": 141, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. ### methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (\u226518 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. ### findings Between Oct 24 , 2016 , and Jan 24 , 2018 , 861 patients were randomly assigned to receive pembrolizumab plus axitinib ( n=432 ) or sunitinib monotherapy ( n=429 ) . With a median follow-up of 30\u00b76 months (IQR 27\u00b72-34\u00b72), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35\u00b77 months [95% CI 33\u00b73-not reached] with sunitinib); hazard ratio [HR] 0\u00b768 [95% CI 0\u00b755-0\u00b785], p=0\u00b70003) and progression-free survival (median 15\u00b74 months [12\u00b77-18\u00b79] vs 11\u00b71 months [9\u00b71-12\u00b75]; 0\u00b771 [0\u00b760-0\u00b784], p<0\u00b70001). The most frequent (\u226510% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. ### interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. ### funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.", "source": "https://pubmed.ncbi.nlm.nih.gov/33284113/"}
{"doc_id": "d762cec75711543c49da82dff94ed22a", "sentence": "Patients received 175 mg/m of paclitaxel over a 3 h infusion , followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 30, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "nedaplatin", "start": 75, "end": 85, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A retrospective study of paclitaxel combining nedaplatin chemotherapy for esophageal cancer. The aim of this study was to evaluate the efficacy and tolerability of the combination of paclitaxel and nedaplatin in patients with advanced esophageal cancer. Patients (n = 310) with recurrent or metastatic esophageal squamous cell carcinoma, who had a maximum of one previous chemotherapy regimen, were enrolled in this study. All patients had bidimensionally measurable disease. Patients received 175 mg/m of paclitaxel over a 3 h infusion , followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles . The overall response rate was 47.7%, with complete and partial response rates of 6.1 and 41.7%, respectively. The median time to progression for all patients was 6.8 months (95% confidence interval, 6.2-7.4 months) and the 3-year disease-free survival probability was 3 (15.8%). The major toxicity observed was cumulative neutropenia, with 29% patients developing grade 4 toxicity. There was no treatment-related death. The most common nonhematologic toxicity encountered with this regimen was pain and cumulative peripheral neuropathy, with 26% patients experiencing grade 2 or 3 toxicity. The combination of paclitaxel and nedaplatin shows significant antitumor activity and a favorable toxicity profile in patients with metastatic carcinoma of esophageal cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/25222530/"}
{"doc_id": "b6c21f8f5634747e728badfc6d8eb528", "sentence": "After a median follow-up of 9.5 years , 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin ( LV5FU2 ) and LV5FU2 plus oxaliplatin ( FOLFOX4 ) arms were 67.1 % versus 71.7 % ( hazard ratio [ HR ] , 0.85 ; P = .043 ) in the whole population , 79.5 % versus 78.4 % for stage II ( HR , 1.00 ; P = .980 ) , and 59.0 % versus 67.1 % for stage III ( HR , 0.80 ; P = .016 ) disease .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 81, "end": 93, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "leucovorin", "start": 99, "end": 109, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "LV5FU2", "start": 125, "end": 131, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "oxaliplatin", "start": 137, "end": 148, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. The MOSAIC (Multicenter International Study of oxaliplatin/fluorouracil/leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. ### methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. ### results After a median follow-up of 9.5 years , 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin ( LV5FU2 ) and LV5FU2 plus oxaliplatin ( FOLFOX4 ) arms were 67.1 % versus 71.7 % ( hazard ratio [ HR ] , 0.85 ; P = .043 ) in the whole population , 79.5 % versus 78.4 % for stage II ( HR , 1.00 ; P = .980 ) , and 59.0 % versus 67.1 % for stage III ( HR , 0.80 ; P = .016 ) disease . Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. ### conclusion The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.", "source": "https://pubmed.ncbi.nlm.nih.gov/26527776/"}
{"doc_id": "89852eabc5c5a033839f43602db85e9b", "sentence": "[ Effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs ] .", "spans": [{"span_id": 0, "text": "dofetilide", "start": 29, "end": 39, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "verapamil", "start": 44, "end": 53, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs ] . To test the effects of combined use of dofetilide and verapamil on the action potential of papillary muscles in guinea pigs. ### methods Under the stimulation of different frequencies (0.2, 0.5, 1.0, 1.25 or 2.0 Hz), the action potential of papillary muscles in guinea pigs was recorded with the standard microelectrode techniques. The impacts of different concentrations of amiodarone (1, 5 or 10 micromol/L), dofetilide (10, 50, 100 nmol/L), and a combination of 100 nmol/L dofetilide and 1 micromol/L verapamil on the action potential were tested. ### results amiodarone prolonged the action potential duration (APD) significantly, measured both at 50% (APD50) and 90% (APD90) of repolarization, in a concentration-dependent manner independent from stimulation frequencies. dofetilide prolonged APD in a concentration-dependent manner, which was negatively dependent on stimulation frequencies. The frequency-dependent effect was ameliorated by adding 1 micromol/L verapamil to dofetilide. ### conclusion Both amiodarone and dofetilide prolong APD in a concentration-dependent manner. The class III antiarrhythmic compounds, amiodarone, has less frequency-dependent effect than the pure class III antiarrhythmic drug. A combined use of potassium and calcium antagonists may reduce the frequency-dependence of the pure class III antiarrhythmic drug.", "source": "https://pubmed.ncbi.nlm.nih.gov/19950594/"}
{"doc_id": "e54f6bdb2e26e38522cbd9d86f9cda86", "sentence": "Patients with pancreatic adenocarcinoma , pre-treated with gemcitabine-based chemotherapy , were treated with capecitabine ( 800 mg/m(2 ) orally , twice a day for 14 days ) and docetaxel ( 75 mg/m(2 ) i.v , on day 1 ) , every 3 weeks .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 110, "end": 122, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "docetaxel", "start": 177, "end": 186, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas. ### Patients And Methods Patients with pancreatic adenocarcinoma , pre-treated with gemcitabine-based chemotherapy , were treated with capecitabine ( 800 mg/m(2 ) orally , twice a day for 14 days ) and docetaxel ( 75 mg/m(2 ) i.v , on day 1 ) , every 3 weeks . The primary end-point was overall response rate (RR). ### results Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0-1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80-48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6-3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38-9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%. ### conclusion The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/20428874/"}
{"doc_id": "e57340a652b30cdb82156c64b7b39d08", "sentence": "Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 97, "end": 107, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "cyclophosphamide", "start": 112, "end": 128, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer . A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. ### Patients And Methods In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. ### results In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. ### conclusion In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/9193328/"}
{"doc_id": "90f9283bb0869bd11721e467f718e869", "sentence": "The hearts were treated during the whole procedure either with vehicle , 0.5 \u03bcM flecainide ( sodium channel blocker ) or 100 \u03bcM streptomycin ( here used as stretch-activated ion-channel blocker ) .", "spans": [{"span_id": 0, "text": "flecainide", "start": 80, "end": 90, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "streptomycin", "start": 128, "end": 140, "token_start": 23, "token_end": 24}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Arrhythmogenic effects by local left ventricular stretch: effects of flecainide and streptomycin. Mechanical stretch has been shown to provoke arrhythmia. We wanted to analyze ventricular arrhythmia induced by local left ventricular stretch in order to find out, where arrhythmias originate and whether they can be prevented pharmacologically. Isolated rabbit hearts (Langendorff technique) were submitted to increased left ventricular stretch at the left wall by insertion of an additional intraventricular balloon and adjusting the end-diastolic pressure (EDP) to 25 mmHg for 10 min followed by 20 min recovery at normal EDP of 5-8 mmHg. Activation and repolarization processes were investigated by ventricular 256 electrode epicardial mapping. The hearts were treated during the whole procedure either with vehicle , 0.5 \u03bcM flecainide ( sodium channel blocker ) or 100 \u03bcM streptomycin ( here used as stretch-activated ion-channel blocker ) . In addition, we performed a series of experiments, in which we enhanced EDP to 30 mmHg (global stretch instead of local stretch) by inflating the left ventricular pressure balloon (strain, 0.148\u2009\u00b1\u20090.034). Each series was performed with n\u2009=\u20096. Stretch resulted in local strain of 25% at the left wall together with a local slowing of the activation process at the left wall, in a change in the activation pattern, and in ventricular arrhythmia. Coronary flow was not affected. Ventricular arrhythmias originated from the border between the stretched area and the non-stretched region. flecainide and streptomycin reduced the prolongation of the activation process at the stretched left wall and mitigated the difference in total activation time between left and front wall but only partially prevented arrhythmia. In the additional global stretch experiments relative coronary flow and the other parameters remained unchanged, in particular TAT. Thus, in contrast to the local stretch series, there was no difference in the change in TAT between left and front wall. Only rare single ventricular extrasystoles (<1/min; originating from LV (front and left wall) i.e. from within the stretched region) were seen during stretch (but not at the beginning) and during recovery. Local left ventricular stretch can elicit ventricular arrhythmias. Local slowing of electrical activation seems involved so that the difference in total activation time of the stretched free left wall and the non-stretched increased.", "source": "https://pubmed.ncbi.nlm.nih.gov/24858181/"}
{"doc_id": "fd589e56235bfb107bb352c60763500e", "sentence": "In the APHINITY study ( NCT01358877 , BIG 4 - 11/BO25126/TOC4939 G ) , pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer .", "spans": [{"span_id": 0, "text": "pertuzumab", "start": 71, "end": 81, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "trastuzumab", "start": 91, "end": 102, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Pharmacokinetics of pertuzumab administered concurrently with trastuzumab in Chinese patients with HER2-positive early breast cancer.  In the APHINITY study ( NCT01358877 , BIG 4 - 11/BO25126/TOC4939 G ) , pertuzumab added to trastuzumab and chemotherapy significantly improved invasive disease-free survival as adjuvant treatment for patients with HER2-positive early breast cancer . The objective of this analysis was to assess the pharmacokinetics of pertuzumab in combination with trastuzumab in Chinese patients with early breast cancer. Samples for pertuzumab and trastuzumab pharmacokinetic analysis were taken from Chinese patients during cycle 1 of treatment and at steady-state in cycle 10. Noncompartmental analysis was used to estimate minimum and maximum serum concentrations (Cmax and Cmin), area under the concentration-time curve, clearance, and other pharmacokinetic parameters. In 15 patients, mean steady-state Cmax and Cmin pertuzumab serum concentrations (368 \u00b1 177 \u03bcg/ml, and 122 \u00b1 47 \u03bcg/ml, respectively) were numerically higher than observed previously in a pharmacokinetic analysis of the global population in APHINITY and in patients treated in the metastatic setting. The geometric mean ratio and corresponding 90% confidence interval for trastuzumab Cmax and Cmin in the presence (n = 15) or absence (n = 17) of pertuzumab were 104.6 (91.09-120) and 98.23 (84.58-114), respectively, indicating no apparent impact of pertuzumab on the pharmacokinetics of trastuzumab. Increases in pertuzumab Cmax and Cmin were not associated with an increase in adverse events. The APHINITY Chinese pharmacokinetic substudy analysis supports the dosing regimen for pertuzumab (840 mg loading dose followed by 420 mg maintenance doses every 3 weeks administered by intravenous infusion) in a Chinese HER2-positive early breast cancer patient population.", "source": "https://pubmed.ncbi.nlm.nih.gov/31305270/"}
{"doc_id": "842c481f52d8e56971342febee357ad0", "sentence": "In two trials , an anti-EGFR antibody ( panitumumab or cetuximab ) reduced median survival when added to bevacizumab in previously untreated patients .", "spans": [{"span_id": 0, "text": "panitumumab", "start": 40, "end": 51, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cetuximab", "start": 55, "end": 64, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "bevacizumab", "start": 105, "end": 116, "token_start": 18, "token_end": 19}], "rels": [{"class": "NEG", "spans": [0, 2], "is_context_needed": false}, {"class": "NEG", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Chemotherapy of metastatic colorectal cancer. Without treatment, patients with inoperable or metastatic colorectal cancer have a median life expectancy of about 8 months. The following article is an update of our 2005 review of chemotherapy regimens used in metastatic colorectal cancer, based on the standard Prescrire methodology. In 2005, the de Gramont protocol, based on fluorouracil (always combined with folinic acid) plus either oxaliplatin (Folfox protocol) or irinotecan (Folfiri protocol), was the standard first-line chemotherapy in this setting. Four trials comparing monotherapy versus combination therapy in previously untreated patients showed that initial fluorouracil (or fluorouracil precursor) monotherapy, followed by the Folfox or Folfiri protocol in case of failure, was not associated with shorter overall survival. Two trials compared first-line treatment with the Folfiri regimen versus the Folfoxiri regimen (fluorouracil + oxaliplatin + irinotecan). One of these studies showed an increase in median survival with the Folfoxiri protocol (24 versus 17 months), but at a cost of greater neurotoxicity. The only tangible advantage of capecitabine and tegafur, two oral fluorouracil precursors, is their convenience of use. pemetrexed was less effective and more toxic than the Folfiri protocol in one trial. bevacizumab and panitumumab have yielded disappointing results in previously untreated patients. Neither of these monoclonal antibodies has yet been shown to improve overall survival. Three trials have assessed the addition of cetuximab to combinations consisting of fluorouracil or capecitabine plus oxaliplatin or irinotecan. In two of these trials, the median survival time of patients whose tumours carried the wild-type KRAS gene was about 3 months longer in the cetuximab arms, although the increase was statistically significant in only one trial. cetuximab had no impact on survival time in the third trial. In two trials , an anti-EGFR antibody ( panitumumab or cetuximab ) reduced median survival when added to bevacizumab in previously untreated patients . When progression occurs after treatment with the Folfiri protocol (or equivalent), a combination of the Folfox protocol and bevacizumab seems to increase median survival time by about 2 months versus Folfox alone, but it is also more toxic. In patients who progress after receiving the fluorouracil + oxaliplatin combination (Folfox) or the fluorouracil+ irinotecan combination (Folfiri), neither panitumumab nor cetuximab has been shown to provide a clinically meaningful increase in overall survival. It remains to be shown whether these drugs are more effective in patients with the wild-type KRAS gene than in patients with KRAS mutations. In early 2010, the standard cytotoxic drugs for treatment of metastatic colorectal cancer are fluorouracil (combined with folinic acid), oxaliplatin and irinotecan. Initial combination therapy may be beneficial when the metastases are borderline operable. When the metastases are inoperable and are unlikely to become operable after chemotherapy, it seems best to begin treatment with single-agent fluorouracil (+ folinic acid) or capecitabine. The use of monoclonal antibodies in first-line treatment of patients with colorectal cancer is not justified. Further trials of these drugs are warranted as second-line treatment for patients with KRAS wild-type tumours.", "source": "https://pubmed.ncbi.nlm.nih.gov/21180382/"}
{"doc_id": "32d6f9ea24ebefa67b7f337223591178", "sentence": "The results of the APPEARANCE trial indicate that adapalene does not prevent acne-like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect .", "spans": [{"span_id": 0, "text": "adapalene", "start": 50, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "minocycline", "start": 148, "end": 159, "token_start": 23, "token_end": 24}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Adapalene Gel 0.1% Versus Placebo as Prophylaxis for Anti-Epidermal Growth Factor Receptor-Induced Acne-Like Rash: A Randomized Left-Right Comparative Evaluation (APPEARANCE).  The results of the APPEARANCE trial indicate that adapalene does not prevent acne-like rash over placebo when added to topical moisturizer and oral minocycline but instead may have a detrimental effect . Therefore, adapalene is not recommended as prophylaxis against acne-like rash induced by anti-epidermal growth factor receptor therapies.Given that acne-like rash was completely controlled with placebo in approximately half of patients, predictive measures to identify patients needing intensive prophylaxis are required. ### background Anti-epidermal growth factor receptor (EGFR) therapies are frequently associated with acne-like rash. To evaluate the prophylactic efficacy of adapalene, a topical retinoid used as first-line therapy for acne vulgaris, we conducted a randomized, placebo-controlled, evaluator-blinded, left-right comparative trial. ### methods Patients with non-small cell lung, colorectal, or head and neck cancer scheduled to receive anti-EGFR therapies were randomly assigned to once-daily adapalene application on one side of the face, with placebo on the other side. All patients had topical moisturizer coapplied to both sides of the face, and received oral minocycline. The primary endpoint was the difference in total facial lesion count of acne-like rash at 4\u2009weeks. Secondary endpoints included complete control rate (CCR) of acne-like rash (\u22645 facial lesions) and global skin assessment (Investigator's Global Assessment [IGA] scale, grade 0-4) at 4\u2009weeks. Two blinded dermatologists independently evaluated the endpoints from photographs. ### results A total of 36 patients were enrolled, of whom 26 were evaluable. adapalene treatment was associated with a greater lesion count than placebo at 4\u2009weeks, although the difference was not statistically significant (mean, 12.6 vs. 9.8, ### conclusion adapalene is not recommended as prophylaxis against acne-like rash induced by anti-EGFR therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/30890624/"}
{"doc_id": "fe491984e9df643f36a53c19d1b92689", "sentence": "Both regimens included cyclophosphamide , methotrexate , 5-FU , prednisone , and doxorubicin .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 23, "end": 39, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "methotrexate", "start": 42, "end": 54, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "5-FU", "start": 57, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "prednisone", "start": 64, "end": 74, "token_start": 9, "token_end": 10}, {"span_id": 4, "text": "doxorubicin", "start": 81, "end": 92, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 4], "is_context_needed": true}], "paragraph": "Randomized comparison of two combination chemotherapy regimens containing doxorubicin in patients with metastatic breast cancer: a Western Cancer Study Group trial. Ninety-six patients with metastatic breast cancer were entered in a prospectively randomized trial comparing a five-drug doxorubicin (Adriamycin)-containing regimen given in two different schedules. Both regimens included cyclophosphamide , methotrexate , 5-FU , prednisone , and doxorubicin . On one schedule, referred to as \"combination\" treatment, doxorubicin was given every 21 days and cyclophosphamide was given daily. On the less intensive \"fixed-rotation\" schedule, doxorubicin was given on alternative cycles every 42 days and cyclophosphamide was given for 21 days of the 42-day cycle. Response frequency and survival were comparable among patients receiving either regimen. Significantly less (P < 0.05) nausea and leukopenia occurred on the fixed-rotation schedule. Therefore, similar therapeutic benefit along with decreased toxicity was obtained by use of combination chemotherapy involving doxorubicin and cyclophosphamide given in the less intensive schedule.", "source": "https://pubmed.ncbi.nlm.nih.gov/7004635/"}
{"doc_id": "d8c8bee379a8e9440c10b70d55a1dd89", "sentence": "In 2011 , new drugs were approved by the U.S. Food and Drug Administration , including peginterferon alfa-2b for patients with stage III disease , vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation , and ipilimumab , a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor , to combat metastatic melanoma in patients who do not have the BRAF V600E mutation .", "spans": [{"span_id": 0, "text": "peginterferon alfa-2b", "start": 87, "end": 108, "token_start": 16, "token_end": 18}, {"span_id": 1, "text": "vemurafenib", "start": 147, "end": 158, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "ipilimumab", "start": 232, "end": 242, "token_start": 38, "token_end": 39}], "rels": [], "paragraph": "Cutaneous melanoma: new advances in treatment. Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011 , new drugs were approved by the U.S. Food and Drug Administration , including peginterferon alfa-2b for patients with stage III disease , vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation , and ipilimumab , a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor , to combat metastatic melanoma in patients who do not have the BRAF V600E mutation . Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life.", "source": "https://pubmed.ncbi.nlm.nih.gov/24770508/"}
{"doc_id": "7710b6d76f366019125879999cf7208f", "sentence": "Individual studies have reported differences between antiandrogens in terms of both tolerability and efficacy-for example , bicalutamide has been shown to be better tolerated than flutamide , and may be associated with improved survival .", "spans": [{"span_id": 0, "text": "bicalutamide", "start": 124, "end": 136, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "flutamide", "start": 180, "end": 189, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Combination hormonal therapy: a reassessment within advanced prostate cancer. Combination hormonal therapy, comprising a luteinising hormone-releasing hormone analogue (LHRHa) with an antiandrogen, is widely used in the treatment of advanced prostate cancer. There is ongoing debate regarding the use of combination hormonal therapy as opposed to LHRHa monotherapy. The pivotal consideration is whether there are adequate benefits with combination hormonal therapy in terms of increased survival and decreased disease progression to outweigh the increased risk of adverse events and additional cost. The most recent meta-analysis by the Prostate Cancer Trialists' Collaborative Group indicates a small but statistically significant survival benefit with combination hormonal therapy using nonsteroidal antiandrogens. It is, however, noteworthy that combined conclusions derived from such meta-analyses may not apply across each of the individual antiandrogens. Individual studies have reported differences between antiandrogens in terms of both tolerability and efficacy-for example , bicalutamide has been shown to be better tolerated than flutamide , and may be associated with improved survival . In addition, it is essential that treatment decisions are taken in consultation with the patient. Owing to an increasing proportion of cases presenting with early-stage disease, combination hormonal therapy is increasingly used in the neoadjuvant or adjuvant setting with radiotherapy and, in cases of prostate-specific antigen recurrence after prior localised therapy. Further data are awaited to optimise the use of combination hormonal therapy in these new settings.", "source": "https://pubmed.ncbi.nlm.nih.gov/15365575/"}
{"doc_id": "778960b473d357bcf187c40c2b8bd36f", "sentence": "A Randomized , Multicenter , Double-blind , Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis .", "spans": [{"span_id": 0, "text": "Montelukast", "start": 145, "end": 156, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "Levocetirizine", "start": 161, "end": 175, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Randomized , Multicenter , Double-blind , Phase III Study to Evaluate the Efficacy on Allergic Rhinitis and Safety of a Combination Therapy of Montelukast and Levocetirizine in Patients With Asthma and Allergic Rhinitis . The aim of this study was to evaluate the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma compared with the efficacy and safety of montelukast alone. ### methods This study was a 4-week, randomized, multicenter, double-blind, Phase III trial. After a 1-week placebo run-in period, the subjects were randomized to receive montelukast (10 mg/day, n\u202f=\u202f112) or montelukast (10 mg/day)/levocetirizine (5 mg/day) (n\u202f=\u202f116) treatment for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score. Other efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, overall assessment of allergic rhinitis by both subjects and physicians, forced expiratory volume in 1 second (FEV ### findings Of 333 patients screened for this study, 228 eligible patients were randomized to treatment. The mean (SD) age of patients was 43.32 (15.02) years, and two thirds of subjects were female (66.67%). The demographic characteristics were similar between the treatment groups. Compared with the montelukast group, the montelukast/levocetirizine group reported significant reductions in mean daytime nasal symptom score (least squares mean [SE] of combination vs montelukast, -0.98 [0.06] vs -0.81 [0.06]; P\u202f=\u202f0.045). For all other allergic rhinitis efficacy end points, the montelukast/levocetirizine group showed greater improvement than the montelukast group. Similar results were observed in overall assessment scores and in FEV ### implications The fixed-dose combination of montelukast and levocetirizine was effective and safe in treating perennial allergic rhinitis in patients with asthma compared with montelukast alone. ClinicalTrials.gov identifier: NCT02552667.", "source": "https://pubmed.ncbi.nlm.nih.gov/29945738/"}
{"doc_id": "dec2ee86c2d3ab1e469f8cc6645bcc97", "sentence": "Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects .", "spans": [{"span_id": 0, "text": "cefoperazone", "start": 30, "end": 42, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "sulbactam", "start": 47, "end": 56, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Multiple-dose pharmacokinetics and toleration of intravenously administered cefoperazone and sulbactam when given as single agents or in combination. The multiple-dose pharmacokinetics and toleration of cefoperazone (3 g every 12 h) and sulbactam (1.5 g every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen male volunteers participated in an open, three-way crossover study of Latin Square design with a 1-week washout period between phases. On days 1 and 7 of each phase, serial serum samples and urine were collected for drug assay over a 12-h period. Hematological and clinical chemistry determinations were made within 10 days before the first antibiotic dose and for each treatment phase just before the first dose, on day 4 of treatment, and within 24 h of the last dose. For cefoperazone as a single agent on days 1 and 7, the average maximal concentration in serum (Cmax) was approximately 430 micrograms/ml, the terminal elimination half-life (t1/2) was 1.8 h, and the average percentage of dose excreted unchanged in the urine (%Ur) was 30%. For sulbactam as a single agent, the Cmax was approximately 90 micrograms/ml, the t1/2 was 1 h, and the %Ur was 89% on days 1 and 7. When comparing individual versus simultaneous drug administration, the only pharmacokinetic alteration observed was a statistically significant but minor (about 10%) decrease in sulbactam renal clearance, on both days 1 and 7, resulting in a similar decrease in total body clearance (CL). The area under the curve, apparent volume of distribution by the area method (V), t1/2, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal clearance, and V were modestly higher from day 1 to day 7. Because Cmax and t1/2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects . The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that either drug given alone under the conditions of this study.", "source": "https://pubmed.ncbi.nlm.nih.gov/3348612/"}
{"doc_id": "97fe69f307e811dcf18ff2b21cef466f", "sentence": "HDC with cyclophosphamide , carmustine and thiotepa was given from day -7 to -5 .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 9, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "carmustine", "start": 28, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "thiotepa", "start": 43, "end": 51, "token_start": 6, "token_end": 7}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Interleukin-2 and granulocyte-macrophage-colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Immunomodulation with cytokines was used to improve the result of high-dose chemotherapy (HDC)/autologous hematopoietic stem cell transplantation (AHST). We examined the use of IL-2 and growth factors for mobilization, ex vivo activation of peripheral blood stem cell (PBSC) and maintenance therapy after HDC/AHST in metastatic breast cancer. Eligible patients with metastatic breast cancer for HDC/AHST were assigned to 1 of 3 protocols for PBSC mobilization: G-CSF (group 1); IL-2 + G-CSF (group 2); or IL-2 + G-CSF + GM-CSF (group 3). HDC with cyclophosphamide , carmustine and thiotepa was given from day -7 to -5 . PBSCs were treated ex vivo with IL-2 for 24 h and reinfused on day 0. Maintenance therapy included low-dose IL-2, followed by 2 courses of intermediate-dose IL-2. GM-CSF was given from day 1 until neutrophil recovery. Thirty-four patients (10 in group 1, 14 in group 2, and 10 in group 3) were included. Comparable numbers of CD34(+) cells were collected from all 3 groups; incremental increases of CD3(+) cells were collected from groups 1 to 2 and to 3 (p = 0.03). Major adverse effects from IL-2 were fever, hypotension and fatigue; no treatment-related mortality was seen. At a median follow-up of 790.5 days (range 150-2,722 days), median progression-free survival was 434 days and median overall survival was 1,432 days. Estimated 3-year progression-free and overall survival rates were 31 and 57%. Our study suggested that the use of IL-2 and growth factors immunomodulation with HDC/AHST was feasible with comparable survival rates.", "source": "https://pubmed.ncbi.nlm.nih.gov/19998065/"}
{"doc_id": "44ad2538e2540fa90b878956d4de15df", "sentence": "Melatonin or sulpiride could replace these environmental factors .", "spans": [{"span_id": 0, "text": "Melatonin", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "sulpiride", "start": 13, "end": 22, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Controlling retinal pigment epithelium injury after experimental detachment of the retina. Damage induced by detachment of the neural retina and the retinal pigment epithelium (RPE) can be reduced by dark adaptation. The authors evaluated the influence of the duration of dark adaptation, time of day, and modification of the melatonin-dopamine pathway on acute RPE lesions induced by mechanical detachment. ### methods BALB/c mice were studied at different times of day and different periods of dark adaptation. Some mice were treated with melatonin or sulpiride, a D2 dopamine receptor antagonist. Enucleated eyes and different saline solutions were used in experiments ex vivo. Retinal detachments in vivo were made by subretinal injections of hyaluronic acid. RPE cell damage was quantitatively evaluated with a dye exclusion procedure, and their viability was tested by preservation of tight junctions in culture. Lectin histochemistry was used to examine the interphotoreceptor matrix (IPM). ### results Significant propidium iodide (PI) incorporation in RPE cells was detected after ex vivo separation during daytime, but it was very low when detachment took place at night after 24 to 48 hours of dark adaptation. PI exclusion was achieved during daytime after a single hour of dark adaptation when mice were pretreated with melatonin or sulpiride. Reduction of RPE cell damage was accompanied by decreased lectin binding to cone sheaths. ### conclusions A combination of time of day and length of dark adaptation decreased damage induced by detachment of the retina ex vivo and in vivo. Melatonin or sulpiride could replace these environmental factors . Therefore, melatonin and dopamine pathways might be involved in the control of IPM properties and retina/RPE interactions.", "source": "https://pubmed.ncbi.nlm.nih.gov/17325183/"}
{"doc_id": "1df7aefd099152b9e422ca4f3480841f", "sentence": "Trastuzumab and Pertuzumab Plant Biosimilars : Modification of Asn297-linked Glycan of the mAbs Produced in a Plant with Fucosyltransferase and Xylosyltransferase Gene Knockouts .", "spans": [{"span_id": 0, "text": "Trastuzumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "Pertuzumab", "start": 16, "end": 26, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Trastuzumab and Pertuzumab Plant Biosimilars : Modification of Asn297-linked Glycan of the mAbs Produced in a Plant with Fucosyltransferase and Xylosyltransferase Gene Knockouts . Plant biosimilars of anticancer therapeutic antibodies are of interest not only because of the prospects of their practical use, but also as an instrument and object for study of plant protein glycosylation. In this work, we first designed a pertuzumab plant biosimilar (PPB) and investigated the composition of its Asn297-linked glycan in comparison with trastuzumab plant biosimilar (TPB). Both biosimilars were produced in wild-type (WT) Nicotiana benthamiana plant (PPB-WT and TPB-WT) and transgenic \u0394XTFT N. benthamiana plant with XT and FT genes knockout (PPB-\u0394XTFT and TPB-\u0394XTFT). Western blot analysis with anti-\u03b11,3-fucose and anti-xylose antibodies, as well as a test with peptide-N-glycosidase F, confirmed the absence of \u03b11,3-fucose and xylose in the Asn297-linked glycan of PPB-\u0394XTFT and TPB-\u0394XTFT. Peptide analysis followed by the identification of glycomodified peptides using MALDI-TOF/TOF showed that PPB-WT and TPB-WT Asn297-linked glycans are mainly of complex type GnGnXF. The core of PPB-WT and TPB-WT Asn297-linked GnGn-type glycan contains \u03b11,3-fucose and \u03b21,2-xylose, which, along with the absence of terminal galactose and sialic acid, distinguishes these plant biosimilars from human IgG. Analysis of TPB-\u0394XTFT total carbohydrate content indicates the possibility of changing the composition of the carbohydrate profile not only of the Fc, but also of the Fab portion of an antibody produced in transgenic \u0394XTFT N. benthamiana plants. Nevertheless, study of the antigen-binding capacity of the biosimilars showed that absence of xylose and fucose residues in the Asn297-linked glycans does not affect the ability of the glycomodified antibodies to interact with HER2/neu positive cancer cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/28371609/"}
{"doc_id": "ab76770db4af60662537ffbe504aa0c9", "sentence": "A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective ( overall response rate 75 % ) and well tolerated , with the major side effects being typical of single-agent vinorelbine .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 57, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "vinorelbine", "start": 74, "end": 85, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "vinorelbine", "start": 214, "end": 225, "token_start": 35, "token_end": 36}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "New combinations with Herceptin in metastatic breast cancer. Preclinical data indicate that trastuzumab (Herceptin) has the potential for synergistic or additive effects in combination with therapies including chemotherapy and hormonal agents, providing the rationale for a number of clinical trials in women with HER2-positive metastatic breast cancer. A recently reported phase II trial has demonstrated that trastuzumab plus vinorelbine is both effective ( overall response rate 75 % ) and well tolerated , with the major side effects being typical of single-agent vinorelbine . Other combinations of trastuzumab with a variety of other chemotherapeutic and hormonal agents are also being assessed. In an effort to overcome the cardiotoxicity observed with trastuzumab plus doxorubicin in the pivotal phase III trial, combination regimens involving potentially less toxic anthracyclines such as epirubicin and liposomal formulations of doxorubicin are ongoing. In addition, trials are investigating whether trastuzumab can reverse the resistance to hormonal therapy that develops in most women with metastatic breast cancer. These and other studies will identify the regimens that produce the best outcomes with the fewest possible side effects in women with HER2-positive breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/11694788/"}
{"doc_id": "e1c3fcbebfbf9bd3d6eb900c930c8bc1", "sentence": "Men with prostate cancer were randomly assigned to one of four treatment arms : leuprorelin , goserelin , cyproterone acetate ( CPA ) , or close clinical monitoring .", "spans": [{"span_id": 0, "text": "leuprorelin", "start": 80, "end": 91, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "goserelin", "start": 94, "end": 103, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "cyproterone", "start": 106, "end": 117, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. To investigate the effects of different management strategies for non-localized prostate cancer on men's quality of life and cognitive functioning. ### Patients Subjects And Methods Men with prostate cancer were randomly assigned to one of four treatment arms : leuprorelin , goserelin , cyproterone acetate ( CPA ) , or close clinical monitoring . In a repeated-measures design, men were assessed before treatment (baseline) and after 6 and 12 months of treatment. A community comparison group of men of the same age with no prostate cancer participated for the same length of time. The men were recruited from public and private urology departments from university teaching hospitals. All those with prostate cancer who were eligible for hormonal therapy had no symptoms requiring immediate therapy. In all, 82 patients were randomized and 62 completed the 1-year study, and of the 20 community participants, 15 completed the study. The main outcome measures were obtained from questionnaires on emotional distress, existential satisfaction, physical function and symptoms, social and role function, subjective cognitive function, and sexual function, combined with standard neuropsychological tests of memory, attention, and executive functions. ### results Sexual dysfunction increased for patients on androgen-suppressing therapies, and emotional distress increased in those assigned to CPA or close clinical monitoring. Compared with before treatment there was evidence of an adverse effect of leuprorelin, goserelin, and CPA on cognitive function. ### conclusions In deciding the timing of androgen suppression therapy for prostate cancer, consideration should be given to potential adverse effects on quality of life and cognitive function.", "source": "https://pubmed.ncbi.nlm.nih.gov/15142146/"}
{"doc_id": "7bd97010e6ca716490f2fe6f366d14b6", "sentence": "There were no significant differences between the two treatment groups , except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response ( low quality of evidence ) .", "spans": [{"span_id": 0, "text": "amantadine", "start": 85, "end": 95, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "mycophenolate", "start": 112, "end": 125, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Aminoadamantanes versus other antiviral drugs for chronic hepatitis C. Hepatitis C virus infection affects around 3% of the world population or approximately 160 million people. A variable proportion (5% to 40%) of the infected people develop clinical symptoms. Hence, hepatitis C virus is a leading cause of liver-related morbidity and mortality with hepatic fibrosis, end-stage liver cirrhosis, and hepatocellular carcinoma as the dominant clinical sequelae. Combination therapy with pegylated (peg) interferon-alpha and ribavirin achieves sustained virological response (that is, undetectable hepatitis C virus RNA in serum by sensitivity testing six months after the end of treatment) in approximately 40% to 80% of treated patients, depending on viral genotype. Recently, a new class of drugs have emerged for hepatitis C infection, the direct acting antivirals, which in combination with standard therapy or alone can lead to sustained virological response in 80% or more of treated patients. Aminoadamantanes, mostly amantadine, are antiviral drugs used for the treatment of patients with chronic hepatitis C. We have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of the amantadine on all-cause mortality or liver-related morbidity and on adverse events in patients with hepatitis C. Overall, we did not observe a significant effect of amantadine on sustained virological response. In this review, we systematically review aminoadamantanes versus other antiviral drugs. ### objectives To assess the beneficial and harmful effects of aminoadamantanes versus other antiviral drugs for patients with chronic hepatitis C virus infection by conducting a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. ### Search Methods The Cochrane Hepato-Biliary Group Controlled Trials Register (1996 to December 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11 of 12, 2013), MEDLINE (1946 to December 2013), EMBASE (1974 to December 2013), Science Citation Index EXPANDED (1900 to December 2013), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp), Google Scholar, and Eudrapharm up to December 2013. Furthermore, full text searches were conducted until December 2013. ### Selection Criteria Randomised clinical trials assessing aminoadamantanes in participants with chronic hepatitis C virus infection. ### Data Collection And Analysis Two authors independently extracted data. RevMan Analysis was used for statistical analysis of dichotomous data using risk ratio (RR) with 95% confidence intervals (CI). Methodological domains were used to assess the risk of systematic errors ('bias'). We used trial sequential analysis to assess risk of random errors ('play of chance'). ### Main Results Six randomised clinical trials with 581 participants with chronic hepatitis C were included. All trials had high risk of bias. The included trials compared amantadine versus other antiviral drugs: ribavirin, mycophenolate mofetil, interferon-alpha, or interferon-gamma. Standard antiviral therapy (interferon-alpha, interferon-alpha plus ribavirin, or peg interferon alpha) was administered equally to the intervention and the control groups in five trials, depending on when the trial was conducted. Four trials compared amantadine versus ribavirin. There were no deaths or liver-related morbidity in the two intervention groups (0/216 (0%) versus 0/211 (0%); 4 trials; very low quality of the evidence). The lower estimated risk for (serious) adverse events leading to treatment discontinuation with amantadine was imprecise (RR 0.56, 95% CI 0.27 to 1.16; based on 10/216 (5%) versus 18/211 (9%) participants in 4 trials; very low quality of the evidence). There were more participants with failure of sustained virological response in the amantadine group than in the ribavirin group (206/216 (96%) versus 176/211 (84%); RR 1.14, 95% CI 1.07 to 1.22, 4 trials; low quality of the evidence). amantadine versus ribavirin more often failed to achieve end-of follow-up biochemical response (41/46 (89%) versus 31/46 (67%); RR 1.31, 95% CI 1.05 to 1.63; 2 trials; very low quality of the evidence). One trial compared amantadine versus mycophenolate mofetil. There were no significant differences between the two treatment groups , except that amantadine was inferior to mycophenolate mofetil regarding the outcome failure to achieve end-of treatment virological response ( low quality of evidence ) . One trial each compared amantadine versus interferon-alpha or interferon-gamma. Both comparisons showed no significant differences in the treatment outcomes (very low quality of the evidence). The observed effects could be due to real effects, systematic errors (bias), or random errors (play of chance). This possible influence on the observed effect by play of chance is due to the fact that trial sequential analyses could not confirm our findings. We were not able to perform meta-analyses on failure of histological improvement and quality of life due to lack of valid data in all trial comparisons. ### Authors Conclusions This systematic review has identified evidence of very low quality for the key outcomes of all-cause mortality or liver-related morbidity and adverse events in people with chronic hepatitis C when treated with amantadine compared with ribavirin, mycophenolate, interferon-alpha, or interferon-gamma. The timeframe for measuring the composite outcome was insufficient in the included trials. There was low quality evidence that amantadine led to more participants who failed to achieve sustained virological response compared with ribavirin. This observation may be real or caused by systematic errors (bias), but it does not seem to be caused by random error (play of chance). Due to the low quality of the evidence, we are unable to determine definitively whether amantadine is less effective than other antivirals in patients with chronic hepatitis C. As it appears less likely that future trials assessing amantadine or potentially other aminoadamantanes for patients with chronic hepatitis C would show strong benefits, it is probably better to focus on the assessments of other direct acting antiviral drugs. We found no evidence assessing other aminoadamantanes in randomised clinical trials in order to recommend or refute their use.", "source": "https://pubmed.ncbi.nlm.nih.gov/24937404/"}
{"doc_id": "1b70191abaf8f7a0e189322a31ad5a10", "sentence": "Furthermore , more incidences of severe fatigue , thrombocytopenia , and neutropenia were recorded for sunitinib , but pazopanib had more liver toxicity .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 103, "end": 112, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "pazopanib", "start": 119, "end": 128, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Pazopanib has equivalent anti-tumor effectiveness and lower Total costs than Sunitinib for treating metastatic or advanced renal cell carcinoma: a meta-analysis. sunitinib and pazopanib are extensively used as first-line treatment of metastatic renal cell carcinoma (mRCC). We performed this meta-analysis to assess the anti-tumor effectiveness, toxicity, and total costs of the two drugs among patients with mRCC/advanced RCC (aRCC). ### Materials And Methods PubMed, ScienceDirect, Scopus, Web of Science, Ovid MEDLINE, the Cochrane Library, Embase, and Google Scholar were searched to obtain eligible articles. The endpoints included progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and per-patient-per-month (PPPM) costs. ### results We included 14 medium- to high-quality studies. Both drugs were valid for mRCC/aRCC, with equivalent PFS (hazard ratio (HR) =1.06, 95% confidence interval [CI]: 0.98-1.15, P\u2009=\u20090.13), OS (HR\u2009=\u20090.92, 95% CI: 0.79-1.07, P\u2009=\u20090.29), objective response rate (ORR, risk ratio (RR) =1.03, 95% CI: 0.93-1.13, p\u2009=\u20090.58), and disease control rate (DCR, RR\u2009=\u20091.03, 95% CI: 0.94-1.22, P\u2009=\u20090.54). sunitinib had more dosage reductions and higher PPPM (weighted mean difference\u2009=\u2009-\u20091.50 thousand US dollars, 95% CI: -\u20092.27 to -\u20090.72, P\u2009=\u20090.0002). Furthermore , more incidences of severe fatigue , thrombocytopenia , and neutropenia were recorded for sunitinib , but pazopanib had more liver toxicity . In subgroup analysis, studies from the US reported longer OS (HR\u2009=\u20090.86, 95% CI: 0.77-0.95, P\u2009=\u20090.004) and higher ORR (RR\u2009=\u20091.24, 95% CI: 1.03-1.51, P\u2009=\u20090.03). ### conclusions pazopanib provides equivalent anti-tumor effectiveness and lower PPPM as compared with sunitinib for mRCC/aRCC. Great care should be given to pazopanib-treated patients with abnormal liver function. Nevertheless, more large-scale, high-quality studies are required.", "source": "https://pubmed.ncbi.nlm.nih.gov/31122210/"}
{"doc_id": "0b7d45d16b3ab6f016d055f1cfd7b822", "sentence": "Streptomycin appears to be the most effective agent followed by gentamicin and the least active was netilmicin .", "spans": [{"span_id": 0, "text": "Streptomycin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gentamicin", "start": 64, "end": 74, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "netilmicin", "start": 100, "end": 110, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Activity of aminoglycosides against phagocytosed bacteria. The intracellular activity of streptomycin, gentamicin, and netilmicin on Escherichia coli phagocytosed by murine peritoneal macrophages was studied using a sensitive and standardized method. Intracellular activity of streptomycin and gentamicin at therapeutic concentrations was seen after 1 h of incubation of antibiotics with macrophages containing phagocytosed bacteria, whilst for netilmicin a significant intracellular activity was observed only after 3 h exposure. The activity of these antibiotics against intraphagocytic bacteria was significantly lower than that observed against extracellular bacteria. Sub-inhibitory concentrations of streptomycin were active against intracellular E. coli. streptomycin was also active for a phagocytosed streptomycin-resistant strain of E. coli, but this activity was eliminated when the O2-dependent killing mechanisms of macrophages were inhibited by sodium fluoride. The data demonstrate that aminoglycosides may exert a dose-dependent intraphagocytic activity against E. coli that correlates with the time of incubation of the antibiotics with infected macrophages. Streptomycin appears to be the most effective agent followed by gentamicin and the least active was netilmicin . In the case of streptomycin, the intraphagocytic activity seems to be due, at least in part, to the stimulation of O2-dependent cellular microbactericidal mechanisms.", "source": "https://pubmed.ncbi.nlm.nih.gov/1816186/"}
{"doc_id": "ef0a5c606391305316e0d00ede66a186", "sentence": "Neither behavioral therapy , clomipramine , methylphenidate , buspirone , nor naltrexone was effective in monotherapeutic trials .", "spans": [{"span_id": 0, "text": "clomipramine", "start": 29, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "methylphenidate", "start": 44, "end": 59, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "buspirone", "start": 62, "end": 71, "token_start": 8, "token_end": 9}, {"span_id": 3, "text": "naltrexone", "start": 78, "end": 88, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Comprehensive management of trichotillomania in a young autistic girl. The coexistence of trichotillomania and autistic disorder has rarely been reported in psychiatric literature. The current study describes successful treatment of trichotillomania in a young autistic girl, using combined clomipramine and behavioral therapy. Neither behavioral therapy , clomipramine , methylphenidate , buspirone , nor naltrexone was effective in monotherapeutic trials . We postulate a synergistic effect of combined treatment with clomipramine and behavioral therapy, suggesting that both pharmacological and behavioral treatment of hair pulling may be necessary for many patients. This model is consistent with the extant literature and suggests that future clinical trials of clomipramine for trichotillomania, in both developmentally disabled and normal subjects, must evaluate this multimodal approach.", "source": "https://pubmed.ncbi.nlm.nih.gov/8005911/"}
{"doc_id": "b95a84fc95f0619053e07be8a81b50c8", "sentence": "Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride .", "spans": [{"span_id": 0, "text": "granisetron", "start": 186, "end": 197, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "mosapride", "start": 202, "end": 211, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics. To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis. ### methods Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [(18)F]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [(18)F]FDG. ### results Teriparatide delayed the time-radioactivity profile of [(18)F]FDG in blood and significantly reduced its absorption rate constant (k a ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k a of [(18)F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [(18)F]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride . ### conclusions Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.", "source": "https://pubmed.ncbi.nlm.nih.gov/26869173/"}
{"doc_id": "836714985a9765014b9095f0827ada4d", "sentence": "Differences were observed when palbociclib or ribociclib was used in combination with letrozole or anastrozole or fulvestrant .", "spans": [{"span_id": 0, "text": "palbociclib", "start": 31, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "ribociclib", "start": 46, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "letrozole", "start": 86, "end": 95, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "anastrozole", "start": 99, "end": 110, "token_start": 14, "token_end": 15}, {"span_id": 4, "text": "fulvestrant", "start": 114, "end": 125, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 3], "is_context_needed": true}, {"class": "COMB", "spans": [0, 4], "is_context_needed": true}], "paragraph": "First clinical experience with CDK4/6 inhibitors in breast cancer therapy. For hormone receptor-positive, HER2-negative breast cancer patients with metastatic or advanced disease, therapy with CDK4/6 inhibitors in addition to aromatase inhibitors (AIs) or to the estrogen receptor (ER) downregulator fulvestrant has resulted in an additional therapy option and a longer progression-free survival. In the Gynecologic-Oncology Clinic, Diakonie-Klinikum Schw\u00e4bisch Hall, we followed and registered our initial clinical experience with CDK4/6 inhibitors, following the side effects and tumor response over two years since they were officially approved for general use in Germany. Differences were observed when palbociclib or ribociclib was used in combination with letrozole or anastrozole or fulvestrant . The dynamic side effects and tumor response under therapy with palbociclib or ribociclib were found to be comparable with the main reported data in the official drug information. The CDK4/6 inhibitors have an important and promising role in the therapy of breast cancer patients. Patient age and therapy duration do not influence the use of palbociclib or ribociclib, although it may be important which AI is used in combination with palbociclib.", "source": "https://pubmed.ncbi.nlm.nih.gov/33815595/"}
{"doc_id": "df9fa8081eca7b7f4600cb17b04878f1", "sentence": "Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 56, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "lovastatin", "start": 73, "end": 83, "token_start": 9, "token_end": 10}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients. Hyperlipidemia, particularly hypercholesterolemia, occurs in cardiac transplant recipients both as a preexisting condition and as a consequence of immunosuppressive therapy. lovastatin (Mevacor) has emerged as an agent that may effectively manage this condition. Few serious side effects of this drug have been observed. We describe two cardiac transplant recipients treated with lovastatin in conjunction with their other medications, including cyclosporine, who developed acute renal failure and rhabdomyolysis. Resolution of muscle damage followed discontinuation of cyclosporine and lovastatin therapy . We postulate that hepatic dysfunction secondary to cyclosporine predisposed these patients to lovastatin-induced muscle damage. Use of this drug in cardiac and other organ transplant recipients should be accompanied by close surveillance of creatine kinase, hepatic transaminases, and cyclosporine levels.", "source": "https://pubmed.ncbi.nlm.nih.gov/3290520/"}
{"doc_id": "0297c1d33bb07c4fa544ea21c302579a", "sentence": "In order to elucidate the possible interference of the antiparkinson drug 1-aminoadamantane ( D-1 , PK Merz ) and the antispastic compound 1,3-dimethyl-5-aminoadamantane ( DMAA , D-145 , memantine , Memantine ) on neurotransmitter metabolism , the effect of D-1 and its C-alkyl derivatives memantine , 1-amino-3,5,7-trimethyladamantane ( D-191 ) , and 1-amino-3-(n)-butyladamantane ( D-178 ) on MAO activity in brain , liver , and kidney of the rat was investigated .", "spans": [{"span_id": 0, "text": "PK Merz", "start": 100, "end": 107, "token_start": 15, "token_end": 17}, {"span_id": 1, "text": "memantine", "start": 187, "end": 196, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "Memantine", "start": 199, "end": 208, "token_start": 30, "token_end": 31}, {"span_id": 3, "text": "memantine", "start": 290, "end": 299, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Effect of 1-aminoadamantanes on the MAO activity in brain, liver, and kidney of the rat.  In order to elucidate the possible interference of the antiparkinson drug 1-aminoadamantane ( D-1 , PK Merz ) and the antispastic compound 1,3-dimethyl-5-aminoadamantane ( DMAA , D-145 , memantine , Memantine ) on neurotransmitter metabolism , the effect of D-1 and its C-alkyl derivatives memantine , 1-amino-3,5,7-trimethyladamantane ( D-191 ) , and 1-amino-3-(n)-butyladamantane ( D-178 ) on MAO activity in brain , liver , and kidney of the rat was investigated . A radioisotope method using [14C]5-hydroxytryptamine as substrate was used. The highest MAO activity was found in liver followed by brain and kidney (Vmax: 137, 64, and 26 nmol/mg protein X h, respectively). The Km values did not differ significantly for the three tissues (liver: 107 mumol/l; brain: 96 mumol/l; kidney: 86 mumol/l). The MAO activity in liver, brain and kidney was noncompetitively inhibited by all 1-aminoadamantanes studied, each derivative, respectively, showing in all three tissues about the same percentage inhibition. The inhibitory activity was found to be increased with the degree of C-alkylation: D-1 (Ki approximately 1 mmol/l) less than D-145 (Ki approximately 0.1 mmol/l) less than D-191 (Ki approximately 0.07 mmol/l) less than D 178 (Ki approximately 0.02 mmol/l).", "source": "https://pubmed.ncbi.nlm.nih.gov/6891223/"}
{"doc_id": "4a0c95a8282db45a6e5e58d864180a45", "sentence": "Primary chemotherapy with gemcitabine , liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer : results of a phase I trial .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 26, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxorubicin", "start": 50, "end": 61, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "docetaxel", "start": 66, "end": 75, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Primary chemotherapy with gemcitabine , liposomal doxorubicin and docetaxel in patients with locally advanced breast cancer : results of a phase I trial . The primary objective was to determine the optimal doses for gemcitabine (prolonged infusion), liposomal doxorubicin (Myocet) and docetaxel as primary (neoadjuvant) chemotherapy for locally advanced breast cancer. Secondary objectives included evaluation of the safety and efficacy of the regimen. Patients (n=19) with histologically confirmed stage II or III breast cancer were treated with liposomal doxorubicin (50-60 mg/m2) and docetaxel (60-75 mg/m2) on day 1, and gemcitabine as 4-h infusion (350-400 mg/m2) on day 4. Treatment was repeated every 3 weeks for a maximum of 6 cycles. The maximum tolerated doses were gemcitabine 350 mg/m2, liposomal doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. Dose-limiting toxicities were stomatitis, diarrhea and infection. The predominant hematologic toxicity was mild-to-moderate myelosuppression with grade 3/4 neutropenia in 20% of cycles. Non-hematologic toxicity was generally mild, with no grade 4 toxicities being observed. Predominant non-hematologic toxicity was stomatitis, which occurred in 95% of patients. Grade 3 toxicities were reported for stomatitis, nausea, diarrhea, infection and constipation. No cases of cardiac, renal, pulmonary or neurotoxicity were observed. The clinical response rate was 83% and histologically confirmed, clinically complete remissions occurred in two patients (11%). We conclude that the combination of gemcitabine (prolonged infusion), liposomal doxorubicin and docetaxel is safe and highly effective in patients with locally advanced breast cancer as defined by maximum tolerated doses. The evaluated schedule is suitable for phase II studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/15613900/"}
{"doc_id": "c7bfe36d9357817f952f9c2af200774e", "sentence": "A single bolus of dexamethasone , given before a single large meal , produces a delayed ( 6-hour ) but long-lasting increase in serum leptin ( over 16 hours ) .", "spans": [{"span_id": 0, "text": "dexamethasone", "start": 18, "end": 31, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "leptin", "start": 134, "end": 140, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Effect of one morning meal and a bolus of dexamethasone on 24-hour variation of serum leptin levels in humans. We have previously shown that morning administration of dexamethasone in combination with food induces a doubling of serum leptin levels starting at 7 hours after dexamethasone administration, with a maximum effect at 10 hours, the latest time point that we have studied. However, dexamethasone given in the absence of food had no effect on serum leptin at 10 hours. The present experiment was undertaken to determine the duration of the effect of dexamethasone on 24-hour serum leptin under fasted and fed conditions in humans. ### Research Methods And Procedures Six healthy non-obese male volunteers were studied under the following four conditions: 1) dexamethasone (2 mg intravenously, given at 0900 hours) with fasting; 2) dexamethasone with food (1,700 kcal, 55% carbohydrate, 15% protein, and 30% fat, given in one meal 2 hours after dexamethasone administration at 1100 hours); 3) saline with food (same meal); 4) saline with fasting. Serum leptin, glucose, insulin, and cortisol were monitored every 30 minutes for 24 hours. ### results 1) Under the fasting condition, dexamethasone increased leptin nocturnal secretion between 2100 and 2400 hours. 2) A single meal (1,700 kcal) at 1100 hours increased nocturnal leptin secretion when compared with the fasting condition. The peak increase of leptin was 123% over baseline between 2100 and 2400 hours, 10 to 14 hours after the meal. 3) In the fed + dexamethasone condition, leptin levels increased from baseline starting 8 hours after dexamethasone injection, reached a maximum increase of 260% between 2100 and 2400 hours, then decreased thereafter, remaining elevated compared to baseline for 16 hours. There was a correlation between 24-hour leptin secretion and insulin secretion after a single morning meal. ### discussion A single bolus of dexamethasone , given before a single large meal , produces a delayed ( 6-hour ) but long-lasting increase in serum leptin ( over 16 hours ) . Under fasted conditions, dexamethasone does not increase daytime leptin but does increase leptin during the night.", "source": "https://pubmed.ncbi.nlm.nih.gov/11068953/"}
{"doc_id": "7bcebbcb6a938a791d5b515ab0b481eb", "sentence": "The aim of this single-blind , randomized , controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid ( Ari+Val ) , compared with haloperidol plus valproic acid ( Hal+Val ) , in acute manic patients .", "spans": [{"span_id": 0, "text": "aripiprazole", "start": 113, "end": 125, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "valproic", "start": 143, "end": 151, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "haloperidol", "start": 185, "end": 196, "token_start": 31, "token_end": 32}, {"span_id": 3, "text": "valproic", "start": 202, "end": 210, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Combination treatment with aripiprazole and valproic acid for acute mania: an 8-week, single-blind, randomized controlled trial. Despite the fact that combination treatment for patients with acute bipolar is prevalent in clinical practice, the outcomes of adjunct treatment with aripiprazole and a mood stabilizer have rarely been reported. The aim of this single-blind , randomized , controlled trial was to investigate treatment efficacy and safety of aripiprazole as an adjunct to valproic acid ( Ari+Val ) , compared with haloperidol plus valproic acid ( Hal+Val ) , in acute manic patients . ### methods Treatment efficacy was prospectively assessed for 8 weeks in 42 patients with acute mania using the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale. Emergent adverse events were assessed by the Drug-Induced Extrapyramidal Symptoms Scale and the Liverpool University Neuroleptic Side Effect Rating Scale. ### results Both Ari+Val and Hal+Val produced a high rate of response (85.7% and 92.9%, respectively) and remission (82.1% and 85.7%, respectively) after the 8-week trial. Changes in the Young Mania Rating Scale and the Clinical Global Impression-Severity of illness scale over the study period and time to remission and response were not significantly different between the 2 groups. Patients treated with Ari+Val showed significantly fewer extrapyramidal adverse events than those treated with Hal+Val (t = -2.048, F = 40, P = 0.048). However, significant weight gain was more prevalent in the Ari+Val group than the Hal+Val group (t = 2.055, F = 40, P = 0.046). ### conclusions Our findings suggest that both combination strategies with Ari+Val and Hal+Val are beneficial for acute manic episode. Although patients receiving Ari+Val showed fewer extrapyramidal symptoms than those taking Hal+Val, careful consideration of adverse events such as weight gain and sedation is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/22592508/"}
{"doc_id": "634afdc7ed4ee4894a3426d33dc96600", "sentence": "Because the incidence of nausea and vomiting is significantly reduced when ketorolac is used in place of opioids to attenuate postoperative pain , it would appear to be an appropriate choice of agent to use following propofol anesthesia .", "spans": [{"span_id": 0, "text": "ketorolac", "start": 75, "end": 84, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "propofol", "start": 217, "end": 225, "token_start": 36, "token_end": 37}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Ketorolac and propofol administration for prevention of nausea and vomiting in patients undergoing minor gynecologic surgery. This clinical review explores the efficacy of the nonsteroidal antiinflammatory agent, ketorolac tromethamine, added to an anesthetic regimen utilizing intravenous propofol. Both agents have been shown to reduce the incidence of nausea and vomiting postoperatively when administered to patients undergoing minor gynecologic surgery. Because the incidence of nausea and vomiting is significantly reduced when ketorolac is used in place of opioids to attenuate postoperative pain , it would appear to be an appropriate choice of agent to use following propofol anesthesia . The use of this combination of drugs may not only reduce the incidence of postoperative nausea and vomiting in patients undergoing minor gynecologic surgery, but could reduce the duration of hospitalization and enhance recovery from anesthesia.", "source": "https://pubmed.ncbi.nlm.nih.gov/8499507/"}
{"doc_id": "ac00391719a33cac85ce9aa4f853c2d6", "sentence": "The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone .", "spans": [{"span_id": 0, "text": "vandetanib", "start": 19, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bicalutamide", "start": 34, "end": 46, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "bicalutamide", "start": 129, "end": 141, "token_start": 18, "token_end": 19}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy na\u00efve castration-resistant prostate cancer. To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). ### methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-na\u00efve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (\u2265 50 % decline from baseline). ### results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p\u2009=\u20090.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. ### conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Further evaluation of this combination is not warranted in mCRPC.", "source": "https://pubmed.ncbi.nlm.nih.gov/24671507/"}
{"doc_id": "4f1afbea8c1eaa64ea7cb68414fcde1a", "sentence": "Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control , and that this activity is likely due to effects on both BC and microenvironment cells .", "spans": [{"span_id": 0, "text": "Aspirin", "start": 39, "end": 46, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Atenolol", "start": 53, "end": 61, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "Metformin", "start": 65, "end": 74, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells. metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since metformin is frequently used along with aspirin or beta-blockers, we investigated the effect of metformin, aspirin and the beta-blocker atenolol in several BC models. In vitro, aspirin synergized with metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both aspirin and atenolol added to the inhibitory effect of metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, atenolol increased metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. aspirin increased the activity of metformin only in immune-competent HER2+ BC models. Both aspirin and atenolol, when added to metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of atenolol but not by the addition of aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control , and that this activity is likely due to effects on both BC and microenvironment cells .", "source": "https://pubmed.ncbi.nlm.nih.gov/26728433/"}
{"doc_id": "b0b46e31b844bb0b6f220eb00e3d2031", "sentence": "Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest , triggered caspase-dependent apoptosis , and decreased tumorigenicity both in vitro and in vivo .", "spans": [{"span_id": 0, "text": "vorinostat", "start": 20, "end": 30, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "oxaliplatin", "start": 35, "end": 46, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Vorinostat enhances the anticancer effect of oxaliplatin on hepatocellular carcinoma cells. oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest , triggered caspase-dependent apoptosis , and decreased tumorigenicity both in vitro and in vivo . vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/29239146/"}
{"doc_id": "3e9de2eafaad5ecdb3048a0e6206a0e1", "sentence": "Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia .", "spans": [{"span_id": 0, "text": "gentamicin", "start": 25, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxycycline", "start": 40, "end": 51, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia . Chronic Bartonella quintana bacteremia is known to occur in homeless people exposed to lice. We present here the results of an open randomized trial performed to evaluate the efficacy of doxycycline in combination with gentamicin in the eradication of B. quintana bacteremia. From 1 January 2001 to 1 April 2002, homeless people with blood cultures positive for B. quintana were randomized to receive either no treatment (untreated controls) or a combination of gentamicin (3 mg/kg of body weight/day intravenously for 14 days) and doxycycline (200 mg/day orally for 28 days). Patients were evaluated from the results of blood cultures performed between day 28 (the end of treatment) and day 90 postinclusion. Intention-to-treat analysis of 20 included patients showed eradication of bacteremia in 7 out of 9 treated patients versus 2 out of 11 untreated controls (P = 0.01). In the per-protocol analysis, eradication was obtained for 7 out of 7 treated patients versus 2 out of 9 untreated controls (P = 0.003). This study demonstrates the efficiency of the combination of doxycycline and gentamicin in eradicating B. quintana bacteremia.", "source": "https://pubmed.ncbi.nlm.nih.gov/12821469/"}
{"doc_id": "d6a60e2a3810f7b91e415ab7ad060e5d", "sentence": "The role of dual antiplatelet therapy combining aspirin and clopidogrel , is controversial .", "spans": [{"span_id": 0, "text": "aspirin", "start": 48, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "clopidogrel", "start": 60, "end": 71, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[TREATMENT WITH DUAL ANTIPLATELET THERAPY FOR SECONDARY PREVENTION OF STROKE - PROS AND CONS].  The role of dual antiplatelet therapy combining aspirin and clopidogrel , is controversial . There are two settings in which such treatment might be considered: (a) patients presenting with a first ischemic event at high risk for a recurrence; and (b) patients who experience a second ischemic event while being treated with aspirin or clopidogrel monotherapy. In this paper we review the literature dealing with secondary prevention of ischemic stroke, with an emphasis on dual antiplatelet therapy. We examine international guidelines and present a case study which illustrates the application of this information.", "source": "https://pubmed.ncbi.nlm.nih.gov/30582310/"}
{"doc_id": "ed0f2792fe2d83f42414b3c006dad894", "sentence": "We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM ( imatinib mesylate , 600 mg/d ) and cytarabine ( 200 mg/d for 7 days ) , followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs .", "spans": [{"span_id": 0, "text": "daunorubicin", "start": 40, "end": 52, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "imatinib", "start": 85, "end": 93, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "cytarabine", "start": 120, "end": 130, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "The addition of daunorubicin to imatinib mesylate in combination with cytarabine improves the response rate and the survival of patients with myeloid blast crisis chronic myelogenous leukemia (AFR01 study). The median survival of patients with chronic myelogenous leukemia in myeloid blast crisis (MBC-CML) is poor even for patients treated with tyrosine kinase inhibitors (TKIs). ### Design And Methods We conducted a dose-escalating study of daunorubicin combined to fixed doses of IM ( imatinib mesylate , 600 mg/d ) and cytarabine ( 200 mg/d for 7 days ) , followed by hematopoietic stem cell transplantation or maintenance therapy with single-agent IM in patients with MBC-CML at onset or after failure of therapy excluding TKIs . ### results Thirty-six patients were evaluated. Median follow-up is 6.1 years. daunorubicin was escaladed up to 45 mg/m(2)/d 3 days. Twenty eight patients (77.7%) had hematologic response including 20 patients (55.5%) in complete hematologic response (CHR). Patients who received daunorubicin at 30-45 mg/m(2)/d had higher CHR rates compared to other patients. Median overall survival was 16 months. Overall survival in patients with hematological response was 35.4 months. Better results were observed in patients diagnosed with MBC-CML at onset. ### conclusions The combination of IM with a standard \"3+7\" regiment was well tolerated and provided a high response rate. More than 55% of the patients achieved CHR and hematopoietic stem cell transplantation (SCT) was feasible in half of the cases. This trial was registered at www.clinicaltrials.gov as # NCT00219765.", "source": "https://pubmed.ncbi.nlm.nih.gov/21145590/"}
{"doc_id": "2ba04bc0fd1492479197971616f7e32b", "sentence": "[ Combination chemo-endocrine therapy of metastatic and stage IV breast cancer with cyclophosphamide , adriamycin , prednisolone and tamoxifen (CAPT)--with special reference to management of brain and liver metastasis ] .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 84, "end": 100, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "adriamycin", "start": 103, "end": 113, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "prednisolone", "start": 116, "end": 128, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "tamoxifen", "start": 133, "end": 142, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "[ Combination chemo-endocrine therapy of metastatic and stage IV breast cancer with cyclophosphamide , adriamycin , prednisolone and tamoxifen (CAPT)--with special reference to management of brain and liver metastasis ] . Sixty-three evaluable patients with metastatic and stage IV breast cancer who had not previously undergone chemo-endocrine therapy were treated with a combination chemoendocrine therapy regimen consisting of cyclophosphamide 100 mg p.o. every day, adriamycin 10 mg i.v. on day 1 to 5, prednisolone 10 mg or 20 mg (20 mg was given on day 1 to 5) p.o. every day, and tamoxifen 20 mg p.o. every day. Adriamycin on day 1 to 5 was repeated three times every two weeks. After a total dose of 150 mg of adriamycin, the patients were changed to maintenance therapy consisting of cyclophosphamide 100 mg p.o., prednisolone 10 mg p.o. and tamoxifen 20 mg p.o. every day. After 72 months of the treatment there were 61 patients good for evaluation, 13 patients achieved a complete response (21.3%) with a median survival of 30.5 months and 18 patients had a partial response (29.5%) with a median survival of 21.0 months, and 30 patients failed to respond (49.2%) with a median survival of 8.5 months. There was a significant difference in survival time between responders (CR + PR) and non-responders (NC + PD) (p less than 0.001). Responses by site were seen in lung 10/18 (55.6%), liver 3/6 (50.0%), brain 2/4 (50.0%), bone 6/17 (35.3%) and soft tissue 14/24 (56.3%). A Satisfactory response for brain and liver metastasis, which are usually viewed as a sign of grim prognosis, was obtained similar to other sites of metastasis. Retreatment with CAPT, which was attempted in patients with secondary brain metastasis who responded to CAPT for initial brain metastasis, was uniformly effective. High ration of androgen to corticosteroid, positive estrogen receptors, long disease-free survival (over two years), premenopausal, high Broca' index (above 110) resulted from the chemo-endocrine therapy regimen CAPT. Toxicity was minimal and consisted of nausea, vomiting, alopecia and leucopenia.", "source": "https://pubmed.ncbi.nlm.nih.gov/2919892/"}
{"doc_id": "9e003c170aa4b269bf61e3bbb7679d71", "sentence": "Ra ( rate of production ) was measured during infusion of variable doses of epinephrine with or without variable doses of propranolol , a competitive beta-adrenergic antagonist to isolate the alpha-adrenergic agonist effects .", "spans": [{"span_id": 0, "text": "epinephrine", "start": 76, "end": 87, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "propranolol", "start": 122, "end": 133, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Alpha-adrenergic agonists stimulate neonatal glucose production less than beta-adrenergic agonists in the lamb. epinephrine, a catecholamine with both alpha (alpha)- and beta (beta)-adrenergic agonist effects, may produce clinical hyperglycemia in the adult by increasing glucose production and decreasing glucose clearance. However, the relative contribution of alpha v beta adrenergic agonists in control of neonatal glucose kinetics has not been defined. Twenty-three term lambs (weighing 4.4 +/- 0.2 kg, mean +/- SEM, and aged 3.8 +/- 0.4 days) were infused with 0.9% NaCl at 0.6 mL.kg-1 min-1 + 100 microCi/kg D[6-3H]-glucose by prime plus constant infusion for 210 minutes. Ra ( rate of production ) was measured during infusion of variable doses of epinephrine with or without variable doses of propranolol , a competitive beta-adrenergic antagonist to isolate the alpha-adrenergic agonist effects . All basal kinetic data were comparable. Under conditions of epinephrine infusion, the plasma glucose concentration increased from 95 +/- 10 mg/dL to 129 +/- 18 mg/dL (50 ng.kg-1 min-1 epinephrine; P less than .0001) and from 85 +/- 6 mg/dL to 253 +/- 8 mg/dL (500 ng.kg-1 min-1 epinephrine; P less than .00001) compared with controls (96 +/- 7 mg/dL to 95 +/- 8 mg/dL). When epinephrine and propranolol were infused simultaneously, plasma glucose concentration increased from 95 +/- 10 mg/dL to 122 +/- 12 mg/dL (50 ng.kg-1 min-1 epinephrine + 1.1 micrograms.kg-1 min-1; P less than .0001) and from 78 +/- 9 mg/dL to 134 +/- 12 mg/dL (500 ng.kg-1 min-1 epinephrine + 11 micrograms.kg-1 min-1; P less than .0001) compared with controls (no epinephrine, no propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/2901659/"}
{"doc_id": "3d4d260b7bf8ccf63264df8f4be236e8", "sentence": "The ranking order of the response rate was LD ( best ) , doxorubicin , epirubicin , ED , and DD ( worst ) .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 57, "end": 68, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "epirubicin", "start": 71, "end": 81, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Comparisons of Cardiotoxicity and Efficacy of Anthracycline-Based Therapies in Breast Cancer: A Network Meta-Analysis of Randomized Clinical Trials. The effects of anthracycline-based chemical therapies on breast cancer are controversial and inconclusive. We undertook a network meta-analysis to assess the cardiotoxicity and effects of anthracycline therapies in breast cancer. The PubMed, Embase, and Cochrane databases up to August 2018 were reviewed. We identified 19 randomized clinical trials including 3,484 patients with breast cancer which assessed both cardiotoxicity and the effects of anthracycline-based therapies. Eligible studies included the following five treatment strategies: doxorubicin, epirubicin, liposomal doxorubicin (LD), doxorubicin + dexrazoxane (DD), and epirubicin + dexrazoxane (ED). In a direct meta-analysis, epirubicin, LD, DD, and ED had significantly superior cardioprotective effects compared with doxorubicin with odds ratios and 95% CIs of 1.64 (1.04, 2.57), 3.75 (2.46, 5.70), 2.88 (1.93, 4.29), and 3.66 (1.09, 12.33), respectively. doxorubicin showed no significant difference of response rate compared with epirubicin or LD or DD, respectively. In a network meta-analysis, the ranking order of cardiotoxicity was doxorubicin (worst), epirubicin, DD, LD, and ED (best). The ranking order of the response rate was LD ( best ) , doxorubicin , epirubicin , ED , and DD ( worst ) . The most favorable balance between benefit and risk was shown for ED (best) followed by LD, DD, epirubicin, and doxorubicin. In conclusion, LD or ED is the suitable anthracycline treatment for breast cancer in consideration of both cardiotoxicity and efficacy.", "source": "https://pubmed.ncbi.nlm.nih.gov/31104059/"}
{"doc_id": "fe55149b98f840d75595f19e4bd9c92e", "sentence": "Systemic treatment with physostigmine , an inhibitor of acetylcholinesterase , modestly reduced the acquisition and rate of heroin self-administration , and this suppression of heroin intake was reversed by pretreatment with scopolamine but not by mecamylamine .", "spans": [{"span_id": 0, "text": "physostigmine", "start": 24, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "scopolamine", "start": 225, "end": 236, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "mecamylamine", "start": 248, "end": 260, "token_start": 35, "token_end": 36}], "rels": [], "paragraph": "Role of acetylcholine transmission in nucleus accumbens and ventral tegmental area in heroin-seeking induced by conditioned cues. The involvement of cholinergic transmission in heroin self-administration and the reinstatement of heroin-seeking was examined in rats trained to nose-poke for i.v. heroin. Systemic treatment with physostigmine , an inhibitor of acetylcholinesterase , modestly reduced the acquisition and rate of heroin self-administration , and this suppression of heroin intake was reversed by pretreatment with scopolamine but not by mecamylamine . Following 10-14 days of self-administration, rats were left in the home environment for 14 days. Subsequently, rats were evaluated for extinction of nose-pokes during the first hour after being returned to the self-administration apparatus. One hour later a conditioned stimulus (house light, light in the nose-poke hole, sound of the infusion pump) was presented to initiate cue-induced reinstatement. Physostigmine produced a dose-dependent inhibition of cue-induced reinstatement, but only the dose of 0.5 mg/kg significantly decreased nose-poke responding in the extinction test. Chronic treatment with physostigmine (0.1 mg/kg) did not impair performance during acquisition of heroin self-administration. However, during a subsequent reinstatement test conducted in the absence of physostigmine pretreatment, heroin seeking was significantly below that of rats chronically pretreated with saline. To evaluate brain regions mediating the effects of systemic drug treatment on reinstatement, physostigmine was microinjected into the nucleus accumbens (NAc) or ventral tegmental area (VTA). Microinjection of physostigmine into the NAc prior to presenting conditioned cues inhibited the reinstatement of heroin-seeking, without affecting extinction responding. In contrast, microinjection of physostigmine into the VTA augmented the reinstatement induced by conditioned cues and extinction responding. Inactivation of either NAc or VTA by microinjecting tetrodotoxin blocked both extinction responding and cue-induced reinstatement. These data demonstrate that cholinergic transmission influences heroin self-administration and reinstatement. Moreover, cue-induced reinstatement was inhibited by physostigmine in the NAc and potentiated by cholinergic stimulation in the VTA.", "source": "https://pubmed.ncbi.nlm.nih.gov/17184925/"}
{"doc_id": "730e94daa49737e329a573ba8ce4b419", "sentence": "First-line lenvatinib , which was shown to be noninferior to sorafenib , excluded patients with main portal trunk invasion .", "spans": [{"span_id": 0, "text": "lenvatinib", "start": 11, "end": 21, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "sorafenib", "start": 61, "end": 70, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Hepatocellular Carcinoma with Portal Vein Tumor Involvement: Best Management Strategies. Portal vein tumor thrombosis (PVTT) commonly occurs in patients with hepatocellular carcinoma (HCC). Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months. Historically, many aspects of PVTT have impacted the theoretical and practical safety and efficacy of treatment, for example, disordered blood flow and associated impairment of liver function, heat-sink effects of blood flow in the area of the PVTT, and risk of recurrence due to tumor location in the blood vessel. The current Barcelona Clinic Liver Cancer staging system categorizes HCC patients with PVTT as advanced stage, for which the standard of care is targeted therapy with sorafenib. However, sorafenib is associated with only marginal benefits among patients with PVTT. First-line lenvatinib , which was shown to be noninferior to sorafenib , excluded patients with main portal trunk invasion . regorafenib and nivolumab, an immune-based therapy, were recently approved in the United States for second-line therapy after sorafenib. Preliminary results for cabozantinib suggest a benefit in the second-/third-line after sorafenib failure. In addition, rapid advances in many fields (surgery, interventional radiology, nuclear medicine, and immunotherapy) have increased the potential treatment options for the management of this complex disease entity. A large portion of the emerging evidence focuses on the broader category of advanced HCC of which PVTT is a subgroup. While many of these studies show promising results, the efficacy among PVTT patients requires validation in prospective studies. Real-world data may help fill the evidence gap for patients not eligible for clinical trials due to common hepatic function requirements. The variety of new treatment advances for the heterogeneous and complex disease entity of HCC with PVTT means that personalized, multidisciplinary management may be necessary to achieve optimal outcomes. In this narrative review, we summarize the evolving management strategies for patients with HCC and PVTT.", "source": "https://pubmed.ncbi.nlm.nih.gov/30041276/"}
{"doc_id": "283410cfc7f4ebae3f474db63d477f10", "sentence": "The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer .", "spans": [{"span_id": 0, "text": "atezolizumab", "start": 51, "end": 63, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "docetaxel", "start": 71, "end": 80, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Fast progression in non-small cell lung cancer: results from the randomized phase III OAK study evaluating second-line atezolizumab versus docetaxel. Treatment-induced accelerated tumor growth is a progression pattern reported with immune checkpoint inhibitors that has never been evaluated in randomized phase III studies because it requires two pretreatment scans. This study aimed to develop clinically relevant and applicable criteria for fast progression (FP), incorporating tumor growth kinetics and early death from disease progression to analyze data from the randomized phase III OAK study. ### methods The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer . FP rates and associated baseline factors were analyzed. FP was defined as either a \u226550% increase in the sum of largest diameters (SLDs) within 6 weeks of treatment initiation or death due to cancer progression within 12 weeks (absent post-baseline scan). ### results Forty-two of 421 patients (10%) receiving atezolizumab and 37 of 402 (9%) receiving docetaxel had FP. Twenty patients with FP (48%) receiving atezolizumab versus 12 (30%) receiving docetaxel had a \u226550%\u2009SLD increase within 6 weeks. FP was significantly associated with an ECOG (Eastern Cooperative Oncology Group) performance status of 1 (vs 0), \u22653 metastatic sites at baseline, and failure of preceding first-line treatment within 6 months, but not with epidermal growth factor receptor mutation, programmed cell death 1 ligand 1 or tumor mutational burden. Overall survival in patients with FP and a \u226550%\u2009SLD increase at week 6 was similar with atezolizumab and docetaxel (unstratified HR 0.89 (95% CI 0.41 to 1.92)). ### conclusions FP rates were similar with atezolizumab and docetaxel in the OAK study, suggesting that FP may not be unique to checkpoint inhibitors, although the underlying mechanisms may differ from those of chemotherapy. Applying the FP criteria to other phase III checkpoint inhibitor trials may further elucidate the risk factors for FP. ### Trial Registration Number NCT02008227.", "source": "https://pubmed.ncbi.nlm.nih.gov/33737340/"}
{"doc_id": "8cfd356ecefba9d73f67538b8f8d65cc", "sentence": "In conclusion , combined treatment with 0.375 IU of bleomycin and 4 mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 52, "end": 61, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "triamcinolone", "start": 74, "end": 87, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Results of a combination of bleomycin and triamcinolone acetonide in the treatment of keloids and hypertrophic scars. While treatment of keloids and hypertrophic scars normally shows modest results, we found that treatment with bleomycin was more promising. The present study was divided into two parts. In the first part the aim was to show the results using a combination of bleomycin and triamcinolone acetonide per cm2 (BTA). In the second part the objective was to determine the response to both drugs in large keloids that were divided into 1 cm2 squares, treating each square with the dose previously used. In the first part of the study, the clinical response of 37 keloids ranging from 0.3 to 1.8 cm2 treated with BTA were followed up over a period of 1- 2 years. 0.375 IU bleomycin and 4 mg triamcinolone acetonide were injected every 3 months. In the second part of the study we reviewed the clinical response in six patients with large keloids. The monthly dose administered never exceeded 3 IU of bleomycin. The first study showed 36 keloids (97.29%) softening after the first dose. In the second study, 5 showed different responses (the response was complete in the four smaller keloids). The largest keloid needed 9 doses to achieve an improvement of 70%. In conclusion , combined treatment with 0.375 IU of bleomycin and 4 mg of triamcinolone acetonide to 1 cm2 was considered to be an acceptable procedure for the treatment of keloids . The best results were obtained in keloids over 1 cm2 or when divided into 1 cm2 square areas. Larger series need to be performed in order to confirm these results..", "source": "https://pubmed.ncbi.nlm.nih.gov/23793202/"}
{"doc_id": "9b78b0873352d649f96ed2e664b478c1", "sentence": "A 29-year-old man with juvenile myoclonic epilepsy and medically refractory GTCS on a combination of levetiracetam and topiramate was started on lacosamide adjunctive therapy with the plan to replace topiramate .", "spans": [{"span_id": 0, "text": "levetiracetam", "start": 101, "end": 114, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "topiramate", "start": 119, "end": 129, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "lacosamide", "start": 145, "end": 155, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "topiramate", "start": 200, "end": 210, "token_start": 29, "token_end": 30}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "NEG", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Absence status induced by lacosamide adjunctive therapy. Since lacosamide was approved as an adjuvant agent for the treatment of medically refractory focal epilepsy over ten years ago, it is becoming more widely used for the treatment of idiopathic (genetic) generalized epilepsies. Several studies have demonstrated efficacy in reducing primary generalized tonic-clonic seizures (GTCS), but efficacy is less well-characterized for myoclonic and absence seizures. A 29-year-old man with juvenile myoclonic epilepsy and medically refractory GTCS on a combination of levetiracetam and topiramate was started on lacosamide adjunctive therapy with the plan to replace topiramate . While his GTCS became controlled, he was witnessed to have confusional episodes, with waxing and waning responsiveness, lasting a few days, several times a month. After eight months of adjunctive lacosamide therapy, he was admitted to the epilepsy monitoring unit, where paroxysms of generalized spike-and-wave complexes, lasting for 30-90 minutes, were recorded, interrupted only by sleep. During these periods, he demonstrated psychomotor slowing and disorientation on examination. The absence status was successfully broken by lorazepam, and lacosamide was discontinued. The patient had no further confusional episodes at the most recent follow-up visit, four months after discharge.", "source": "https://pubmed.ncbi.nlm.nih.gov/30782579/"}
{"doc_id": "338aafe426c99361569ae8732520a6ac", "sentence": "[ A randomized controlled trial of immunochemotherapy using carmofur ( HCFU ) , mitomycin C and immunopotentiators in advanced gastric cancer following noncurative resection and nonresection ] .", "spans": [{"span_id": 0, "text": "carmofur", "start": 60, "end": 68, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "mitomycin", "start": 80, "end": 89, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ A randomized controlled trial of immunochemotherapy using carmofur ( HCFU ) , mitomycin C and immunopotentiators in advanced gastric cancer following noncurative resection and nonresection ] . The cumulative survival rate of 166 gastric cancer patients after noncurative resection and nonresection treated by combination therapy using carmofur (HCFU), mitomycin C (MMC) and immunopotentiators was investigated. A randomized controlled trial composed of MMC and immunopotentiators (group A) versus the addition of HCFU to group A (group B) was undertaken. In all patients, the survival curve of group B was superior to that of group A (g. Wilcoxon test, p = 0.078). Noncurative resection or nonresection patients presented significantly higher survival rates in group B (p less than 0.05) after analysis according to the duration of the treatment period (Z-test). Stratification of backgrounds for noncurative patients also showed significantly higher survival rates in group B (p less than 0.05) at S 3, P, stage IV. From these results, it might be suggested that HCFU therapy is useful for gastric cancer patients after noncurative resection and nonresection.", "source": "https://pubmed.ncbi.nlm.nih.gov/3088298/"}
{"doc_id": "0a76598f2f1316d0277e6320f68ac00a", "sentence": "We thus undertook an extensive longitudinal immunologic study , including phenotypic , transcriptomic , and functional analyses , on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial ( Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma ) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL .", "spans": [{"span_id": 0, "text": "Obinutuzumab", "start": 213, "end": 225, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "Lenalidomide", "start": 240, "end": 252, "token_start": 34, "token_end": 35}, {"span_id": 2, "text": "lenalidomide", "start": 333, "end": 345, "token_start": 48, "token_end": 49}, {"span_id": 3, "text": "obinutuzumab", "start": 350, "end": 362, "token_start": 50, "token_end": 51}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Lenalidomide triggers T-cell effector functions in vivo in patients with follicular lymphoma. The immunomodulatory drug lenalidomide is used in patients with follicular lymphoma (FL) with the aim of stimulating T-cell antitumor immune response. However, little is known about the effects of lenalidomide on T-cell biology in vivo in patients with FL. We thus undertook an extensive longitudinal immunologic study , including phenotypic , transcriptomic , and functional analyses , on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial ( Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma ) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL . lenalidomide rapidly and transiently induced an activated T-cell phenotype, including HLA-DR, Tim-3, CD137, and programmed cell death protein 1 (PD-1) upregulation. Furthermore, sequential RNA-sequencing of sorted PD-1+ and PD-1- T-cell subsets revealed that lenalidomide triggered a strong enrichment for several gene signatures related to effector memory T-cell features, including proliferation, antigen receptor signaling, and immune synapse restoration; all were validated at the phenotypic level and with ex vivo functional assays. Correlative analyses pinpointed a negative clinical impact of high effector T-cell and regulatory T-cell percentages before and during treatment. Our findings bring new insight in lenalidomide mechanisms of action at work in vivo and will fuel a new rationale for the design of combination therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/33877296/"}
{"doc_id": "7eaad3968ff192fa9bd239415a2168ed", "sentence": "Blockade of beta-receptors by the nonselective beta-blocking agent propranolol did not modify the brachial artery diameter , whereas pindolol increased this parameter for the same degree of blood pressure reduction .", "spans": [{"span_id": 0, "text": "propranolol", "start": 67, "end": 78, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "pindolol", "start": 133, "end": 141, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Beta-blockade and brachial artery hemodynamics in hypertension. The effect of systemic adrenergic blockade on hypertensive brachial arteries was studied in humans with pulsed Doppler flowmetry. Blockade of beta-receptors by the nonselective beta-blocking agent propranolol did not modify the brachial artery diameter , whereas pindolol increased this parameter for the same degree of blood pressure reduction . The beta1-selective blocking agents atenolol and bisoprolol caused similar decreases in blood pressure and a reduction in the diameters of the brachial artery and abdominal aorta, respectively. The combination of alpha- and beta-blockade produced a rapid drop in blood pressure but did not change the brachial arterial diameter. Thus, following beta-blockade, the arterial diameter increased, did not change, or even decreased despite an adequate blood pressure reduction. It is suggested that beta-blockade in some instances resets the pressure-diameter curve and therefore has a direct action on the arterial wall independent of the mechanical effect of blood pressure reduction.", "source": "https://pubmed.ncbi.nlm.nih.gov/11527134/"}
{"doc_id": "2e2c524d37b2d036f3b49ee6d6288b44", "sentence": "Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel ; based on this , we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC .", "spans": [{"span_id": 0, "text": "Nab-paclitaxel", "start": 0, "end": 14, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 107, "end": 117, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "carboplatin", "start": 212, "end": 223, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "bevacizumab", "start": 228, "end": 239, "token_start": 30, "token_end": 31}, {"span_id": 4, "text": "nab-paclitaxel", "start": 192, "end": 206, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [2, 3, 4], "is_context_needed": true}], "paragraph": "Nab-paclitaxel/bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer. Triple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options. Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophor-solubilized paclitaxel ; based on this , we examined the efficacy and safety of combining weekly nab-paclitaxel with carboplatin and bevacizumab in TNMBC . ### Patients And Methods In this phase II, multicenter trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m(2)) and carboplatin (area under the curve\u00a0= 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was calculated using the Kaplan-Meier method. ### results Between July 16, 2007, and October 3, 2011, 34 patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1 months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the combination. The regimen was well tolerated with the most common grade 3/4 adverse events being neutropenia (n\u00a0= 18; 53%) and thrombocytopenia (n\u00a0= 6; 18%), with other serous events including 1 grade 3 and 1 grade 4 thrombotic event and 1 febrile neutropenia. ### conclusion The combination of nab-paclitaxel, bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/24099649/"}
{"doc_id": "41d554b6fdbce2aa310be0253e6de7b9", "sentence": "Acute renal failure ( ARF ) occurred concomitantly with the administration of gentamicin in combination with clindamycin in three patients in whom no other known predisposing cause of ARF could be demonstrated .", "spans": [{"span_id": 0, "text": "gentamicin", "start": 78, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "clindamycin", "start": 109, "end": 120, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Renal failure following gentamicin in combination with clindamycin.  Acute renal failure ( ARF ) occurred concomitantly with the administration of gentamicin in combination with clindamycin in three patients in whom no other known predisposing cause of ARF could be demonstrated . The evidence for combined nephrotoxicity consisted of the temporal relationship between administration of the antibiotics and the development of ARF, and the prompt improvement in renal function upon cessation of therapy. Complete or partial recovery of renal function occured in all patients. Renal function should be carefully monitored in patients receiving this antibiotic combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/951016/"}
{"doc_id": "6309c83d434bba5f9f972fcc701f6454", "sentence": "However , nicotinic acid , nicotinamide , and pyridoxamine are not able to reverse the effect of isoniazid .", "spans": [{"span_id": 0, "text": "nicotinamide", "start": 27, "end": 39, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "isoniazid", "start": 97, "end": 106, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Protection of Escherichia coli from isoniazid inhibition. Inhibition of Escherichia coli by isonicotinic acid hydrazide (isoniazid) is a function of the initial cell concentration, concentration of antibiotic, and chemical composition of the medium. An initial concentration of 5 x 10(5) cells/ml in a minimal medium is inhibited by 1 mM isoniazid. The E. coli cells are protected from this inhibitory effect by a high concentration of cells in the medium. Protection is also obtained from vitamin-free Casamino Acids, methionine, or choline plus homocystine. However , nicotinic acid , nicotinamide , and pyridoxamine are not able to reverse the effect of isoniazid . Colonies arising on minimal medium supplemented with isoniazid are not due to selection of resistant mutants, because this resistance is transitory and not passed on to the daughter cells. It is hypothesized that this transitory resistance is a manifestation of the cells' ability to transfer the methyl group of methionine to either isoniazid or accumulated nicotinic acid and/or nicotinamide.", "source": "https://pubmed.ncbi.nlm.nih.gov/4599120/"}
{"doc_id": "c446432e28122964998c2e2d2d6286d5", "sentence": "To explore the role of augmenting neutrophil function in B-cell lymphoma , we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20", "spans": [{"span_id": 0, "text": "pegfilgrastim", "start": 152, "end": 165, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "rituximab", "start": 170, "end": 179, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma.  To explore the role of augmenting neutrophil function in B-cell lymphoma , we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20 ### Patients And Methods Twenty patients with indolent B-NHL were treated with rituximab (375\u00a0mg/m ### results The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III-IV disease. The median number of previous therapies was 2 (range, 0-5); 90% had received previous anti-CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab-related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression-free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9-27.6 months); the median overall survival was not reached. A shorter time-to-peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P\u00a0= .04) and longer PFS (P\u00a0= .03). ### conclusion The pegfilgrastim-rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A\u00a0shorter time-to-peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-NHL.", "source": "https://pubmed.ncbi.nlm.nih.gov/29233743/"}
{"doc_id": "18cd496eadd55ca0fd22e758dec9772b", "sentence": "The aim of this paper is to compare intravitreous aflibercept versus dexamethasone implant followed by aflibercept ( sequential treatment group ) in patients with diabetic macular edema ( DME ) .", "spans": [{"span_id": 0, "text": "aflibercept", "start": 50, "end": 61, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "dexamethasone", "start": 69, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "aflibercept", "start": 103, "end": 114, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Sequential Dexamethasone and Aflibercept Treatment in Patients with Diabetic Macular Edema: Structural and Functional Outcomes at 52 Weeks.  The aim of this paper is to compare intravitreous aflibercept versus dexamethasone implant followed by aflibercept ( sequential treatment group ) in patients with diabetic macular edema ( DME ) . ### methods We conducted an observational retrospective study in na\u00efve DME patients, 15 treated only with aflibercept (a monthly injection for the first 5 consecutive doses, followed by an injection every 2 months), and 15 treated with a single dexamethasone implant followed by bimonthly aflibercept. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and qualitative features as well as adverse events were assessed at baseline and at 2, 6, and 12 months. ### results BCVA increased from 70.8 \u00b1 4.1 to 83.5 \u00b1 2.7 letters with aflibercept and from 75.6 \u00b1 2.7 to 86.5 \u00b1 2.5 with sequential treatment (p = 0.551). CMT decreased from 411 \u00b1 26.1 to 288.1 \u00b1 10.5 with aflibercept and from 411.4 \u00b1 24.3 to 260.8 \u00b1 17.9 in the sequential treatment group. The differences between the 2 groups, in terms of visual gain and decreased MT, were not statistically significant (p > 0.05). Nine and 6 injections and 9 and 7 monitoring visits were performed. ### conclusion Sequential treatment in DME, starting with dexamethasone and followed by aflibercept, is a promising alternative that can reduce the treatment burden in the first year without statistically significant differences in terms of visual gain and decreased MT compared to aflibercept only.", "source": "https://pubmed.ncbi.nlm.nih.gov/29996128/"}
{"doc_id": "325c8adc26eb89b99972504e4cf4fbc1", "sentence": "Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 ( Schedule A ) or day 8 ( Schedule B ) , repeated every 21 d.", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 63, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "carboplatin", "start": 78, "end": 89, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "CP-870,893", "start": 141, "end": 151, "token_start": 23, "token_end": 24}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. CD40 is a cell-surface molecule that critically regulates immune responses. CP-870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP-870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 ( Schedule A ) or day 8 ( Schedule B ) , repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP-870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP-870,893, 16 patients on each schedule. Two dose-limiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by RECIST. Following CP-870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP-870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/23483678/"}
{"doc_id": "ffdbb009607a99d5a098d1e8645df481", "sentence": "Thirty-two patients with advanced breast carcinoma were randomized to receive increasing doses of paclitaxel ( 45 , 65 , 80 , 90 and 100 mg/m2 ) or docetaxel ( 30 , 35 , 40 , 45 and 50 mg/m2 ) together with the CMF agents at the same dose as that used in the conventional regimen .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 98, "end": 108, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "docetaxel", "start": 148, "end": 157, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Design and development of new combinations of the CMF agents with taxanes (paclitaxel or docetaxel) in advanced breast cancer: a feasibility study. We previously designed and tested combinations made up of the CMF agents, two at a time by rotation, and of doxorubicin or epirubicin. The present study was aimed to similarly test new combinations made up of the CMF agents, two at a time by rotation, and paclitaxel or docetaxel. ### methods The doses of each taxane were escalated with the objective of reaching at least a single dose level of 90 mg/m2 of paclitaxel and 45 mg/m2 of docetaxel on days 1 and 8 of each four-week cycle. Thirty-two patients with advanced breast carcinoma were randomized to receive increasing doses of paclitaxel ( 45 , 65 , 80 , 90 and 100 mg/m2 ) or docetaxel ( 30 , 35 , 40 , 45 and 50 mg/m2 ) together with the CMF agents at the same dose as that used in the conventional regimen . Each dose level was administered to a triplet of patients. No direct comparison of the two taxanes was made. ### results The fourth dose level was reached for paclitaxel and docetaxel. The most important toxicities were grade 4 neutropenia and grade 1-2 nausea/vomiting and stomatitis. The objective response rate, assessed only after the third cycle at any dose level, was 31% (95% CI, 15-47%). ### conclusions The combinations of the CMF agents (two at a time in rotation) with paclitaxel (90 mg/m2) or docetaxel (45 mg/m2) on days 1 and 8 of each four-week cycle are feasible and lead to definite signs of therapeutic activity, and the side effects are generally mild. Further studies are therefore warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/15315305/"}
{"doc_id": "4b5419c4e7013f2b9aa3e47ecdcbdbcb", "sentence": "In a 52-week , open-label , multicenter , extension study , HDL-C , TG , and LDL-C levels continued to improve , or were maintained , during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin ( atorvastatin 40 mg , rosuvastatin 20 mg , or simvastatin 40 mg ) .", "spans": [{"span_id": 0, "text": "fenofibric", "start": 177, "end": 187, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "atorvastatin", "start": 230, "end": 242, "token_start": 40, "token_end": 41}, {"span_id": 2, "text": "rosuvastatin", "start": 251, "end": 263, "token_start": 44, "token_end": 45}, {"span_id": 3, "text": "simvastatin", "start": 275, "end": 286, "token_start": 49, "token_end": 50}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "POS", "spans": [0, 3], "is_context_needed": true}], "paragraph": "Fenofibric acid: in combination therapy in the treatment of mixed dyslipidemia. fenofibric acid activates peroxisome proliferator-activated receptor alpha to modify fatty acid and lipid metabolism. fenofibric acid is the first member of the fibric acid derivatives (fibrates) class approved for use as combination therapy with HMG-CoA reductase inhibitors (statins). In three randomized, double-blind, multicenter, phase III trials in adult patients with mixed dyslipidemia, up to 12 weeks' treatment with once-daily fenofibric acid 135 mg plus a low- or moderate-dose statin (atorvastatin 20 or 40 mg, rosuvastatin 10 or 20 mg, or simvastatin 20 or 40 mg) improved high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels to a significantly greater extent than statin monotherapy, and improved low-density lipoprotein cholesterol (LDL-C) levels to a significantly greater extent than fenofibric acid monotherapy. In a 52-week , open-label , multicenter , extension study , HDL-C , TG , and LDL-C levels continued to improve , or were maintained , during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin ( atorvastatin 40 mg , rosuvastatin 20 mg , or simvastatin 40 mg ) . Once-daily fenofibric acid 135 mg plus a statin was generally as well tolerated as monotherapy with fenofibric acid 135 mg/day or the corresponding statin dosage in the three phase III trials in patients with mixed dyslipidemia. The incidence of adverse events was similar between the combination therapy group and both monotherapy groups. In the extension trial, once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg) for up to 52 weeks was generally well tolerated.", "source": "https://pubmed.ncbi.nlm.nih.gov/19929038/"}
{"doc_id": "5511884d05b2f45195a0c930f28abca2", "sentence": "To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy .", "spans": [{"span_id": 0, "text": "lamivudine", "start": 49, "end": 59, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "zidovudine", "start": 86, "end": 96, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "zidovudine", "start": 112, "end": 122, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group.  To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy . ### design Double-blind, randomized, multicenter, comparative trial of 223 patients treated for 24 weeks. ### setting Patients from 32 hospitals in Europe were enrolled throughout a 1-year period. ### patients Adult human immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced ( > or = 24 weeks prior zidovudine) patients with CD4+ cell counts between 0.10 and 0.40 x 10(9)/L (100-400 cells/microL). ### intervention Patients received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus zidovudine for 24 weeks. All patients were then allowed to receive zidovudine and open-label lamivudine combination therapy. Twelve patients withdrew because of adverse events during the 24-week treatment period. ### Main Outcome Measures Efficacy was measured by evaluating immunological and viral load changes, and safety was assessed by evaluating clinical manifestations and laboratory indexes of toxic effects. ### results Patients receiving low- or high-dose combination therapy had greater treatment effects compared with patients receiving continued zidovudine monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02 x 10(9)/L, respectively; P < .001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL, respectively; P < .001) or log10 HIV-1 RNA measured by the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02 copies/mL, respectively; P < .011); and immune-complex dissociated (ICD) p24 antigen (-74% vs -68% vs +27%, respectively; P < .001). There were no statistically significant differences in viral measurements, in CD4+ cell counts, or in safety profile between the groups receiving 2 doses of lamivudine in combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen were sustained throughout 48 weeks for patients continuing combination therapy. Patients switching to combination therapy at week 24 showed improvement. ### conclusion In zidovudine-experienced HIV-1-infected patients, combination treatment with lamivudine and zidovudine is well tolerated and provides greater and more sustained increases in CD4+ cell counts and decreases in viral load than continued zidovudine monotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/8656502/"}
{"doc_id": "12c2283c9ba7350e63e1dd29bcd7fb28", "sentence": "Bradykinin enhanced the effect of carbachol by about 10 - 15 % .", "spans": [{"span_id": 0, "text": "Bradykinin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "carbachol", "start": 34, "end": 43, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Ca(2+)-independent, Ca(2+)-dependent, and carbachol-mediated arachidonic acid release from rat brain cortex membrane. Synaptoneurosomes obtained from the cortex of rat brain prelabeled with [14C]arachidonic acid [( 14C]AA) were used as a source of substrate and enzyme in studies on the regulation of AA release. A significant amount of AA is liberated in the presence of 2 mM EGTA, independently of Ca2+, primarily from phosphatidic acid and polyphosphoinositides (poly-PI). Quinacrine, an inhibitor of phospholipase A2 (PLA2), suppressed AA release by about 60% and neomycin, a putative inhibitor of phospholipase C (PLC), reduced AA release by about 30%. An additive effect was exhibited when both inhibitors were given together. Ca2+ activated AA release. The level of Ca2+ present in the synaptoneurosomal preparation (endogenous level) and 5 microM CaCl2 enhance AA liberation by approximately 25%, whereas 2 mM CaCl2 resulted in a 50% increase in AA release relative to EGTA. The source for Ca(2+)-dependent AA release is predominantly phosphatidylinositol (PI); however, a small pool may also be liberated from neutral lipids. carbachol, an agonist of the cholinergic receptor, stimulated Ca(2+)-dependent AA release by about 17%. Bradykinin enhanced the effect of carbachol by about 10 - 15 % . This agonist-mediated AA release occurs specifically from phosphoinositides (PI + poly-PI). Quinacrine almost completely suppresses calcium-and carbachol-mediated AA release. neomycin inhibits this process by about 30% and totally suppresses the effect of bradykinin. Our results indicate that both phospholipases PLA2 and PLC with subsequent action of DAG lipase are responsible for Ca(2+)-independent AA release. Ca(2+)-dependent and carbachol-mediated AA liberation occurs mainly as the result of PLA2 action. A small pool of AA is probably also released by PLC, which seems to be exclusively responsible for the effect of bradykinin.", "source": "https://pubmed.ncbi.nlm.nih.gov/1910075/"}
{"doc_id": "83a954708b00b9b6e15d0d627b50420f", "sentence": "Here , we report that combinatorial treatment using EGFRis , such as gefitinib or erlotinib , with PI3K/AKT pathway inhibitors ( PI3K/AKTis ) demonstrated a synergistic , anti-proliferative effect in cell lines of the basal-like ( BL ) subtype , a subtype of TNBC .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 69, "end": 78, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "erlotinib", "start": 82, "end": 91, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "PI3K/AKTis", "start": 129, "end": 139, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Inhibition of the PI3K/AKT pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple-negative breast cancer cells. Triple-negative breast cancers (TNBCs) are known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical trials for TNBCs using EGFR inhibitors (EGFRis) as single agents have yielded disappointing results. Here , we report that combinatorial treatment using EGFRis , such as gefitinib or erlotinib , with PI3K/AKT pathway inhibitors ( PI3K/AKTis ) demonstrated a synergistic , anti-proliferative effect in cell lines of the basal-like ( BL ) subtype , a subtype of TNBC . Western blot analysis revealed that the gefitinib/PI-103 combination significantly reduced the level of both phospho-AKT and phospho-ERK in two susceptible BL subtype cell lines, SUM149PT and MDA-MB-468, whereas it had little or no effect on the level of phospho-ERK in two non-susceptible cell lines (HS578T and MDA-MB-231) of mesenchymal stem-like (MSL) TNBC subtype. The gefitinib/PI-103 combination also significantly induced caspase-3/7-mediated PARP cleavage and reduced two anti-apoptotic proteins, XIAP and Bcl-2 in the susceptible cell lines. In addition, the level of myeloid cell leukemia 1 (Mcl-1) protein was markedly decreased by gefitinib/PI-103 combination in the BL TNBC cells, but showed no significant change by this combination in MSL subtype cells. These results suggest that pharmacological inhibition of EGFR used in combination of PI3K/AKTis is a potential therapeutic approach to treat a subtype of TNBCs.", "source": "https://pubmed.ncbi.nlm.nih.gov/23601074/"}
{"doc_id": "bd68176608c1e1091d907d818f76921d", "sentence": "Patients received gemcitabine 1000 mg/m\u00b2 intravenously on days 1 and 8 , capecitabine 1300 mg/m\u00b2 oral daily from day 1 to 14 , and dovitinib oral daily 5 days on and 2 days off , every 21-day cycle .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 18, "end": 29, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "capecitabine", "start": 73, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "dovitinib", "start": 131, "end": 140, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients. Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. ### Materials And Methods Patients received gemcitabine 1000 mg/m\u00b2 intravenously on days 1 and 8 , capecitabine 1300 mg/m\u00b2 oral daily from day 1 to 14 , and dovitinib oral daily 5 days on and 2 days off , every 21-day cycle . The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. ### results A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300\u2009mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. ### conclusions dovitinib 300\u2009mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/30418178/"}
{"doc_id": "76cbd79e657a1ad54cf36da520ec4f51", "sentence": "A reduced dose of oxaliplatin 105 mg/m(2 ) on day 1 with doxorubicin at 20 mg/m(2)/dose on days 1 - 3 was well tolerated .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 18, "end": 29, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxorubicin", "start": 57, "end": 68, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Oxaliplatin and Doxorubicin for relapsed or refractory high-risk neuroblastoma. Patients with relapsed or refractory neuroblastoma have poor long-term survival. New therapeutic regimens are needed. doxorubicin and cisplatin are commonly used in the treatment of high-risk neuroblastoma. oxaliplatin, a platinum compound with a 1,2-diaminocyclohexan carrier ligand, is more potent than cisplatin with less nephrotoxicity and ototoxicity. We treated seven relapsed/refractory neuroblastoma patients using oxaliplatin (105-130 mg/m(2)) and doxorubicin (60-75 mg/m(2)) together with dexrazoxane (10 mg/mg of doxorubicin) administered intravenously every three weeks. Prolonged thrombocytopenia causing treatment delay was observed when oxaliplatin was administered at 130 mg/m(2). A reduced dose of oxaliplatin 105 mg/m(2 ) on day 1 with doxorubicin at 20 mg/m(2)/dose on days 1 - 3 was well tolerated . Sensory neuropathies were mild and transient. No cardiotoxicity was noted despite all patients having a history of prior anthracycline exposure. Best responses included 1 complete response, 1 partial response, 1 mixed response, 3 stable diseases. In our cohort of heavily pretreated relapsed and refractory neuroblastoma patients, the combination of oxaliplatin and doxorubicin demonstrated anti-tumor activity and merits further investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/25551355/"}
{"doc_id": "f53333587fca7842b3c70bb79390b818", "sentence": "In terms of recurrent disease , two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication .", "spans": [{"span_id": 0, "text": "trebananib", "start": 76, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "cediranib", "start": 91, "end": 100, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer. In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease , two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication . Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.", "source": "https://pubmed.ncbi.nlm.nih.gov/26500886/"}
{"doc_id": "76a47d0103d5bb645cef53e3849f296e", "sentence": "A total of 80 patients were randomized , including 44 to the combination group ( tamsulosin 0.4 mg and tolterodine early release 4 mg ) and 36 to the monotherapy group ( tamsulosin 0.4 mg and placebo ) .", "spans": [{"span_id": 0, "text": "tamsulosin", "start": 81, "end": 91, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "tolterodine", "start": 103, "end": 114, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "tamsulosin", "start": 170, "end": 180, "token_start": 32, "token_end": 33}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Does Combination Therapy with Tamsulosin and Tolterodine Improve Ureteral Stent Discomfort Compared with Tamsulosin Alone? A Double-Blind, Randomized, Controlled Trial. Ureteral stent discomfort is a significant postoperative problem for\u00a0many patients. Despite the use of narcotics and \u03b1-blockers patients often experience bothersome lower urinary tract symptoms and pain, which impair daily activities. We compared combination therapy with an \u03b1-blocker and an anticholinergic to monotherapy with an \u03b1-blocker. ### Materials And Methods A double-blind, randomized, controlled trial was performed from December 2012 to April 2014. A total of 80 patients were randomized , including 44 to the combination group ( tamsulosin 0.4 mg and tolterodine early release 4 mg ) and 36 to the monotherapy group ( tamsulosin 0.4 mg and placebo ) . Patients with preexisting ureteral stent placement or current anticholinergic therapy were excluded from study. Patients completed USSQ (Urinary Stent Symptom Questionnaire) before stent placement on the day of surgery, the day after stent placement, the morning of stent removal and the day after stent removal. The questionnaire included questions regarding urinary symptoms, general health, body pain, and work and sexual history. ### results A total of 80 patients (40 males and 40 females) were studied. Mean age was 51.5 vs 51.3 years (p = 0.95) and mean body mass index was 33.6 vs 31.9\u00a0kg/m(2) (p = 0.44) in monotherapy group 1 vs combination therapy group 2. Between\u00a0the 2 groups there was no significant difference in urinary symptoms, body pain and activities of daily living from baseline to just before stent removal (p = 0.95, 0.40 and 0.95, respectively). Although there was no difference between the groups, both showed improvement in urinary symptoms from the time of\u00a0initial stent insertion to just prior to stent removal (difference -0.50 for combination therapy and -0.40 for monotherapy). The mean stent indwelling time of 9.6 and 8.7 days in the combination and monotherapy groups, respectively, did not differ (p = 0.67). On ANOVA it had no significant impact on results (p = 0.64). ### conclusions Combination therapy with tamsulosin and tolterodine does not appear to improve urinary symptoms, bodily pain or quality of life in patients after ureteral stent placement for nephrolithiasis compared to tamsulosin alone. Both groups experienced worse urinary symptoms, pain and quality of life with a stent, suggesting that further research is necessary to improve stent discomfort.", "source": "https://pubmed.ncbi.nlm.nih.gov/26393904/"}
{"doc_id": "f1b0ff0b76130677d5b50ae333b2ff89", "sentence": "However , thiostrepton , dexamethasone , 2-methoxyestradiol , \u03b4-tocotrienol , quercetin , and quinine sulphate were effective in pancreatic , prostate , breast , lungs , melanoma , \u0392-lymphocytes , and T-cells ( Jurkat : 40 % to 95 % ) compared to respective controls .", "spans": [{"span_id": 0, "text": "dexamethasone", "start": 25, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "quinine", "start": 94, "end": 101, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs. Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs. ### methods The anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of \u03b4-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-\u03b1 using total RNAs derived from plasmas of hepatitis C patients was investigated. ### results Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, \u03b4-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5-20\u00a0\u03bcM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, \u03b4-tocotrienol, and quercetin were 70% - 92%. However , thiostrepton , dexamethasone , 2-methoxyestradiol , \u03b4-tocotrienol , quercetin , and quinine sulphate were effective in pancreatic , prostate , breast , lungs , melanoma , \u0392-lymphocytes , and T-cells ( Jurkat : 40 % to 95 % ) compared to respective controls . In lung cancer cells, these compounds were effective between 5 and 40\u00a0\u03bcM. The IC ### conclusions These data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, \u03b4-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, \u0392-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.", "source": "https://pubmed.ncbi.nlm.nih.gov/29606130/"}
{"doc_id": "b233b4e3fc9cdd13f716e884102c3d03", "sentence": "Of them , 47 patients started with docetaxel at cycle one due to reaction to paclitaxel ( n=32 ) , fear of NT ( n=4 ) , and other reasons ( n=11 ) , whereas 59 patients switched to docetaxel during cycle 2 - 6 due to NT ( n=32 ) , reaction to paclitaxel ( n=19 ) , and other reasons ( n=8 ) .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 35, "end": 44, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "paclitaxel", "start": 77, "end": 87, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "docetaxel", "start": 181, "end": 190, "token_start": 39, "token_end": 40}, {"span_id": 3, "text": "paclitaxel", "start": 243, "end": 253, "token_start": 54, "token_end": 55}], "rels": [], "paragraph": "Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study. To describe characteristics associated with neurotoxicity (NT) in advanced ovarian cancer patients treated on Gynecologic Oncology Group 218 and examine effect of substituting docetaxel for paclitaxel in these patients. ### methods The development of NT was defined as Common Toxicity Criteria grade (G)\u22651. The association between substitution with docetaxel and NT improvement was explored with generalized estimating equations adjusting for treatment cycle and NT grading at previous cycle. ### results Of 1864 evaluable patients, 1329 (71%) developed G\u22651 NT during the study. Nearly half appeared within the first two cycles of chemotherapy, with 31% experiencing G\u22652. Older patients or those with worse quality of life (QoL) scores at baseline (p<0.05) were more likely to experience NT. One-hundred-six patients received docetaxel as substitute for paclitaxel. Of them , 47 patients started with docetaxel at cycle one due to reaction to paclitaxel ( n=32 ) , fear of NT ( n=4 ) , and other reasons ( n=11 ) , whereas 59 patients switched to docetaxel during cycle 2 - 6 due to NT ( n=32 ) , reaction to paclitaxel ( n=19 ) , and other reasons ( n=8 ) . Although the protocol instructed otherwise, the majority continued paclitaxel despite G\u22652 NT symptoms. There was no evidence that substitution with docetaxel improved NT (Odds Ratio: 1.57; 95% CI 0.98-2.54; p>0.05). Of 59 patients who switched to docetaxel, only seven (12%) discontinued taxane prior to chemotherapy completion. A roughly equal chance of worsening NT was reported on paclitaxel (6%) as on docetaxel (5%). ### conclusions Age and worse QoL at baseline are associated with NT. Substitution of docetaxel did not improve NT symptoms.", "source": "https://pubmed.ncbi.nlm.nih.gov/25529832/"}
{"doc_id": "197fa35b97d4040fda9cd228ffe661ab", "sentence": "Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption , prednisolone and cyclophosphamide .", "spans": [{"span_id": 0, "text": "prednisolone", "start": 89, "end": 101, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "cyclophosphamide", "start": 106, "end": 122, "token_start": 11, "token_end": 12}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption , prednisolone and cyclophosphamide . Ten patients with rapidly progressive glomerulonephritis and acute renal failure were treated with extracorporeal immunoadsorption, prednisolone, and cyclophosphamide. Three patients had systemic lupus erythematosus, five had microscopic polyarteritis and two had Wegener's granulomatosis. All ten patients were dialysis-dependent prior to immunoadsorption. Nine of ten patients rapidly regained renal function and seven continue to have independent renal function between 9 and 30 months after immunoadsorption. Three patients at presentation were not dialysis dependent. Despite treatment with methylprednisolone, cyclophosphamide, and oral prednisolone, renal function continued to deteriorate and they required dialysis. Immunoadsorption was then started without alteration in baseline immunosuppression. Within a mean of 4.6 days, range 3-7 days, renal function improved and the patients no longer required dialysis. Antineutrophil cytoplasmic antibodies and double-stranded DNA antibodies were rapidly removed by immunoadsorption. Only one patient with systemic lupus erythematosus and two with microscopic polyarteritis had significant resynthesis of antibody at 1 month post-immunoadsorption. Renal biopsy before and after immunoadsorption and immunosuppressive therapy showed resolution of glomerular crescents and no evidence of active disease. Immunoadsorption coupled with prednisolone and cyclophosphamide may be of value in the treatment of rapidly progressive glomerulonephritis.", "source": "https://pubmed.ncbi.nlm.nih.gov/1956551/"}
{"doc_id": "9e833fe8bad3c49371b619cf31472d4f", "sentence": "[ Doxifluridine , medroxyprogesterone acetate and cyclophosphamide ( DMpC ) combination therapy is effective against recurrent triple negative breast cancer -- a case report ] .", "spans": [{"span_id": 0, "text": "Doxifluridine", "start": 2, "end": 15, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "medroxyprogesterone", "start": 18, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "cyclophosphamide", "start": 50, "end": 66, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[ Doxifluridine , medroxyprogesterone acetate and cyclophosphamide ( DMpC ) combination therapy is effective against recurrent triple negative breast cancer -- a case report ] . We report a postmenopausal recurrent breast cancer patient with triple negative disease who presented with right recurrent nerve palsy. Nine years previously, she had undergone a mastectomy. FDG-PET scan revealed neck lymph node metastases from the breast cancer. The recurrent nerve palsy was thus considered to have been caused by the lymph node metastases. The patient was orally administered DMpC (doxifluridine, medroxyprogesterone acetate and cyclophosphamide) combination therapy. This resulted in a remarkable response after five months, with the recurrent nerve palsy completely disappearing at six months. No side effects from the treatment were observed. The patient was well and the treatment was being continued without relapse at nine months. Oral anti-cancer treatments such as DMpC appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients with triple negative disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/19098418/"}
{"doc_id": "61d52dccc15e2956f4223de1a92b4cba", "sentence": "Superposition predicted that oral dosing of 1800-mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir .", "spans": [{"span_id": 0, "text": "valganciclovir", "start": 52, "end": 66, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ganciclovir", "start": 153, "end": 164, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Pharmacokinetics of ganciclovir and valganciclovir in the adult horse. Equine herpes myeloencephalopathy, resulting from equine herpes virus type 1 (EHV-1) infection, is associated with substantial morbidity and mortality in the horse. As compared to other antiviral drugs, such as acyclovir, ganciclovir has enhanced potency against EHV-1. This study investigated the pharmacokinetics of ganciclovir and its oral prodrug, valganciclovir, in six adult horses in a randomized cross-over design. ganciclovir sodium was administered intravenously as a slow bolus at a dose of 2.5 mg/kg, and valganciclovir was administered orally at a dose of 1800 mg per horse. Intravenously administered ganciclovir disposition was best described by a three-compartment model with a prolonged terminal half-life of 72 \u00b1 9 h. Following the oral administration of valganciclovir, the mean observed maximum serum ganciclovir concentration was 0.58 \u00b1 0.37 \u03bcg/mL, and bioavailability of ganciclovir from oral valganciclovir was 41 \u00b1 20%. Superposition predicted that oral dosing of 1800-mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir . However, superposition suggested that i.v. administration of ganciclovir at 2.5 mg/kg every 8 h for 24 h followed by maintenance dosing of 2.5 mg/kg every 12 h would maintain effective ganciclovir serum concentrations in most horses throughout the dosing interval.", "source": "https://pubmed.ncbi.nlm.nih.gov/23301502/"}
{"doc_id": "3ebfe9d6dea0a9a490ea2aa0454bbe73", "sentence": "The levels of 3 NF-kappaB transcription factors , the activating inhibitors of NF-kappaB ( IkappaB ) kinases , and the NF-kappaB target matrix metalloproteinase 9 ( MMP9 ) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel , cisplatin , and cyclophosphamide .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 337, "end": 347, "token_start": 52, "token_end": 53}, {"span_id": 1, "text": "cyclophosphamide", "start": 366, "end": 382, "token_start": 57, "token_end": 58}, {"span_id": 2, "text": "cisplatin", "start": 350, "end": 359, "token_start": 54, "token_end": 55}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Recent work has suggested a role for nuclear factor kappaB (NF-kappaB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-kappaB in ovarian cancer is unknown. The authors hypothesized that the NF-kappaB pathway is over activated in aggressive ovarian cancers. ### methods The levels of 3 NF-kappaB transcription factors , the activating inhibitors of NF-kappaB ( IkappaB ) kinases , and the NF-kappaB target matrix metalloproteinase 9 ( MMP9 ) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel , cisplatin , and cyclophosphamide . Associations were made between NF-kappaB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. ### results The presence of NF-kappaB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IkappaB kinase alpha, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-kappaB machinery suggested activity of NF-kappaB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. ### conclusions The deregulation of NF-kappaB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-kappaB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/20564628/"}
{"doc_id": "6cb24a0aa6f5f1697a1eee72f33a27f2", "sentence": "The clonidine DV suppression was reliably reversed by yohimbine ( 1.75 micrograms ) , but by none of the other adrenoceptor antagonists or naloxone .", "spans": [{"span_id": 0, "text": "clonidine", "start": 4, "end": 13, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "yohimbine", "start": 54, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "naloxone", "start": 139, "end": 147, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "The role of brain norepinephrine in clonidine suppression of isolation-induced distress in the domestic chick. Distress vocalizations (DV) induced by social isolation were measured in 1-day-old domestic chicks after intracerebroventricular injections of drugs believed to exert their effects through the noradrenergic system. The alpha-adrenoreceptor agonist clonidine reliably suppressed DV rates at doses low as 0.08 micrograms. When given alone, phentolamine, phenoxybenzamine, propranolol, sotalol, and yohimbine (adrenoreceptor antagonists) did not reliably alter DV rates at doses that were not toxic. The clonidine DV suppression was reliably reversed by yohimbine ( 1.75 micrograms ) , but by none of the other adrenoceptor antagonists or naloxone . 6-Hydroxydopamine at doses as high as 120 micrograms, which essentially eliminated forebrain norepinephrine, failed to suppress DV rates reliably when given alone and, when given in combination with clonidine (0.1 micrograms) or morphine (0.05 micrograms), failed to reverse the severe DV suppression imposed by these drugs. The results suggest that clonidine suppresses DV rates in or by some means other than prejunctional alpha 2-adrenoreceptor stimulation.", "source": "https://pubmed.ncbi.nlm.nih.gov/6407049/"}
{"doc_id": "f65d266d877f06ce911e476b58ade05a", "sentence": "There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status ; the mean shrinkage was -17 % vs -25 % for sunitinib-treated patients with high vs low tumour CAIX expression , compared to -13 % vs + 9 % for sorafenib-treated patients ( P interaction , 0.05 ) .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 52, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "sorafenib", "start": 65, "end": 74, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy. To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy. ### Patients And Methods We identified 118 patients with mRCC initiating first-line VEGF-targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed. ### results There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status ; the mean shrinkage was -17 % vs -25 % for sunitinib-treated patients with high vs low tumour CAIX expression , compared to -13 % vs + 9 % for sorafenib-treated patients ( P interaction , 0.05 ) . A higher tumour clear-cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02). ### conclusions Although CAIX expression had no prognostic value in patients with clear-cell mRCC treated with VEGF-targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear-cell component in their tumours are likely to have a superior clinical benefit from VEGF-targeted therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/20230385/"}
{"doc_id": "373e5d7f0b58c2077b7b3e990ecd028c", "sentence": "Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer .", "spans": [{"span_id": 0, "text": "Seribantumab", "start": 29, "end": 41, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "Erlotinib", "start": 62, "end": 71, "token_start": 9, "token_end": 10}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer . seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 ( ### Materials And Methods Patients with ### results One hundred twenty-nine patients received seribantumab + erlotinib ( ### conclusion The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). ### Implications For Practice The poor prognosis of patients with non-small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open-label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin-positive advanced adenocarcinoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/30975923/"}
{"doc_id": "9dbe60379e343d03771d72567b7e1952", "sentence": "Trabectedin in combination with pegylated liposomal doxorubicin ( PLD ) has been fully available privately in the UK since 2009 for treating patients with ROC .", "spans": [{"span_id": 0, "text": "Trabectedin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 52, "end": 63, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Real-life experience using trabectedin plus pegylated liposomal doxorubicin combination to treat patients with relapsed ovarian cancer. The goal of recurrent ovarian cancer (ROC) treatment is no longer just palliation, but prolonging survival. This is usually through administering a new line of chemotherapy at each relapse. A novel treatment sequencing strategy to achieve this is through the intercalation of an effective non-platinum alternative, in between platinum-based therapies. Trabectedin in combination with pegylated liposomal doxorubicin ( PLD ) has been fully available privately in the UK since 2009 for treating patients with ROC . A single institution's experience with the trabectedin + PLD combination, as a non-platinum/non-taxane alternative, to intercalate between platinum-based therapies is reported here. To date 6 patients have been successfully treated with trabectedin + PLD at Broomfield Hospital, Chelmsford, Essex. Here we describe a new, practice-changing treatment approach in a real-life case study of a heavily-treated patient with advanced ROC treated with trabectedin + PLD at fourth-line and then subsequently rechallenged at seventh-line; with treatment continuing until disease progression.", "source": "https://pubmed.ncbi.nlm.nih.gov/26759528/"}
{"doc_id": "4301abf0739a41ba2cdbb7b62a226409", "sentence": "More interestingly , lumefantrine tolerance is associated with an increase in chloroquine susceptibility , raising the possibility of re-introducing chloroquine .", "spans": [{"span_id": 0, "text": "lumefantrine", "start": 21, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "chloroquine", "start": 78, "end": 89, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "chloroquine", "start": 149, "end": 160, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Update on the in vivo tolerance and in vitro reduced susceptibility to the antimalarial lumefantrine. Coartem(\u00ae), the combination of artemether (an artemisinin derivative) and lumefantrine, has been adopted as the first-line treatment for uncomplicated malaria in many countries. The emergence of resistance to artemisinin derivatives has now been proven in South-East Asia, and there is concern that this may spread to other endemic areas. Strategies to contain and control the spread of artemisinin resistance have been proposed. On the other hand, not much attention has been given to lumefantrine. Indeed, for more than 7 years, reports have been emerging that the use of Coartem(\u00ae) is associated with rapid selection of lumefantrine-tolerant parasites. These parasites can survive in the presence of sub-therapeutic lumefantrine concentrations, and, interestingly, this in vivo phenotype is translated in vitro into reduced susceptibility to lumefantrine. As a result, such parasites could form the setting in which lumefantrine resistance would emerge. Thus, identifying genetic markers that reflect this phenotype (both in vitro and in vivo) could yield information on the mechanisms of lumefantrine resistance. More interestingly , lumefantrine tolerance is associated with an increase in chloroquine susceptibility , raising the possibility of re-introducing chloroquine . In this work, we have reviewed the current knowledge, and we present existing challenges and gaps with regard to the mechanisms of in vivo tolerance and in vitro reduced susceptibility to lumefantrine. The re-introduction of chloroquine in areas of high lumefantrine resistance is also discussed.", "source": "https://pubmed.ncbi.nlm.nih.gov/22761327/"}
{"doc_id": "ae0bd2532fba1ddf22f0e68f16423f74", "sentence": "Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine .", "spans": [{"span_id": 0, "text": "Estramustine", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "vinblastine", "start": 73, "end": 84, "token_start": 10, "token_end": 11}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Vinblastine and estramustine phosphate in metastatic renal cell carcinoma: a phase II trial of the Fox Chase Network. It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine . The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine. ### methods Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy. ### results Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks. ### conclusions Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/14584064/"}
{"doc_id": "c1075bb61cf549c452bcc7f9aef03755", "sentence": "Cohort 7 ( gemcitabine 600 mg/m/wk and carboplatin 2 AUC ) showed 4 dose limiting toxicities : 2 grade 3 esophagitis ; one grade 3 febrile neutropenia ; and one grade 4 neutropenia .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 11, "end": 22, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "carboplatin", "start": 39, "end": 50, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "RTOG 0017: a phase I trial of concurrent gemcitabine/carboplatin or gemcitabine/paclitaxel and radiation therapy (\"ping-pong trial\") followed by adjuvant chemotherapy for patients with favorable prognosis inoperable stage IIIA/B non-small cell lung cancer. The optimal dose of gemcitabine that can be used with concurrent radiation therapy for locally advanced non-small cell lung cancer has not been well defined. This trial addresses this question in an alternating sequence \"ping-pong\" design trial to find the maximum tolerated dose (MTD) for gemcitabine/carboplatin (Sequence A) or gemcitabine/paclitaxel (Sequence B) and thoracic radiation therapy followed by adjuvant gemcitabine/carboplatin chemotherapy. ### Patients And Methods Thirty-five patients with histologically confirmed Stage IIIA/B non-small cell lung cancer were entered into two separate sequences, each with multiple cohorts. A dose level was considered acceptable if, of the first six eligible patients on each cohort, fewer than three experienced dose limiting toxicities. ### results Sequence B of this 2 sequence \"ping-pong\" trial closed early due to toxicity in cohort 2 (gemcitabine 300 mg/m/wk and paclitaxel 30 mg/m/wk). On Sequence A, the MTD was the cohort 5 dose: gemcitabine 450 mg/m/wk and carboplatin 2 area under curve (AUC) concurrently with thoracic radiation. Cohort 7 ( gemcitabine 600 mg/m/wk and carboplatin 2 AUC ) showed 4 dose limiting toxicities : 2 grade 3 esophagitis ; one grade 3 febrile neutropenia ; and one grade 4 neutropenia . ### conclusion Concurrent gemcitabine/paclitaxel chemoradiation regimen followed by adjuvant gemcitabine/carboplatin produced excessive toxicity at the lowest tested dose combination and was not suitable for further study in this trial. Meanwhile, the MTD of concurrent gemcitabine/carboplatin chemoradiation was determined to be gemcitabine 450 mg/m and carboplatin AUC-2. This combination was found to be tolerable. Although not a primary end point, survival results are summarized as well.", "source": "https://pubmed.ncbi.nlm.nih.gov/19096311/"}
{"doc_id": "8e05f49203e45d0f5d18bf08087c48a2", "sentence": "Treatment with IFN-\u03b1 plus bevacizumab or standard targeted therapy ( sunitinib ) may lead to similar one-year overall mortality ( RR 0.37 , 95 % CI 0.13 to 1.08 ; 1 study ; 83 participants ; low-quality evidence ) and AEs of grade 3 or greater ( RR 1.18 , 95 % CI 0.85 to 1.62 ; 1 study ; 82 participants ; low-quality evidence ) .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 26, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "sunitinib", "start": 69, "end": 78, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "IFN-\u03b1", "start": 15, "end": 20, "token_start": 2, "token_end": 3}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Immunotherapy for metastatic renal cell carcinoma. Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. ### objectives To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. ### Search Methods We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. ### Selection Criteria We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. ### Data Collection And Analysis We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. ### Main Results We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-\u03b1 monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-\u03b1 plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-\u03b1 alone may slightly increase one-year overall mortality compared to IFN-\u03b1 plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data. Treatment with IFN-\u03b1 plus bevacizumab or standard targeted therapy ( sunitinib ) may lead to similar one-year overall mortality ( RR 0.37 , 95 % CI 0.13 to 1.08 ; 1 study ; 83 participants ; low-quality evidence ) and AEs of grade 3 or greater ( RR 1.18 , 95 % CI 0.85 to 1.62 ; 1 study ; 82 participants ; low-quality evidence ) . QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). ### Authors Conclusions Evidence of moderate quality demonstrates that IFN-\u03b1 monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-\u03b1 alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-\u03b1 plus bevacizumab. Low-quality evidence shows no difference for IFN-\u03b1 plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.", "source": "https://pubmed.ncbi.nlm.nih.gov/28504837/"}
{"doc_id": "35396e2be6839ef529a93eff596364a0", "sentence": "In vitro , ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib .", "spans": [{"span_id": 0, "text": "selumetinib", "start": 92, "end": 103, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "trametinib", "start": 107, "end": 117, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P\u2009=\u20090.130), and improved response rates (32% vs 14%, P\u2009=\u20090.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. ### methods A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. ### results In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro , ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib . In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib. ### conclusions ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity. ### Clinical Trial Registration DOC-MEK (EudraCT no: 2009-018153-23).", "source": "https://pubmed.ncbi.nlm.nih.gov/31839677/"}
{"doc_id": "aed14eca85db89b8b0b3d86c37c2081b", "sentence": "Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC ( mRCC ) .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 44, "end": 53, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "sunitinib", "start": 58, "end": 67, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Sorafenib, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma. Induction of regulatory T cells (Treg) is an important mechanism leading to tolerance against tumors. Increased levels of Treg have been described in renal cell carcinoma (RCC) patients and seem to correlate with an adverse outcome. Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC ( mRCC ) . Treg were analyzed by flow cytometry in the peripheral blood (PB) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). Blood samples were taken before treatment and during the first, second, and third months of therapy. Flow cytometric analysis of PB mononuclear cells was performed using fluorochrome-labeled antibodies against CD3, CD4, CD25, and FOXp3. During the first month of therapy, patients treated with sorafenib showed a significant increase in FOXp3CD3CD4CD25 Treg (13.5 vs. 36.3% of gated cells, P=0.02, or 0.35 vs. 0.49% of total cells) and the ratio FOXp3 T cells/FOXp3 T cells (0.16 vs. 0.56 of gated cells, P=0.02). These elevated levels persisted throughout the treatment period. There was no influence of sunitinib on the frequency of Treg in our cohort of patients. sorafenib, but not sunitinib, leads to an early and sustained increase in Treg in PB of mRCC patients. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. Our study suggests that sorafenib should be avoided in such a therapeutic setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/22156795/"}
{"doc_id": "1eab299f82afbf61906b779959587b5e", "sentence": "Naloxone ( 5 x 10(-7 ) mol/kg iv ) and atropine ( 0.1 mg/kg iv ) induced isolated orad contractions .", "spans": [{"span_id": 0, "text": "Naloxone", "start": 0, "end": 8, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "atropine", "start": 39, "end": 47, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Rhythmic oscillating complex: characterization, induction, and relationship to MMC in chickens. Migrating myoelectrical complexes (MMCs) and rhythmic oscillating complexes (ROCs) have been investigated in chickens prepared for electromyography. Animals were chronically implanted with electrodes in stomach, duodenum, jejunum, ileum, ceca, and rectum. MMCs showing phases I-III were found in the jejunum and ileum both in fed and fasted states. Repetitive spike bursts were recorded in the duodenum (0.5-1/h), disrupting the gastroduodenal coordination and preceding a phase III in the jejunum. ROCs appeared spontaneously in fasted animals and in 75% of the recordings during the dark period. Four consecutive intestinal myoelectrical patterns have been described during a ROC. Briefly, they consisted in series of high-speed propagated abroad contractions of great amplitude that progressively changed into others of orad direction. In relation to the MMC, the ROC pattern appeared just after a phase III reached the distal ileum, and a pattern of duodenal repetitive spike bursts, followed by a migrating phase III in the jejunum, started at the duodenum after a ROC. No myoelectrical changes were recorded in cecorectal activity during ROC. Vagotomized animals showed the ROC pattern. Neither apomorphine (5-100 micrograms/kg iv) nor cholecystokinin (10(-9) mol/kg iv) induced ROCs. Naloxone ( 5 x 10(-7 ) mol/kg iv ) and atropine ( 0.1 mg/kg iv ) induced isolated orad contractions . Myoelectrical and functional similarities can be found between retrograde giant contractions, described in mammals, and ROCs. However, they differ in their origin and mechanism of induction.", "source": "https://pubmed.ncbi.nlm.nih.gov/8178997/"}
{"doc_id": "91a967a9455079d236d1c9191fe1aa68", "sentence": "FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the \u226575-yr model ( p=0.003 ) , with no difference in the < 75-yr model ( p>0.9 ) .", "spans": [{"span_id": 0, "text": "abiraterone", "start": 53, "end": 64, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "enzalutamide", "start": 74, "end": 86, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial. abiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL). ### objective To assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide. ### Design Setting And Participants We randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357). ### intervention Patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment. ### Outcome Measurements And Statistical Analysis To compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and \u226575yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test. ### Results And Limitations In the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the \u226575-yr model ( p=0.003 ) , with no difference in the < 75-yr model ( p>0.9 ) . A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating. ### conclusions Patient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup. ### Patient Summary In this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/30591354/"}
{"doc_id": "d6e707bfab45da269027b64b4534859e", "sentence": "The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy .", "spans": [{"span_id": 0, "text": "verapamil", "start": 21, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxorubicin", "start": 90, "end": 101, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Doxorubicin in combination with verapamil in advanced colorectal cancer. A phase II trial.  The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy . The treatment started with oral verapamil, which was escalated up to the individual maximum tolerable dose (defined by prolongation of P-Q in ECG, fall in blood pressure, or dizziness). The median maximum tolerable dose was 600 mg (range 320-1,440 mg). During continued verapamil administration the patients then got weekly infusions of doxorubicin, 25 mg/m2. The median number of doxorubicin courses was 8 (range 2-22). Among 21 patients evaluable for response and toxicity two partial remissions occurred but no complete remission. The study did not indicate enhanced cardiac, hematological or non-hematological toxicity from the combined treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/2009180/"}
{"doc_id": "516f23cdd806a08725fc0664796a5694", "sentence": "Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine ( 20 mg/m2 on D1 , D15 ) , followed by paclitaxel ( 175 mg/m2 on D1 ) , every 3 weeks .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 147, "end": 158, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "paclitaxel", "start": 198, "end": 208, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II study of paclitaxel combined with vinorelbine in patients with advanced breast cancer. paclitaxel and vinorelbine are two drugs active against breast cancer. A phase II study was initiated with the aim of assessing the efficacy and feasibility of the combination. Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine ( 20 mg/m2 on D1 , D15 ) , followed by paclitaxel ( 175 mg/m2 on D1 ) , every 3 weeks . A 48% (95% CI: 35-61) response rate was obtained in the 23 patients evaluable for response. vinorelbine was administered on D15, as scheduled, in 72% of cycles. The main toxicity observed was grade III to IV neutropenia in 73% of patients. Febrile neutropenia was reported in three patients. Disease-free survival was 118 days, and overall median survival was 361 days. This combination of paclitaxel and vinorelbine is feasible and effective in patients with early relapse or previously treated with first-line chemotherapy for metastatic disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/15170156/"}
{"doc_id": "f10f68be5ebe5d09547fc181228e3653", "sentence": "Although monotherapy with cytotoxic agents , including docetaxel and pemetrexed , is recommended for patients with previously treated advanced non-small cell lung cancer ( NSCLC ) , its outcomes are unsatisfactory .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 55, "end": 64, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "pemetrexed", "start": 69, "end": 79, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer. In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. ### background Although monotherapy with cytotoxic agents , including docetaxel and pemetrexed , is recommended for patients with previously treated advanced non-small cell lung cancer ( NSCLC ) , its outcomes are unsatisfactory . S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. ### methods Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m ### results Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. ### conclusion This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/31040252/"}
{"doc_id": "c560366d3211f10db393fbae2d29f7ca", "sentence": "Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine , it has not previously been reported for combination therapy that includes diltiazem .", "spans": [{"span_id": 0, "text": "verapamil", "start": 102, "end": 111, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "nifedipine", "start": 115, "end": 125, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "diltiazem", "start": 202, "end": 211, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Combination therapy with diltiazem and propranolol: precipitation of congestive heart failure.  Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine , it has not previously been reported for combination therapy that includes diltiazem . The following case documents the occurrence of clinical congestive failure in a patient with baseline left ventricular dysfunction and severe angina pectoris. Although the patients had tolerated propranolol therapy for years without difficulty, and high-dose diltiazem monotherapy with an excellent clinical response, the combination of diltiazem and propranolol resulted in the development of congestive heart failure. Thus, although generally well tolerated, given the suitable scenario of reduced left ventricular function, the combination of diltiazem and a beta blocker may adversely affect left ventricular performance.", "source": "https://pubmed.ncbi.nlm.nih.gov/4006348/"}
{"doc_id": "31a6bbc586c08e3c8ff0a066bf1a97f2", "sentence": "Relationships between heart rate , exercise tolerance and cardiac output in atrial fibrillation : the effects of treatment with digoxin , verapamil and diltiazem .", "spans": [{"span_id": 0, "text": "digoxin", "start": 128, "end": 135, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "verapamil", "start": 138, "end": 147, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "diltiazem", "start": 152, "end": 161, "token_start": 23, "token_end": 24}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Relationships between heart rate , exercise tolerance and cardiac output in atrial fibrillation : the effects of treatment with digoxin , verapamil and diltiazem . Six patients with chronic atrial fibrillation (AF) took single doses of digoxin, verapamil and diltiazem, alone and in combination. Three hours after dosing, resting and post-exercise heart rate, exercise tolerance and resting and post-exercise cardiac output were measured. Post-exercise heart rates ranged from 167 bpm (after placebo) to 122 bpm (after digoxin plus diltiazem) (P less than 0.05). However, the lower ventricular rates seen after treatment with the calcium antagonists were not associated with improved exercise tolerance, which did not differ significantly between the various treatments. Reduction of the ventricular rate was associated with a small increase in stroke volume but the benefits of this were offset by a rate related reduction in cardiac output. Further reduction of the rapid ventricular rates seen in digitalized patients with AF does not appear to be of benefit in terms of improving either exercise tolerance or cardiac output.", "source": "https://pubmed.ncbi.nlm.nih.gov/3169046/"}
{"doc_id": "293b50fc8d6d4c34305176b415115cb6", "sentence": "Oxaliplatin , which is effective for colorectal cancer ( CRC ) in combination with 5-fluorouracil ( 5-FU ) and leucovorin ( LV ) , is widely used for metastatic CRC .", "spans": [{"span_id": 0, "text": "Oxaliplatin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "leucovorin", "start": 111, "end": 121, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "5-fluorouracil", "start": 83, "end": 97, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Scheduled prospective tri-weekly modified FOLFOX6 maintenance chemotherapy in the treatment of metastatic colorectal cancer.  Oxaliplatin , which is effective for colorectal cancer ( CRC ) in combination with 5-fluorouracil ( 5-FU ) and leucovorin ( LV ) , is widely used for metastatic CRC . With the increasing use of oxaliplatin, however, serious adverse events have been experienced, including hematologic and neurologic toxicities. The aim of this study was to evaluate whether tri-weekly modified FOLFOX6 (mFOLFOX6) maintenance chemotherapy is associated with a low incidence of severe hematologic and neurologic toxicities in the treatment of patients with metastatic CRC. ### methodology We developed a new treatment regimen with mFOLFOX6 biweekly for 8-10 consecutive cycles (induction phase) followed by a 3-week rest period, after which treatment was resumed with cycles of tri-weekly mFOLFOX6 at standard doses (maintenance phase). Validity and complications were investigated retrospectively. ### results Twenty-nine patients were enrolled in this study. The median progression-free survival (PFS) and overall survival (OS) times were 9.4 months and 23 months, respectively. All patients had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 2 patients (6.9%). ### conclusions mFOLFOX6 maintenance chemotherapy was associated with a very low incidence of grade 3 hematologic and neurologic toxicities. The toxicities associated with PFS and OS were comparable to those reported in the treatment of patients with metastatic CRC. A tri-weekly mFOLFOX maintenance strategy of alternative treatment with a less-toxic regimen may reduce toxicity and maintain efficacy.", "source": "https://pubmed.ncbi.nlm.nih.gov/22234064/"}
{"doc_id": "67b30dffc6de839918db012062658e49", "sentence": "The cytotoxicity of sequential combinations of a taxoid [ paclitaxel ( TAX ) or docetaxel ( TXT ) ] with a vinca alkaloid [ vinorelbine ( NVB ) ] was compared in differentiated and undifferentiated HT29-D4 cells .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 58, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "docetaxel", "start": 80, "end": 89, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "vinorelbine", "start": 124, "end": 135, "token_start": 24, "token_end": 25}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "The effect of combining antitubulin agents on differentiated and undifferentiated human colon cancer cells.  The cytotoxicity of sequential combinations of a taxoid [ paclitaxel ( TAX ) or docetaxel ( TXT ) ] with a vinca alkaloid [ vinorelbine ( NVB ) ] was compared in differentiated and undifferentiated HT29-D4 cells . Agents were titrated from low doses inducing no modification of microtubule network to high doses corresponding to the clinically relevant concentrations that block mitosis. For undifferentiated cells, the sequential combination NVB/TAX was more efficient than TAX/NVB (22% cell survival versus 37% for 5 nM TAX and NVB). Surprisingly, we successively obtained synergism for low doses of both compounds [NVB (1-5 nM) and TAX (1-15 nM)], then additivity and finally antagonism when one of the compounds was at the concentration inducing mitotic block. The three patterns of results were also obtained with NVB/TXT combinations. For the synergistic combinations at the lowest concentrations, cytotoxicity occurred by apoptosis following mitosis. For differentiated cells, the most cytotoxic combinations were 1 microM TAX or TXT for 3 days followed by 1 microM NVB for 3 days, and 0.75 nM TAX or TXT for 9 days followed by 1 microM NVB for 3 days, the latter producing synergistic effects. Cytotoxicity occurred by apoptosis for the two states of differentiation. Major differences depending on cell phenotype were demonstrated: low sensitivity of differentiated cells to antitubulin agents and the difference in apoptotic pathways since mitosis is not involved in differentiated cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/9625431/"}
{"doc_id": "2d82fb93fb6b942eb0e64bf06d08cece", "sentence": "Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 45, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ipilimumab", "start": 57, "end": 67, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. In the phase III CheckMate 227 study, first-line nivolumab\u00a0+\u00a0ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; \u226510 mutations/megabase). ### aim To evaluate patient-reported outcomes (PROs) in this population. ### methods Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI)\u00a0and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. ### results In the high TMB population, PRO questionnaire completion rates were \u223c90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab\u00a0+\u00a0ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab\u00a0+\u00a0ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab\u00a0+\u00a0ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures . ### conclusion First-line nivolumab\u00a0+\u00a0ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. ### Clinical Trial Registration NCT02477826.", "source": "https://pubmed.ncbi.nlm.nih.gov/31195357/"}
{"doc_id": "f59f33fd8ec9cbe50b31da1f0cf1ae9b", "sentence": "In the present study , we investigated the effect atorvastatin , celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells .", "spans": [{"span_id": 0, "text": "atorvastatin", "start": 50, "end": 62, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "celecoxib", "start": 65, "end": 74, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "tipifarnib", "start": 79, "end": 89, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effects of atorvastatin in combination with celecoxib and tipifarnib on proliferation and apoptosis in pancreatic cancer sphere-forming cells. Cancer stem cell (CSC) plays an important role in pancreatic cancer pathogenesis and treatment failure. CSCs are characterized by their ability to form tumor spheres in serum-free medium and expression of CSC related markers. In the present study , we investigated the effect atorvastatin , celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells . The sphere-forming cells were isolated from Panc-1\u00a0cells by sphere-forming method. These sphere-forming cells showed CSC properties. The levels of CD44, CD133 and ALDH1A1 in the sphere-forming cells were increased. Moreover, Panc-1 sphere-forming cells were resistant to chemotherapeutic drug gemcitabine. Combined atorvastatin with celecoxib and tipifarnib synergistically decreased the sphere forming ability of Panc-1\u00a0cells and the drug combination also strongly inhibited cell proliferation and promoted apoptosis in the sphere-forming cells. The effects of the drug combination on the Panc-1 sphere-forming cells were associated with decreases in the levels of CD44, CD133 and ALDH1A1, and suppression of Akt and NF-\u03baB activation. Results of the present study indicate that the combination of atorvastatin, celecoxib and tipifarnib may represent an effective approach for inhibiting pancreatic CSCs.", "source": "https://pubmed.ncbi.nlm.nih.gov/33359649/"}
{"doc_id": "7c401c1d411b0113dc808c946ee82227", "sentence": "As SD , donepezil , galantamine , rivastigmine , and memantine are now usable .", "spans": [{"span_id": 0, "text": "donepezil", "start": 8, "end": 17, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "galantamine", "start": 20, "end": 31, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "rivastigmine", "start": 34, "end": 46, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "memantine", "start": 53, "end": 62, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "[The Use of Symptomatic Drugs for Dementia]. The treatment of Alzheimer's disease (AD) can be roughly divided into Disease-modifying Drugs (DMD) and Symptomatic Drugs (SD). Major strategies of DMD are the amyloid vaccine therapy and \u03b2/\u03b3-secretase inhibitors, which have been developed with high expectations as fundamental treatments for AD. As SD , donepezil , galantamine , rivastigmine , and memantine are now usable . While memantine is an NMDA receptor inhibitor, the remaining three agents are cholinesterase inhibitors. The inhibitory mechanisms of the four agents exhibit some differ- ences. Although they may offer tips for proper use, the SD guidelines have so far stated that there are no significant differences among SD. The guidelines also state that no SD can stop the progression of AD and that their use for MCI should not be encouraged. There are some criticisms about the use of SD because they are not root treatments. In contrast, there are some reports that SD delay AD progression, preserve ADL, reduce the care burden and have an effect on BPSD. Therefore, in proper combination with non-drug treat- ments, the use of SD is considered to be valuable.", "source": "https://pubmed.ncbi.nlm.nih.gov/30620505/"}
{"doc_id": "f48415452d7b0e6ce4967eaeb91f01cf", "sentence": "Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen .", "spans": [{"span_id": 0, "text": "Raloxifene", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "tamoxifen", "start": 87, "end": 96, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "The pharmacokinetics of raloxifene and its interaction with apigenin in rat.  Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen . As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin. ### methods The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the pharmacokinetic profiles of raloxifene administered alone and in combination with apigenin were compared. ### results Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the C(max) and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the C(max) and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and C(max) of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug. ### conclusions The results showed that apigenin decreased the first-pass metabolism of raloxifene but did not increase its absorption from the gastrointestinal tract.", "source": "https://pubmed.ncbi.nlm.nih.gov/21088662/"}
{"doc_id": "6da26e74359677fd1d5ba9e66a1a400d", "sentence": "Recipients received the dual endothelin-1 ( ET-1 ) receptor blocker , bosentan ( 100 mg/kg ) , the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril ( 5 mg/kg ) , bosentan plus ramipril ( doses as just noted ) or vehicle .", "spans": [{"span_id": 0, "text": "endothelin-1", "start": 29, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "bosentan", "start": 70, "end": 78, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "ramipril", "start": 149, "end": 157, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "bosentan", "start": 172, "end": 180, "token_start": 31, "token_end": 32}, {"span_id": 4, "text": "ramipril", "start": 186, "end": 194, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [3, 4], "is_context_needed": true}], "paragraph": "Effects of blockade of the renin-angiotensin and endothelin systems on experimental bronchiolitis obliterans. Blockade of the renin-angiotensin and the endothelin (ET) systems ameliorates fibrous airway obliteration in rat tracheal allografts. The aim of this study was to test which of these pharmacologic interventions attenuates the process more effectively, and whether combination therapy confers additional benefit. ### methods Rat tracheas were heterotopically transplanted from Brown-Norway donors into Lewis recipients. Recipients received the dual endothelin-1 ( ET-1 ) receptor blocker , bosentan ( 100 mg/kg ) , the angiotensin-converting enzyme ( ACE ) inhibitor , ramipril ( 5 mg/kg ) , bosentan plus ramipril ( doses as just noted ) or vehicle . Grafts were harvested at Days 7 and 21 for morphometric studies and molecular analysis by real-time polymerase chain reaction (PCR). ### results At Day 21, bosentan and ramipril treatment reduced the percentage of luminal occlusion compared with vehicle to a similar extent. In animals that received the combined treatment, luminal obliteration was further reduced compared with the respective monotherapies. Furthermore, rats treated with bosentan plus ramipril showed a lower percent of epithelial necrosis. The beneficial effects of bosentan and ramipril, alone or in combination, were associated with reduced mRNA levels of transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF)-A in the tracheal allografts. ### conclusions Our data suggest that ET receptor blockade prevents fibrous airway obliteration to a similar extent as ACE inhibition in this model. Interruption of both pathways provides superior graft protection as compared with single-system blockade.", "source": "https://pubmed.ncbi.nlm.nih.gov/17097496/"}
{"doc_id": "735602428e2782a5443ff74b8692b68a", "sentence": "After surgery , she received a sequential chemotherapy , ie , intraabdominal injection of carboplatin ( CBDCA 300 mg/m2 ) and div administration of paclitaxel ( PTX 180 mg/m2 ) as a standard regimen for advanced ovarian cancer .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 90, "end": 101, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "paclitaxel", "start": 148, "end": 158, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[Weekly paclitaxel administration and intraabdominal CBDCA injection possibly beneficial treatment for recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation--a case report]. A 46-year-old woman who had received mastectomy for breast cancer 6 years earlier complained of abdominal distension. Computed tomography and ultrasonography revealed massive ascites and ovarian swelling of both sides. She was diagnosed as having primary ovarian cancer and peritoneal dissemination, and underwent a total hysterectomy as well as ovarectomy on both sides. After surgery , she received a sequential chemotherapy , ie , intraabdominal injection of carboplatin ( CBDCA 300 mg/m2 ) and div administration of paclitaxel ( PTX 180 mg/m2 ) as a standard regimen for advanced ovarian cancer . However, detailed histological examinations showed that the ovarian cancer had metastasized from her breast cancer. It is well-known that breast cancer easily metastasizes to the bone, liver, pleura and lymph node, but rarely to the ovarium or peritoneum when chemotherapy is conducted. Therefore, no standard therapy has been established for breast cancer metastasizing to the ovarium. Our patient received 4 cycles of weekly administration of PTX (PTX 80 mg/m2, 3 consecutive weeks, 1-week break), followed by oral administration of doxifluridine+anastrozole on an outpatient basis. No evidence of recurrence of breast cancer has been noted 1 year after surgery. This result suggests that weekly administration of PTX and intraabdominal injection of CBDCA might be beneficial in the treatment of recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation.", "source": "https://pubmed.ncbi.nlm.nih.gov/15791819/"}
{"doc_id": "124c8b6c6bf2b30f2f78adefcf61a980", "sentence": "They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine .", "spans": [{"span_id": 0, "text": "ranolazine", "start": 101, "end": 111, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "ivabradine", "start": 116, "end": 126, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Pharmacodynamic effects in the cardiovascular system: the modeller's view. Cardiovascular disease, and the cardiovascular side effects of drugs, are essentially multifactorial problems involving interactions between many proteins, dependent on highly organized cell, tissue and organ structures. This is one reason why the side effects of drugs are often unanticipated. It is impossible to unravel such problems without using a systems approach, i.e. focussing on processes, not just molecular components. This inevitably involves modelling as the interactions require quantitative analysis. Modelling is a tool of analysis aimed at understanding, first, and predicting, eventually. We illustrate these principles using modelling of the heart. Models of the cardiac myocyte have benefited from several decades of interaction between experimentation and simulation. They are now sufficiently detailed to have been of use in the development of new drug compounds like ranolazine and ivabradine . With the help of cardiac modelling, we have also been able to unravel the mechanisms underlying the beneficial effect of sodium calcium exchange block for long QT syndrome (LQTS) 2 and LQTS3 patients. Detailed models of the interaction between ion channels and blocking agents provide the basis for modelling drug action from basic principles and predict changes in the inhomogeneous tissue of the heart. We demonstrate that mathematical models are beneficial for unravelling the complex interactions of pharmacodynamics in the heart. Embedding these detailed biophysical cellular scale models into anatomically correct models of the ventricle geometry will enable reconstructions of Torsades de Pointes arrhythmias and of fibrillation, providing a mechanism for linking detailed cellular scale experimental data to clinical applications.", "source": "https://pubmed.ncbi.nlm.nih.gov/20470255/"}
{"doc_id": "575a700b1cd7fe934b3fc3817ad38ce4", "sentence": "Based on clinical knowledge , we re-prioritized 30 potentially repurposable drugs against COVID-19 ( including pseudoephedrine , andrographolide , chloroquine , abacavir , and thalidomide ) .", "spans": [{"span_id": 0, "text": "pseudoephedrine", "start": 111, "end": 126, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "andrographolide", "start": 129, "end": 144, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "chloroquine", "start": 147, "end": 158, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "abacavir", "start": 161, "end": 169, "token_start": 21, "token_end": 22}, {"span_id": 4, "text": "thalidomide", "start": 176, "end": 187, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Network bioinformatics analysis provides insight into drug repurposing for COVID-19. The COVID-19 disease caused by the SARS-CoV-2 virus is a health crisis worldwide. While developing novel drugs and vaccines is long, repurposing existing drugs against COVID-19 can yield treatments with known preclinical, pharmacokinetic, pharmacodynamic, and toxicity profiles, which can rapidly enter clinical trials. In this study, we present a novel network-based drug repurposing platform to identify candidates for the treatment of COVID-19. At the time of the initial outbreak, knowledge about SARS-CoV-2 was lacking, but based on its similarity with other viruses, we sought to identify repurposing candidates to be tested rapidly at the clinical or preclinical levels. We first analyzed the genome sequence of SARS-CoV-2 and confirmed SARS as the closest virus by genome similarity, followed by MERS and other human coronaviruses. Using text mining and database searches, we obtained 34 COVID-19-related genes to seed the construction of a molecular network where our module detection and drug prioritization algorithms identified 24 disease-related human pathways, five modules, and 78 drugs to repurpose. Based on clinical knowledge , we re-prioritized 30 potentially repurposable drugs against COVID-19 ( including pseudoephedrine , andrographolide , chloroquine , abacavir , and thalidomide ) . Our work shows how in silico repurposing analyses can yield testable candidates to accelerate the response to novel disease outbreaks.", "source": "https://pubmed.ncbi.nlm.nih.gov/33817623/"}
{"doc_id": "93a123749afedefac98a5460298616f9", "sentence": "To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein ( PBP ) 3-specific beta-lactam antibiotic cefuroxime , the aminoglycoside tobramycin , and a combination of the two , and to test the relationship between bacterial killing rate and endotoxin release .", "spans": [{"span_id": 0, "text": "cefuroxime", "start": 171, "end": 181, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "tobramycin", "start": 203, "end": 213, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release.  To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein ( PBP ) 3-specific beta-lactam antibiotic cefuroxime , the aminoglycoside tobramycin , and a combination of the two , and to test the relationship between bacterial killing rate and endotoxin release . ### methods A clinical isolate of Escherichia coli in logarithmic phase was exposed to 0.1, 2, 10, and 50 x minimum inhibitory concentration (MIC) of cefuroxime, tobramycin, and a combination of the two. Samples for viable counts and endotoxin analysis were drawn immediately before and after the addition of the antibiotics and at 1, 2, 4, 6, and 24 h. All experiments were performed in triplicate. For the analysis of endotoxin, a chromogenic limulus amoebocyte lysate assay was used. ### results Endotoxin liberation was found to be proportional to the number of killed bacteria for each antibiotic regimen at each concentration level justifying the endotoxin-liberating potential to be expressed as release of endotoxin per killed bacterium, an expression that was independent of the inoculum size. At all concentration levels there was a statistically significant difference between the treatments, with the highest release of endotoxin per killed bacterium for cefuroxime, lower for tobramycin and the lowest for the combination of the two drugs (P < 0.001). With increasing doses, there was a significant reduction (P < 0.001) in the propensity to release endotoxin. When the bacterial killing rate was correlated to the propensity to release endotoxin in bacteria exposed to tobramycin or the combination of tobramycin and cefuroxime, a significant negative correlation was found (P < 0.01). This reduction in endotoxin release was not caused by an unspecific endotoxin binding of tobramycin. ### conclusions Addition of tobramycin reduced the cefuroxime-induced endotoxin release per killed bacterium to a level which was even lower than that of tobramycin alone in spite of an increased killing rate. Increasing concentrations of tobramycin led to reduction in endotoxin release, which may be of benefit when dosing aminoglycosides once daily.", "source": "https://pubmed.ncbi.nlm.nih.gov/11168076/"}
{"doc_id": "2a359cf25849d20eccded92308b894fd", "sentence": "As CDK7 inhibitors are currently under clinical evaluation in patients , our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients .", "spans": [{"span_id": 0, "text": "ponatinib", "start": 114, "end": 123, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "lapatinib", "start": 127, "end": 136, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "CDK7 inhibitor", "start": 140, "end": 154, "token_start": 23, "token_end": 25}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Combination therapy with the CDK7 inhibitor and the tyrosine kinase inhibitor exerts synergistic anticancer effects against MYCN-amplified neuroblastoma. Patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression have very poor prognosis. The cyclin-dependent kinase 7 (CDK7)/super-enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase phosphatase 1 nuclear targeting subunit (PNUTS) has recently been shown to interact with c-Myc protein and suppresses c-Myc protein degradation. Here we screened the U.S. Food and Drug Administration-Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN-amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, while having little effects in normal nonmalignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. Reverse transcription polymerase chain reaction and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N-Myc protein but not N-Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N-Myc protein but not mRNA expression and decreased MYCN-amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients , our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients .", "source": "https://pubmed.ncbi.nlm.nih.gov/32086952/"}
{"doc_id": "964062c679d44f0b3a91577d0b30722d", "sentence": "An effective treatment for operable breast cancer , NCT with epirubicin plus paclitaxel results in significant downstaging or eliminating of primary tumors in breast cancer , thus expanding the indication of breast conservation therapy .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 61, "end": 71, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "paclitaxel", "start": 77, "end": 87, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[Feasibility of breast conservation surgery after neoadjuvant chemotherapy for breast cancer]. To investigate the efficacy of neoadjuvant chemotherapy (NCT) and the feasibility of conservative breast surgery after reducing the size of a primary tumor by NCT in patients with operable breast cancer. ### methods Thirty patients with stage IIB and IIIA breast cancer underwent NCT including epirubicin 60 mg/m(2) by intravenous injection on day 1 and paclitaxel 150 mg/m(2) by 3-hour continuous infusion on day 2 with 21 days as a cycle from July 2001 to April 2003. All patients received 3 - 4 cycles of NCT. Breast conservation treatment or modified mastectomy was performed after the tumor was reduced to less than 3 cm in diameter. The nonresponders received modified mastectomy. ### results The overall response rate (ORR) was 93% (28/30) for the primary tumors of breast, Fifteen patients (50%) obtained clinical complete response (cCR), including 7 cases (23%) with pathologic complete response (pCR). Thirteen cases (43%) achieved clinical partial response (cPR), and 2 (7%) no change (NC). No case showed progression of disease. Twenty-six (87%) cases were downstaged according to the TNM system classification. The median initial tumor size was 4 cm (3 - 10 cm) before NCT and was reduced to 0.8 cm (0 - 6 cm) after NCT. All 30 patients received operation. Eighteen (60%) of them were candidates for breast conserving therapy, and actually only 11 (37%) selected such surgery. ### conclusion An effective treatment for operable breast cancer , NCT with epirubicin plus paclitaxel results in significant downstaging or eliminating of primary tumors in breast cancer , thus expanding the indication of breast conservation therapy .", "source": "https://pubmed.ncbi.nlm.nih.gov/15949385/"}
{"doc_id": "8df184ac811fb4494fa807e24e4a4add", "sentence": "Carboplatin and etoposide for recurrent malignant glioma following surgical and radiotherapy failure : A clinical study conducted at the Northern Israel Oncology Center .", "spans": [{"span_id": 0, "text": "Carboplatin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "etoposide", "start": 16, "end": 25, "token_start": 2, "token_end": 3}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Carboplatin and etoposide for recurrent malignant glioma following surgical and radiotherapy failure : A clinical study conducted at the Northern Israel Oncology Center . We conducted a phase II study using carboplatin and etoposide on patients with recurrent malignant glioma to investigate tumor response. ### methods From January 1995 to March 1997, 21 patients with recurrent malignant glioma were treated with a carboplatin (300 mg/m(2), day 1)/etoposide (100 mg/m(2), days 1-3) regimen every 3-4 weeks. The following radiologic parameters were evaluated: tumor size, central lucency, degree of contrast enhancement, and mass effect. No patient had received chemotherapy previously. Dose escalation corresponded to hematologic tolerance and to general and neurologic performance status. Most patients were treated postoperatively with involved field radiotherapy followed by a boost to the tumor area, as defined on the presurgery computed tomography scan or on magnetic resonance imaging. Mean interval to introduction of chemotherapy was 8.8 months (range, 7-36 months). Patients received a mean of four cycles [range, 2-8 cycles]. ### results Only 2 patients showed moderate radiological response, while 12 patients died of progressive disease. Mean time to progression following discontinuation of chemotherapy was 5.8 months (range, 1-11 months). The other patients survived with persistent disease and are being treated palliatively. Toxicity was manageable (1, neutropenic sepsis; 1, thrombocytopenia (45,000/mm(3)); 2, temporarily elevated transaminase level; 2, steroid-induced erosive gastritis). ### conclusions This phase II regimen proved to be ineffective in recurrent malignant glioma. Further studies incorporating innovative drug regimens and schedules are warranted. J. Surg. Oncol., 1999;71:167-170.", "source": "https://pubmed.ncbi.nlm.nih.gov/10404133/"}
{"doc_id": "fe6d0e16126ed7cba1f7493904ed6f98", "sentence": "ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib , resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27 M mutant DIPG .", "spans": [{"span_id": 0, "text": "dexamethasone", "start": 32, "end": 45, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "dasatinib", "start": 75, "end": 84, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma. An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). ### objective To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. ### methods The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. ### results Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P\u00a0=\u00a0.0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P\u00a0<\u00a0.001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P\u00a0<\u00a0.001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P\u00a0=\u00a0.0305). ### conclusion ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib , resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27 M mutant DIPG .", "source": "https://pubmed.ncbi.nlm.nih.gov/31225627/"}
{"doc_id": "0988f1d7dca388570b1b818609c4a80e", "sentence": "Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain .", "spans": [{"span_id": 0, "text": "prednisone", "start": 19, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "mitoxantrone", "start": 47, "end": 59, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. A combination of mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL). ### Patients And Methods Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain . HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module-Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients. ### results At 6 weeks, both groups showed improvement in several HQL domains, and only physical functioning and pain were better in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life (P =.009), four functioning domains, and nine symptoms (.001 < P <. 01), and the improvement (> 10 units on a scale of 0 to100) lasted longer than in the prednisone-alone group (.004 < P <.05). The addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life (.001 < P <.003). ### conclusion Treatment with mitoxantrone plus prednisone was associated with greater and longer-lasting improvement in several HQL domains and symptoms than treatment with prednisone alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/10561201/"}
{"doc_id": "bb5a3874cf046983e6858e0f91d42add", "sentence": "Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase .", "spans": [{"span_id": 0, "text": "imatinib", "start": 49, "end": 57, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cytarabine", "start": 71, "end": 81, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase . In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response.", "source": "https://pubmed.ncbi.nlm.nih.gov/12933584/"}
{"doc_id": "71d32890c951bfd74b4107d9656c7f86", "sentence": "Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine : a multicenter , phase II trial of the Swiss Group for Clinical Cancer Research .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 84, "end": 95, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "capecitabine", "start": 101, "end": 113, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine : a multicenter , phase II trial of the Swiss Group for Clinical Cancer Research . To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. ### Patients And Methods Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. ### results Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. ### conclusion Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/18669455/"}
{"doc_id": "cbf4da62141a838ba38d27cc916b1711", "sentence": "as neoadjuvant chemotherapy , and two cycles of doxorubicin/cisplatin and ifosfamide , and two cycles of high-dose methotrexate ( 10 - 12 g/m(2 ) ) were given post-operatively .", "spans": [{"span_id": 0, "text": "doxorubicin/cisplatin", "start": 48, "end": 69, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "ifosfamide", "start": 74, "end": 84, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "methotrexate", "start": 115, "end": 127, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan. From 1997 to 2003, 40 patients (all <40 years of age) with non-metastatic osteosarcoma of the extremities were treated with OOS-D and definitive surgery. Two cycles of doxorubicin 90 mg/m(2) plus cisplatin 120 mg/m(2) and ifosfamide 15 g/m(2) were given as neoadjuvant chemotherapy , and two cycles of doxorubicin/cisplatin and ifosfamide , and two cycles of high-dose methotrexate ( 10 - 12 g/m(2 ) ) were given post-operatively . All patients underwent limb salvage surgeries, and 66% showed good response to neoadjuvant chemotherapy.  With a median follow-up period of 117 months, 31 of the evaluable 40 patients were continuously disease-free, 7 were currently alive with no evidence of disease, and 2 died of disease. There was no local recurrence. The 5-year event-free and overall survival rates were 83 and 98%, respectively.  The 10-year event-free and overall survival rates were 80 and 95%, respectively. The major form of toxicity was haematological one.", "source": "https://pubmed.ncbi.nlm.nih.gov/23433444/"}
{"doc_id": "0ab60b7bf70ff6b6e80353dbdd5002f9", "sentence": "Reported is a case of a 58-year-old female treated in the past with cytostatics and rituximab for follicular lymphoma , in whom HBV infection was detected during a follow-up of the contacts of her partner diagnosed with acute viral hepatitis B. At the beginning , the patient had a very high serum level of HBV DNA ( 4.3 \u00d7 108 IU/mL ) and therefore she was treated with combined antiviral therapy ( lamivudine and tenofovir ) .", "spans": [{"span_id": 0, "text": "rituximab", "start": 84, "end": 93, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "lamivudine", "start": 399, "end": 409, "token_start": 72, "token_end": 73}, {"span_id": 2, "text": "tenofovir", "start": 414, "end": 423, "token_start": 74, "token_end": 75}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "[Viral hepatitis B in a patient with follicular lymphoma treated with biological therapy]. Reactivation, recurrence or acute infection with hepatitis B virus (HBV) represent severe complications of biological therapy. Reported is a case of a 58-year-old female treated in the past with cytostatics and rituximab for follicular lymphoma , in whom HBV infection was detected during a follow-up of the contacts of her partner diagnosed with acute viral hepatitis B. At the beginning , the patient had a very high serum level of HBV DNA ( 4.3 \u00d7 108 IU/mL ) and therefore she was treated with combined antiviral therapy ( lamivudine and tenofovir ) . After 10 months, the serum level of HBV DNA decreased significantly (3,100 IU/mL) and the combined antiviral therapy was switched to monotherapy with tenofovir. Another 5 months later, the serum level of HBV DNA was only 950 IU/mL. This case demonstrates important clinical problems connected with HBV infection in immunocompromised persons.", "source": "https://pubmed.ncbi.nlm.nih.gov/21452121/"}
{"doc_id": "ff12dfaf336d750698f604fab7741017", "sentence": "Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil- , oxaliplatin- and irinotecan-based chemotherapies were randomised ( 1:1 ) to either panitumumab plus irinotecan ( panitumumab arm ) or cetuximab plus irinotecan ( cetuximab arm ) .", "spans": [{"span_id": 0, "text": "fluorouracil-", "start": 65, "end": 78, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "oxaliplatin-", "start": 81, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "irinotecan-based", "start": 98, "end": 114, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "panitumumab", "start": 164, "end": 175, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "irinotecan", "start": 181, "end": 191, "token_start": 25, "token_end": 26}, {"span_id": 5, "text": "panitumumab", "start": 194, "end": 205, "token_start": 27, "token_end": 28}, {"span_id": 6, "text": "cetuximab", "start": 215, "end": 224, "token_start": 31, "token_end": 32}, {"span_id": 7, "text": "irinotecan", "start": 230, "end": 240, "token_start": 33, "token_end": 34}, {"span_id": 8, "text": "cetuximab", "start": 243, "end": 252, "token_start": 35, "token_end": 36}], "rels": [{"class": "COMB", "spans": [3, 4], "is_context_needed": true}, {"class": "POS", "spans": [6, 7], "is_context_needed": true}], "paragraph": "Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan\u00a0and oxaliplatin (WJOG 6510G). cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. ### Patients And Methods Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil- , oxaliplatin- and irinotecan-based chemotherapies were randomised ( 1:1 ) to either panitumumab plus irinotecan ( panitumumab arm ) or cetuximab plus irinotecan ( cetuximab arm ) . The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate\u00a0and safety. ### results From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR\u00a0=\u00a00.64, 95% confidence interval [CI]\u00a0=\u00a00.44-0.94, P\u00a0<\u00a00.001 for non-inferiority, P\u00a0=\u00a00.058 for superiority), and median OS was 14.85 and 11.53 months (HR\u00a0=\u00a00.66, 95% CI\u00a0=\u00a00.44-1.00, P\u00a0=\u00a00.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). ### conclusion panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.", "source": "https://pubmed.ncbi.nlm.nih.gov/32526634/"}
{"doc_id": "bab3251cbe1fd79f43555c7668ec347a", "sentence": "Epirubicin , oxaliplatin , and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer ( REAL3 ):", "spans": [{"span_id": 0, "text": "Epirubicin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "oxaliplatin", "start": 13, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "capecitabine", "start": 31, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 3, "text": "panitumumab", "start": 60, "end": 71, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "NEG", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Epirubicin , oxaliplatin , and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer ( REAL3 ): EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. ### methods In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. ### findings Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade \u2265 3 neutropenia 35 [13%] vs 74 [28%]). ### interpretation Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. ### funding Amgen, UK National Institute for Health Research Biomedical Research Centre.", "source": "https://pubmed.ncbi.nlm.nih.gov/23594787/"}
{"doc_id": "72830b924efe02f8d02dbfad93ee887d", "sentence": "In 2005 , after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen , a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone ; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting ( IPCW ) are used to account for selective crossover to letrozole of patients ( n=619 ) in the tamoxifen arm .", "spans": [{"span_id": 0, "text": "letrozole", "start": 77, "end": 86, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "tamoxifen", "start": 104, "end": 113, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "letrozole", "start": 166, "end": 175, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "tamoxifen", "start": 213, "end": 222, "token_start": 32, "token_end": 33}, {"span_id": 4, "text": "letrozole", "start": 373, "end": 382, "token_start": 57, "token_end": 58}, {"span_id": 5, "text": "tamoxifen", "start": 412, "end": 421, "token_start": 65, "token_end": 66}], "rels": [{"class": "NEG", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8\u00b71 years median follow-up. Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8\u00b71 years median follow-up. ### methods BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005 , after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen , a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone ; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting ( IPCW ) are used to account for selective crossover to letrozole of patients ( n=619 ) in the tamoxifen arm . Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. ### findings 8010 patients were included in the trial, with a median follow-up of 8\u00b71 years (range 0-12\u00b74). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8\u00b77 years from randomisation (range 0-12\u00b74), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0\u00b782 [95% CI 0\u00b774-0\u00b792], overall survival HR 0\u00b779 [0\u00b769-0\u00b790], DRFI HR 0\u00b779 [0\u00b768-0\u00b792], BCFI HR 0\u00b780 [0\u00b770-0\u00b792]; intention-to-treat disease-free survival HR 0\u00b786 [0\u00b778-0\u00b796], overall survival HR 0\u00b787 [0\u00b777-0\u00b7999], DRFI HR 0\u00b786 [0\u00b774-0\u00b7998], BCFI HR 0\u00b786 [0\u00b776-0\u00b798]). At a median follow-up of 8\u00b70 years from randomisation (range 0-11\u00b72) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE \u22641\u00b71%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78\u00b76%, 77\u00b78%, 77\u00b73% for disease-free survival; 87\u00b75%, 87\u00b77%, 85\u00b79% for overall survival; 89\u00b79%, 88\u00b77%, 88\u00b71% for DRFI; and 86\u00b71%, 85\u00b73%, 84\u00b73% for BCFI. ### interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. ### funding Novartis, United States National Cancer Institute, International Breast Cancer Study Group.", "source": "https://pubmed.ncbi.nlm.nih.gov/22018631/"}
{"doc_id": "01b9ba979fcff6b6cdf24f4999f38ca1", "sentence": "CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab ( FIRE-3 trial ) .", "spans": [{"span_id": 0, "text": "FOLFIRI", "start": 176, "end": 183, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "cetuximab", "start": 189, "end": 198, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "bevacizumab", "start": 202, "end": 213, "token_start": 29, "token_end": 30}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab ( FIRE-3 trial ) . To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. ### Patients And Methods CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. ### results Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. ### conclusion In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. ### Clinical Trials Number NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.", "source": "https://pubmed.ncbi.nlm.nih.gov/27234640/"}
{"doc_id": "5c84675aee263d1138ecdc8f62224159", "sentence": "The Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) phase 3 trial was conducted in hospitals in nine countries .", "spans": [{"span_id": 0, "text": "Tamoxifen", "start": 4, "end": 13, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "Exemestane", "start": 14, "end": 24, "token_start": 2, "token_end": 3}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). ### methods The Tamoxifen Exemestane Adjuvant Multinational ( TEAM ) phase 3 trial was conducted in hospitals in nine countries . Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. ### findings 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0\u00b797, 95% CI 0\u00b788-1\u00b708; p=0\u00b760). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. ### interpretation Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. ### funding Pfizer.", "source": "https://pubmed.ncbi.nlm.nih.gov/21247627/"}
{"doc_id": "b3f4393572a850ae5b107fac5a2985ad", "sentence": "Patients used 2.16 ( range 0.0 - 6.3 ) formoterol and 2.34 ( range 0.1 - 7.5 ) terbutaline relief inhalations x day(-1 ) .", "spans": [{"span_id": 0, "text": "formoterol", "start": 39, "end": 49, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "terbutaline", "start": 79, "end": 90, "token_start": 18, "token_end": 19}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma. The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 ( range 0.0 - 6.3 ) formoterol and 2.34 ( range 0.1 - 7.5 ) terbutaline relief inhalations x day(-1 ) . No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.", "source": "https://pubmed.ncbi.nlm.nih.gov/12412676/"}
{"doc_id": "1495e39f848fa37e5076bf8266d3afb4", "sentence": "Preoperative chemotherapy with FLOT ( 5-FU , leucovorin , oxaliplatin and docetaxel ) without radiation therapy is the standard treatment in the West .", "spans": [{"span_id": 0, "text": "5-FU", "start": 38, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "leucovorin", "start": 45, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "oxaliplatin", "start": 58, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "docetaxel", "start": 74, "end": 83, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Advances in the treatment of gastric cancer: 2019. The aim of this study was to review studies published within the past year regarding management of gastric cancer. ### Recent Findings Laparoscopic gastrectomy achieves equivalent survival compared with open gastrectomy in early stage and locally advanced gastric cancer. Adjuvant chemotherapy with 6 months of S-1 and oxaliplatin was superior to 12 months of S-1, and the addition of postoperative radiation therapy did not improve survival. The FLOT regimen is the new standard for preoperative chemotherapy. In metastatic gastric cancer, the addition of docetaxel to S-1 and cisplatin failed to improve overall survival over two-drug chemotherapy. The addition of the immune checkpoint inhibitor pembrolizumab to chemotherapy failed to improve overall survival compared with chemotherapy alone. ### summary Laparoscopic gastrectomy is acceptable in early and locally advanced gastric cancer. Combination adjuvant chemotherapy is superior to S-1 monotherapy. Adjuvant radiation therapy after D2 gastrectomy for node-positive gastric cancer does not improve survival. Preoperative chemotherapy with FLOT ( 5-FU , leucovorin , oxaliplatin and docetaxel ) without radiation therapy is the standard treatment in the West . Two-drug chemotherapy is the optimal initial treatment in metastatic disease. Adding pembrolizumab to front-line chemotherapy did not improve survival, with use of immune checkpoint inhibitors reserved to treat chemotherapy refractory metastatic disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/31436556/"}
{"doc_id": "75d2cb0cce16c32ec61e9f1bbffe1781", "sentence": "The third-generation aromatase inhibitors ( AIs ) , including anastrozole , exemestane and letrozole , have demonstrated improved efficacy versus tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 62, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "exemestane", "start": 76, "end": 86, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "letrozole", "start": 91, "end": 100, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "tamoxifen", "start": 146, "end": 155, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Switching from tamoxifen to aromatase inhibitors for adjuvant endocrine therapy in postmenopausal patients with early breast cancer.  The third-generation aromatase inhibitors ( AIs ) , including anastrozole , exemestane and letrozole , have demonstrated improved efficacy versus tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer . AIs can be used in several adjuvant endocrine settings: as upfront therapy, switch to an AI after 2-3years of tamoxifen or extended therapy following 5years of tamoxifen. In the switch setting, two different types of study designs have been utilized. One is a late randomization design which randomizes patients who are disease-free after 2-3years of tamoxifen to receive an AI versus continuation of tamoxifen. In contrast, an early randomization design randomizes all patients immediately after primary treatment and prior to starting tamoxifen. Efficacy benefits with AIs have been shown in several trials evaluating the late randomization strategy, including the Intergroup exemestane Study, the Italian tamoxifen anastrozole trial and the anastrozole-Nolvadex 95 trial. Similarly, early randomization studies, including the Austrian Breast and Colorectal Cancer Study Group-8 and the Breast International Group (BIG) 1-98 trial, have demonstrated the effectiveness of receiving an AI after tamoxifen. Two trials are assessing an early switch strategy versus upfront AI therapy: the BIG 1-98 trial and the ongoing tamoxifen exemestane Adjuvant Multicentre trial are assessing switching from tamoxifen to an AI after 2-3years versus upfront AI therapy. This paper reviews studies that have investigated a switch strategy with AIs and considers the implications of these data on treatment choice for postmenopausal patients with hormone receptor-positive breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/19944537/"}
{"doc_id": "07c1063282576d4753c0c0db96239065", "sentence": "Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway .", "spans": [{"span_id": 0, "text": "Digoxin", "start": 0, "end": 7, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gemcitabine", "start": 68, "end": 79, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Digoxin sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine via inhibiting Nrf2 signaling pathway . Chemoresistance is a major therapeutic obstacle in the treatment of human pancreatic ductal adenocarcinoma (PDAC). As an oxidative stress responsive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of cytoprotective genes. Nrf2 not only plays a critical role in chemoprevention, but also contributes to chemoresistance. In this study, we found that digoxin markedly reversed drug resistance of gemcitabine by inhibiting Nrf2 signaling in SW1990/Gem and Panc-1/Gem cells. Further research revealed that digoxin regulated Nrf2 at transcriptional level. In in vivo study, we found that digoxin and gemcitabine in combination inhibited tumor growth more substantially when compared with gemcitabine treatment alone in SW1990/Gem-shControl cells-derived xenografts. In the meantime, SW1990/Gem-shNrf2 cells-derived xenografts responded to gemcitabine and combination treatment similarly, suggesting that digoxin sensitized gemcitabine-resistant human pancreatic cancer to gemcitabine, which was Nrf2 dependent. These results demonstrated that digoxin might be used as a promising adjuvant sensitizer to reverse chemoresistance of gemcitabine-resistant pancreatic cancer to gemcitabine via inhibiting Nrf2 signaling.", "source": "https://pubmed.ncbi.nlm.nih.gov/30735911/"}
{"doc_id": "049218fea98c023864d6458df5d2c72d", "sentence": "Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 44, "end": 53, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "5-fluorouracil", "start": 72, "end": 86, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "oxaliplatin", "start": 94, "end": 105, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Effective treatment of advanced colorectal cancer by rapamycin and 5-FU/oxaliplatin monitored by TIMP-1. The mTOR-inhibitor rapamycin has shown antitumor activity in various tumors. Bedside observations have suggested that rapamycin may be effective as a treatment for colorectal carcinomatosis. ### methods We established an orthotopic syngenic model by transplanting CT26 peritoneal tumors in Balb/C mice and an orthotopic xenograft model by transplanting SW620 peritoneal tumors in nu/nu mice. Expression levels of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by enzyme-linked immunosorbent assay. ### results rapamycin significantly suppressed growth of syngenic and xenografted peritoneal tumors. The effect was similar with intraperitoneal or oral rapamycin administration. Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin . The combination treatment showed no acute toxicity. TIMP-1 serum levels correlated well (CC = 0.75; P < 0.01) with rapamycin treatment. ### conclusions rapamycin suppressed advanced stage colorectal cancer, even with oral administration. Combining rapamycin with current chemotherapy regimens significantly increased antitumor efficacy without apparent toxicity. The treatment efficacy correlated with serum TIMP-1 levels, suggesting its potential as a surrogate marker in future clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/19565301/"}
{"doc_id": "4b95bba024fb2e67f272f90f02ed77c0", "sentence": "These structural motifs represent typical azoles , such as econazole , fluconazole , and metyrapone .", "spans": [{"span_id": 0, "text": "econazole", "start": 59, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "fluconazole", "start": 71, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "metyrapone", "start": 89, "end": 99, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "How do azoles inhibit cytochrome P450 enzymes? A density functional study. To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles , such as econazole , fluconazole , and metyrapone . The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH(2) distance of approximately 3.0 A, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.", "source": "https://pubmed.ncbi.nlm.nih.gov/18563875/"}
{"doc_id": "69b943fb5c20147ee6ba43647c87c513", "sentence": "The present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs , including atezolizumab , durvalumab , pembrolizumab , and nivolumab as first-line treatment in patients with ES-SCLC .", "spans": [{"span_id": 0, "text": "atezolizumab", "start": 156, "end": 168, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "durvalumab", "start": 171, "end": 181, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "pembrolizumab", "start": 184, "end": 197, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "nivolumab", "start": 204, "end": 213, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Comparison of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer: A systematic review and network meta-analysis. In recent years, immune checkpoint inhibitors (ICIs) including atezolizumab, durvalumab, pembrolizumab, and nivolumab have reported their efficacy and safety profile in patients with extensive-stage small cell lung cancer (ES-SCLC). However, given the diverse efficacy and inconsistent safety among the ICIs, with the absence of head-to-head researches designed to evaluate the efficacy among them, it might bring with confusion on selection in clinical practice. ### objectives The present systematic review and network meta-analysis was performed to conduct indirect comparisons on efficacy and safety profile among ICIs , including atezolizumab , durvalumab , pembrolizumab , and nivolumab as first-line treatment in patients with ES-SCLC . ### design Several databases were retrieved with established criteria until June 20, 2020, with the main MeSH Terms and their similarities. Hazard ratios of overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) of disease control rate (DCR), objective response rate (ORR), and adverse events (AEs) were compared indirectly with network meta-analysis. ### Data Sources Medline, Cochrane library, and Embase. ### Eligibility Criteria Prospective, randomized, controlled clinical studies, which reported PFS, OS, and AEs. ### Data Extraction And Synthesis Clinical characteristics were extracted by the 2 authors independently. Comparisons of HRs were calculated for PFS and OS by random effect model. ORR, DCR, and AEs were presented with ORs. Based on surface under the cumulative ranking curve, and forest plots, efficacy and safety of the treatments were ranked, with predicted histogram described. ### results In total, there were 4 studies including 1547 patients who met the eligibility criteria and enrolled. For indirect comparisons, no significant difference on PFS was observed between atezolizumab and durvalumab (HR 0.96, 95% CI, 0.72-1.29), or between atezolizumab and pembrolizumab (HR 1.05, 95% CI, 0.78-1.43), or between atezolizumab and nivolumab (HR 1.18, 95% CI, 0.79-1.79), or between durvalumab and pembrolizumab (HR 1.10, 95% CI, 0.84-1.43). or between durvalumab and nivolumab (HR 1.23, 95% CI, 0.83-1.82), or between pembrolizumab and nivolumab (HR 1.12, 95% CI, 0.76-1.66), nor significant difference on OS observed between atezolizumab and durvalumab (HR 0.93, 95% CI, 0.67-1.30), or between atezolizumab and pembrolizumab (HR 0.88, 95% CI, 0.62-1.24), or between atezolizumab and nivolumab (HR 1.04, 95% CI, 0.66-1.66), or between durvalumab and pembrolizumab (HR 0.94, 95% CI, 0.70-1.25), or between durvalumab and nivolumab (HR 1.12, 95% CI, 0.73-1.71), or between pembrolizumab and nivolumab (HR 1.19, 95% CI, 0.77-1.84). However, durvalumab was shown statistical superiority on ORR when compared with atezolizumab (HR 0.79, 95% CI, 0.64-0.98), also with significantly higher risk on immune-related AEs when compared with atezolizumab (OR 0.22, 95% CI, 0.10-0.50), and pembrolizumab (OR 3.12, 95% CI, 1.27-7.64). ### conclusions Results of the study revealed that there was no statistical difference on PFS or OS among agents of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with ES-SCLC. However, durvalumab was shown superiority on ORR when compared with atezolizumab, also with significantly higher risk on immune-related AEs.", "source": "https://pubmed.ncbi.nlm.nih.gov/33847617/"}
{"doc_id": "2ca7b36a7e1a152d5919cdef8a7ccb46", "sentence": "Metformin inhibits obesity but has no effect in reducing myocardial hypertrophy caused by Rosiglitazone .", "spans": [{"span_id": 0, "text": "Metformin", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "Rosiglitazone", "start": 90, "end": 103, "token_start": 13, "token_end": 14}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effects of metformin on rosiglitazone-induced cardiac hypertrophy in mice. Thiazolidinediones (TZD) can cause adipose tissue accumulation and myocardial hypertrophy. This study aimed to determine if combined metformin (Glucophage) and rosiglitazone (Avandia) could reduce the risk of heart failure caused by rosiglitazone in BALB/c mice. BALB/c mice were treated with oral rosiglitazone/metformin twice daily for four weeks. metformin or rosiglitazone alone and non-treated mice acted as double control. Myocardial hypertrophy and associated side effects of the combined therapy were determined through isolated heart and body weights. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were applied to evaluate expression of sulfonylurea receptor 2A (SUR2A) and Kir 6.2. The activities of peroxisome proliferator activated receptor alpha (PPARalpha) in the myocardium were also observed. rosiglitazone/metformin decreased body weight gain and food intake, and inhibited an increasing adipose ratio but did not reduce myocardial hypertrophy. rosiglitazone increased Kir6.2/SUR2A, Kir6.2/SUR2B, and PPARalpha gene expression. The rosiglitazone/metformin combination further increased these gene expressions, especially PPARalpha. Metformin inhibits obesity but has no effect in reducing myocardial hypertrophy caused by Rosiglitazone . Whether metformin can reduce side effects of TZDs in humans warrants further study.", "source": "https://pubmed.ncbi.nlm.nih.gov/20823565/"}
{"doc_id": "a80ae76dc1ab83090b8ebbd9238273d1", "sentence": "The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients .", "spans": [{"span_id": 0, "text": "curcumin", "start": 117, "end": 125, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "docetaxel", "start": 147, "end": 156, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root. ### results Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, three dose-limiting toxicities were observed and two out of three patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with five PR and three SD. Some improvements as biological and clinical responses were observed in most patients. ### Patients And Methods Patients with advanced or metastatic breast cancer were eligible. docetaxel (100 mg/m(2)) was administered as a 1 h i.v. infusion every 3 w on d 1 for six cycles. curcumin was orally given from 500 mg/d for seven consecutive d by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients . Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements and assessment of objective and clinical responses to the combination therapy. ### conclusion The recommended dose of curcumin is 6,000 mg/d for seven consecutive d every 3 w in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/19901561/"}
{"doc_id": "5e1b7e15286c15dfdac6bb72c128fdf7", "sentence": "The subjects were then randomly assigned to treatment with either propranolol or metoprolol and repeated the exercise protocol after 1 week of treatment .", "spans": [{"span_id": 0, "text": "propranolol", "start": 66, "end": 77, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "metoprolol", "start": 81, "end": 91, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Dynamic exercise leads to an increase in circulating ICAM-1: further evidence for adrenergic modulation of cell adhesion. Acute mental and physical stress lead to a marked lymphocytosis, with circulating natural killer cell numbers showing the most prominent increase. Many studies have linked these acute stress effects on lymphocytes with an increase in catecholamine levels. However, the molecular mechanisms which mediate this redistribution of lymphocytes from lymphocyte reservoirs into the circulation remain unknown. We hypothesized that this form of lymphocytosis was in part due to shedding of cell adhesion molecules from the cell surface and a subsequent detachment of lymphocytes adhering to the vascular endothelium in lymphocyte reservoirs. In this study, healthy human volunteers (n = 12) were exercised on a treadmill until exhaustion. The circulating levels of the soluble cell adhesion molecules ICAM-1 and E-Selectin were determined by ELISA. The subjects were then randomly assigned to treatment with either propranolol or metoprolol and repeated the exercise protocol after 1 week of treatment . Prior to drug treatment, soluble ICAM-1 levels rose from 258 +/- 19 to 321 +/- 28 ng/ml following exercise and returned to approximate baseline levels of 263 +/- 22 ng/ml after 1 h of rest. This highly significant effect of exercise on circulating ICAM-1 levels (p < .005) was mitigated after treatment with the beta-adrenergic antagonists. Soluble E-Selectin levels were not significantly affected by exercise. These results suggest that dynamic exercise leads to shedding of the cell adhesion molecule ICAM-1 via adrenergic mechanisms. We believe that these findings will contribute to the understanding of how physical and mental stress modulate lymphocyte migration and adhesion.", "source": "https://pubmed.ncbi.nlm.nih.gov/9512820/"}
{"doc_id": "8a1fe940f1378e72f4fdad3f9fe48547", "sentence": "This case highlights the potential efficacy of combining nivolumab and regorafenib in the treatment of SBAs .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 57, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "regorafenib", "start": 71, "end": 82, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Nivolumab plus regorafenib in patients with small bowel adenocarcinoma: A case report. Small bowel adenocarcinomas (SBAs) are rare cancers that have a distinct clinical characteristic and genetic profile. The only potentially curative treatment for localized SBAs is surgery, and treatment options are limited for patients in the advanced stage of disease. ### Patient Concerns A 39-year-old woman presented in October 2015 with a complaint of persistent vomiting for 8\u200amonths. ### diagnosis The patient had obstruction caused by a 3\u200a\u00d7\u200a2\u200acm mass at the ascending part of the duodenum and suspected metastasis in the right adnexal region. Postoperative pathology showed a moderately differentiated adenocarcinoma with serosal invasion. The diagnosis was stage IV duodenum adenocarcinoma with right adnexal metastasis. ### interventions After the failure of multi-line treatment with chemotherapy and targeted therapy, she was treated with the immune checkpoint inhibitor nivolumab plus regorafenib. ### outcomes Disease control lasted for 15\u200amonths with markedly improved symptoms. ### conclusion To the best of our knowledge, this is the first case of small bowel adenocarcinoma that has been treated with nivolumab combined with regorafenib. This case highlights the potential efficacy of combining nivolumab and regorafenib in the treatment of SBAs .", "source": "https://pubmed.ncbi.nlm.nih.gov/33530218/"}
{"doc_id": "54ea32b020e5101565fb894aa10d6e16", "sentence": "Of the substances tested for inhibition of 11beta-HSD-I and -II , chenodeoxycholic acid was the only one that selectively inhibited 11beta-HSD-I ( IC(50 ) for reduction : 2.8x10(-6)mol/l , IC(50 ) for oxidation : 4.4x10(-6)mol/l ) , whereas ketoconazole preferentially inhibited oxidation and reduction reactions catalyzed by 11beta-HSD-II .", "spans": [{"span_id": 0, "text": "chenodeoxycholic", "start": 66, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "ketoconazole", "start": 241, "end": 253, "token_start": 38, "token_end": 39}], "rels": [], "paragraph": "In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I. Selective inhibitors of 11beta-hydroxysteroid-dehydrogenase type I may be of therapeutical interest for two reasons: i) 9alpha-Fluorinated 11-dehydrosteroids like 11-dehydro-dexamethasone (DH-D) are rapidly activated by human kidney 11beta-hydroxysteroid-dehydrogenase type II (11beta-HSD-II) to dexamethasone (D). If the same reaction by hepatic 11beta-HSD-I could be selectively inhibited, DH-D could be used for selective renal immunosuppressive therapy. ii) Reduction of cortisone to cortisol in the liver may increase insulin resistance in type 2 diabetes mellitus, and inhibition of the enzyme may lead to a decrease in gluconeogenesis. Therefore, we characterized the metabolism of DH-D by human hepatic 11beta-HSD-I and tried to find a selective inhibitor of this isoenzyme. ### methods For kinetic analysis of 11beta-HSD-I, we used microsomes prepared from unaffected parts of liver segments, resected because of hepatocarcinoma or metastatic disease. For inhibition experiments, we also tested 11beta-HSD-II activity with human kidney cortex microsomes. The inhibitory potency of several compounds was evaluated for oxidation and reduction in concentrations from 10(-9) to 10(-5)mol/l. ### results Whereas D was not oxidized by human liver microsomes at all, cortisol was oxidized to cortisone with a maximum velocity (V(max)) of 95pmol/mg per min. The reduction of DH-D to D (V(max)=742pmol/mg per min, Michaelis--Menten constant (K(m))=1.6 micromol/l) was faster than that of cortisone to cortisol (V(max)=187pmol/mg per min). All reactions tested in liver microsomes showed the characteristics of 11beta-HSD-I: K(m) values in the micromolar range, preferred cosubstrate NADP(H), no product inhibition. Of the substances tested for inhibition of 11beta-HSD-I and -II , chenodeoxycholic acid was the only one that selectively inhibited 11beta-HSD-I ( IC(50 ) for reduction : 2.8x10(-6)mol/l , IC(50 ) for oxidation : 4.4x10(-6)mol/l ) , whereas ketoconazole preferentially inhibited oxidation and reduction reactions catalyzed by 11beta-HSD-II . metyrapone, which is reduced to metyrapol by hepatic 11beta-HSD-I, inhibited steroid reductase activity of 11beta-HSD-I and -II and oxidative activity of 11beta-HSD-II. These findings can be explained by substrate competition for reductase reactions and by product inhibition of the oxidation, which is a well-known characteristic of 11beta-HSD-II. ### conclusions Our in vitro results may offer a new concept for renal glucocorticoid targeting. Oral administration of small amounts of DH-D (low substrate affinity for 11beta-HSD-I) in combination with chenodeoxycholic acid (selective inhibition of 11beta-HSD-I) may prevent hepatic first pass reduction of DH-D, thus allowing selective activation of DH-D to D by the high affinity 11beta-HSD-II in the kidney. Moreover, selective inhibitors of the hepatic 11beta-HSD-I, like chenodeoxycholic acid, may become useful in the therapy of patients with hepatic insulin resistance including diabetes mellitus type II, because cortisol enhances gluconeogenesis.", "source": "https://pubmed.ncbi.nlm.nih.gov/10664531/"}
{"doc_id": "afd43fc146bb1d69bc9616348b7c3f1e", "sentence": "Anti-tumor effects of etoposide ( VP-16 ) , vincristine and mitomycin C were evaluated with four human neuroblastoma xenograft , according to Battelle Columbus Laboratories protocol .", "spans": [{"span_id": 0, "text": "etoposide", "start": 22, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "vincristine", "start": 44, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "mitomycin", "start": 60, "end": 69, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "[In vivo assessment on the therapeutic effects of etoposide, vincristine and mitomycin C against human neuroblastoma].  Anti-tumor effects of etoposide ( VP-16 ) , vincristine and mitomycin C were evaluated with four human neuroblastoma xenograft , according to Battelle Columbus Laboratories protocol . etoposide is one of the agents which has been reported to be effective against advanced neuroblastoma clinically, if combined with other agents. While vincristine was effective against 1 out 4 neuroblastoma xenografts, TS-N-2, with 58.1% maximum inhibition rate, etoposide was assessed ineffective as a single agent in all of the 3 xenografts used. Since etoposide had no effect on the weight gain in nude mice in this xenograft experiment, the dose of etoposide was increased two-fold against 2 xenografts, but found ineffective also in the increased dose. mitomycin C, which has not been used in childhood malignant tumors, was effective against 2 out of 4 xenografts, TNB-9 and SK-N-AS, with 72.0% and 78.4% maximum inhibition rates, respectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/1905121/"}
{"doc_id": "2f516285ce6b6a692159675b6e1271f4", "sentence": "Biliary bile acids were mainly amidates of cholic acid and chenodeoxycholic acid , with the former predominating .", "spans": [{"span_id": 0, "text": "cholic", "start": 43, "end": 49, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "chenodeoxycholic", "start": 59, "end": 75, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "The effect of alfalfa-corn diets on cholesterol metabolism and gallstones in prairie dogs. Cholesterol gallstones were present in prairie dogs fed alfalfa plus corn with and without exogenous cholesterol (0.4%). The diets fed to the animals for eight weeks contained alfalfa plus corn in fixed proportions of 50:50, 85:15 and 15:85 (w/w). At sacrifice, all animals were healthy but had not gained weight; no deaths occurred during the experiment. Cholesterol gallstones were present in all groups. In the absence of exogenous cholesterol, the highest stone incidence was found in the animals which received the lowest fiber (highest corn) diets (alfalfa plus corn, 50:50, 67%; alfalfa plus corn, 15:85, 83%). Cholesterol gallstone incidence was 100% when exogenous cholesterol was added to the alfalfa plus corn diets (50:50 and 15:85). No pigment gallstones were detected in any animal. Liver and plasma cholesterol concentrations were highest in the animals receiving alfalfa plus corn (15:85) plus 0.4% cholesterol (4.29 mg/g, and 356 mg/dl, respectively). These values were lowest in animals receiving 85% alfalfa plus 15% corn without cholesterol (2.19 mg/g and 88 mg/dl, respectively). Lithogenic indices were below 1.00 in all groups. Biliary bile acids were mainly amidates of cholic acid and chenodeoxycholic acid , with the former predominating . Thus, gallstones can be formed in prairie dogs in the absence of exogenous cholesterol; gallstone incidence is reduced by dietary fiber.", "source": "https://pubmed.ncbi.nlm.nih.gov/2159098/"}
{"doc_id": "ccca9b4d3e16d02c960609c678d74fb6", "sentence": "Cutaneous T-cell lymphoma-like drug eruption in an HIV-positive patient taking vancomycin and rifampin .", "spans": [{"span_id": 0, "text": "vancomycin", "start": 79, "end": 89, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "rifampin", "start": 94, "end": 102, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Cutaneous T-cell lymphoma-like drug eruption in an HIV-positive patient taking vancomycin and rifampin . Cutaneous T-cell pseudolymphoma (CTPL) is a benign reactive T-cell lymphoproliferative subtype of pseudolymphoma. Some variants of CTPL can resemble the plaques of mycosis fungoides (MF). The vast majority of drug-induced cases have been associated with anticonvulsants. There is only one report in the literature documenting a case of vancomycin-induced CTPL. ### methods We report a cutaneous T-cell lymphoma-like eruption in a human immunodeficiency virus (HIV)-positive patient recently started on vancomycin and rifampin. ### results A skin biopsy showed several histologic features of MF with immunohistochemical and T-cell receptor gene rearrangement studies suggestive of CTPL. This atypical T-cell reaction mimicking MF completely resolved on cessation of rifampin followed by vancomycin. ### conclusion Considering drug-induced causes of MF-like histologic changes is crucial to prevent unnecessary treatment for MF.", "source": "https://pubmed.ncbi.nlm.nih.gov/24138984/"}
{"doc_id": "44b24b773d5f20565a08318a21a3249e", "sentence": "Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting \u03b22 agonist therapy , even in combination with tiotropium .", "spans": [{"span_id": 0, "text": "roflumilast", "start": 26, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "tiotropium", "start": 314, "end": 324, "token_start": 43, "token_end": 44}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting \u03b22 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting \u03b22 agonist treatment. ### methods For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 \u03bcg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting \u03b22 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. ### findings Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13\u00b72% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0\u00b7805 vs placebo 0\u00b7927; rate ratio [RR] 0\u00b7868 [95% CI 0\u00b7753-1\u00b7002], p=0\u00b70529), and 14\u00b72% lower according to a predefined sensitivity analysis using negative binomial regression (0\u00b7823 vs 0\u00b7959; 0\u00b7858 [0\u00b7740-0\u00b7995], p=0\u00b70424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1\u00b78%) deaths occurred in the roflumilast group compared with 18 (1\u00b79%) in the placebo group. ### interpretation Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting \u03b22 agonist therapy , even in combination with tiotropium . ### funding Takeda.", "source": "https://pubmed.ncbi.nlm.nih.gov/25684586/"}
{"doc_id": "02aa33a2d0f251d72f00e97592096cd3", "sentence": "This academic , matched-cohort study , compared 2-year outcomes of 11 consecutive IMN patients who received second-line rituximab therapy for NS persisting or relapsing after previous treatment with steroids alone or combined with alkylating agents , cyclosporine , or immunoglobulin G , with those of 11 age- ( \u00b1 5 years ) , gender- and proteinuria- ( \u00b1 1 g/24h ) matched reference patients given first-line rituximab therapy .", "spans": [{"span_id": 0, "text": "rituximab", "start": 120, "end": 129, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "cyclosporine", "start": 251, "end": 263, "token_start": 36, "token_end": 37}, {"span_id": 2, "text": "rituximab", "start": 409, "end": 418, "token_start": 66, "token_end": 67}], "rels": [], "paragraph": "Efficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study. First-line immunosuppression with the B-cell depleting antibody rituximab reduced proteinuria and induced remission of the disease in patients with nephrotic syndrome (NS) secondary to idiopathic membranous nephropathy (IMN). Here we evaluated whether rituximab is equally effective in patients who failed to respond to previous immunosuppressive treatment. ### methods This academic , matched-cohort study , compared 2-year outcomes of 11 consecutive IMN patients who received second-line rituximab therapy for NS persisting or relapsing after previous treatment with steroids alone or combined with alkylating agents , cyclosporine , or immunoglobulin G , with those of 11 age- ( \u00b1 5 years ) , gender- and proteinuria- ( \u00b1 1 g/24h ) matched reference patients given first-line rituximab therapy . ### results Patients' and reference patients' baseline characteristics were similar. Compared to baseline, 24-hour proteinuria similarly declined at 1 and 2 years post-rituximab (by 50.5 \u00b1 25.1% and 60.9 \u00b1 17.4% in patients and by 52.7 \u00b1 31.5% and 69.4 \u00b1 40.4% in reference patients, respectively; p < 0.01 for all comparisons vs. baseline). 8 patients and 7 reference patients achieved full (3 vs. 2) or partial (5 per cohort) proteinuria remission. Hypoalbuminemia and hyperlipidemia normalized in both groups. Self-limited infusion-related reactions occurred in 1 subject per cohort. ### conclusion rituximab reduced proteinuria in IMN patients with no or only transient response to unselective immunosuppression as effectively and safely as in patients without previous immunosuppression.", "source": "https://pubmed.ncbi.nlm.nih.gov/21508634/"}
{"doc_id": "df4bd424152b18eedfbc2d6ed15dbd0b", "sentence": "Induction chemotherapy with cisplatin , doxorubicin , and cyclophosphamide ( CAP ) in a combined modality approach for locally advanced and inflammatory breast cancer .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 28, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxorubicin", "start": 40, "end": 51, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "cyclophosphamide", "start": 58, "end": 74, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Induction chemotherapy with cisplatin , doxorubicin , and cyclophosphamide ( CAP ) in a combined modality approach for locally advanced and inflammatory breast cancer . Thirty-one patients with locally advanced and inflammatory breast carcinoma (stage IIIA and IIIB) were treated with a combined modality approach between 1985 and 1989. All patients received as induction chemotherapy a combination of cisplatin, doxorubicin, and cyclophosphamide (CAP). Responsive patients and patients with operable stable disease underwent modified radical mastectomy followed by concurrent radiotherapy and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) adjuvant chemotherapy. Thirty patients were evaluable for response to CAP. The rate of objective response to induction chemotherapy was 76.7% with 2 patients (6.7%) obtaining a complete response and 21 patients (70%) a partial response. Twenty-five patients were rendered disease-free after induction chemotherapy and surgery. Only 2 of these had pathological complete response (8%). The median overall survival was 48.7 months, the median time to progression was 22.4 months and the median disease-free survival was 29.1 months. The patients with noninflammatory breast tumor had a significantly better overall survival, disease-free survival, and time to progression. The overall survival and the time to progression were statistically superior in patients with primary tumor size < or = 8 cm. At a median follow-up of 6 years, 29% (95% CI, 13.05 to 45.01) of patients were alive and 28% (95% CI, 10.4 to 45.6) were disease-free. This combined modality treatment seems feasible with quite acceptable toxicity; the CAP combination is an effective alternative to the other standard chemotherapeutic regimens. Our results, although encouraging, are still poor, and new drugs and strategies are required to improve the long-term outcome.", "source": "https://pubmed.ncbi.nlm.nih.gov/8554028/"}
{"doc_id": "be42ba6d693a48f4e534e93d9d0226b7", "sentence": "Methotrexate was efficient in one patient , hydroxychloroquine showed benefit in only 1 out of 3 patients .", "spans": [{"span_id": 0, "text": "Methotrexate", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "hydroxychloroquine", "start": 44, "end": 62, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Oral involvement in sarcoidosis: report of 12 cases. To assess the clinical features, treatment and outcome of oral sarcoidosis and to determine whether oral involvement is associated with a particular clinical phenotype of sarcoidosis. ### design Multicentric retrospective study. ### methods Retrospective chart review. Each patient was matched with four controls. ### results Twelve patients (9 women, 3 men) were identified. Their median age at sarcoidosis diagnosis was 38 years. Oral involvement was the first clinical evidence of sarcoidosis in seven cases and was a relapse symptom in five cases. Clinical presentations were nodules (n = 7) or ulcers (n = 5) and were mostly solitary. The tongue was the commonest site affected (n = 4), followed by lips (n = 3), oral mucosa (n = 2), palate (n = 2) and gingiva (n = 1). Patients with oral sarcoidosis were significantly younger and had more frequent lacrimal or salivary glands and upper airway tract clinical involvement than the controls; increased angiotensin-converting enzyme was less frequent in oral sarcoidosis. Multiple treatments of oral sarcoidosis were used: no treatment (n = 3), surgery (n = 2), corticosteroids (n = 7), hydroxychloroquine (n = 3), methotrexate (n = 2), doxycycline (n = 1). Methotrexate was efficient in one patient , hydroxychloroquine showed benefit in only 1 out of 3 patients . Three patients presented oral relapses. After a mean follow-up of 6 years, 10 patients experienced a complete (n = 7) or partial (n = 3) remission of oral sarcoidosis; stability was observed in the remaining two cases. ### conclusion Although oral manifestations of sarcoidosis are unusual, physicians should be aware that this specific localization is frequently the first manifestation of the disease. Treatment modalities range from observation in asymptomatic patients to immunosuppressants for severe involvement.", "source": "https://pubmed.ncbi.nlm.nih.gov/22422021/"}
{"doc_id": "33f8e5c6071fe4aee2ffdb4316c19bad", "sentence": "Our results show high rates of DR-TB in Nigerian HIV-infected individuals ( 7.0 % for rifampin [ RIF ] and 9.3 % for RIF or isoniazid [ INH ] ) .", "spans": [{"span_id": 0, "text": "rifampin", "start": 86, "end": 94, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "isoniazid", "start": 124, "end": 133, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Genetic determinants of drug-resistant tuberculosis among HIV-infected patients in Nigeria. Tuberculosis (TB) is the most common opportunistic infection in human immunodeficiency virus (HIV)-infected patients and the emergence of drug-resistant tuberculosis (DR-TB) is a growing problem in resource-limited settings. Adequate infrastructure for testing drug sensitivity and sufficient evidence of first-line resistance are currently unavailable in Nigeria. We collected sputum samples from HIV-infected patients enrolled in the Harvard PEPFAR/APIN Plus program over 12 months at two PEPFAR antiretroviral therapy (ART) clinics in the southwest and north central regions in Nigeria. Smear-positive sputum samples were submitted for GenoType MTBDRplus testing (n = 415); mutations were confirmed through sequencing. Our results show high rates of DR-TB in Nigerian HIV-infected individuals ( 7.0 % for rifampin [ RIF ] and 9.3 % for RIF or isoniazid [ INH ] ) . Total RIF resistance indicative of MDR-TB in treatment-naive patients was 5.52%, far exceeding the World Health Organization predictions (0 to 4.3%). RIF resistance was found in 6/213 (2.8%) cases, INH resistance was found in 3/215 (1.4%) cases, and MDR-TB was found in 8/223 (3.6%) cases. We found significantly different amounts of DR-TB by location (18.18% in the south of the country versus 3.91% in the north central region [P < 0.01]). Furthermore, RIF resistance was genetically distinct, suggesting possible location-specific strains are responsible for the transmission of drug resistance (P < 0.04). Finally, GenoType MTBDRplus correctly identified the drug-resistant samples compared to sequencing in 96.8% of cases. We found that total DR-TB in HIV-infection is high and that transmission of drug-resistant TB in HIV-infected patients in Nigeria is higher than predicted.", "source": "https://pubmed.ncbi.nlm.nih.gov/22740709/"}
{"doc_id": "bc93f89378df2b51229fcc631b7c9712", "sentence": "Sorafenib is an orally active multikinase inhibitor , and bortezomib is a proteasome inhibitor that affects multiple signaling pathways .", "spans": [{"span_id": 0, "text": "Sorafenib", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bortezomib", "start": 58, "end": 68, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Phase II study of sorafenib and bortezomib for first-line treatment of metastatic or unresectable renal cell carcinoma.  Sorafenib is an orally active multikinase inhibitor , and bortezomib is a proteasome inhibitor that affects multiple signaling pathways . sorafenib has clinical activity in renal cell carcinoma (RCC), whereas bortezomib has demonstrated activity against RCC cell lines in vitro, with in vitro studies showing synergism between the two agents in the induction of apoptosis in neoplastic cell lines. In this phase II study, we explored the efficacy and toxicity of this regimen. ### methods Adult patients with cytologically confirmed clear cell RCC with no prior chemotherapy, Zubrod performance status of 0-1, serum creatinine <1.5 mg/dL, and normal liver function tests were treated with sorafenib 200 mg orally b.i.d. with bortezomib 1 mg/m(2) intravenously on days 1, 4, 8, and 11 every 21 days. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was median progression-free survival (PFS) of at least 70 weeks. ### results Seventeen patients were enrolled between April 2011 and January 2013. Median age was 62 years (range: 44-75 years). Four of 17 patients had known brain metastasis on enrollment. Median number of cycles was 4 (range: 1 to \u226545). No patient had complete response, 1 had partial response, 12 had stable disease, and 4 had progressive disease (response rate of 6%; 95% confidence interval: 0%-29%) with treatment. Median PFS was 13.7 weeks, and median overall survival was 110 weeks. The study was halted for futility. ### conclusion The combination of sorafenib and bortezomib was well tolerated; however, response rate and PFS were comparable to sorafenib monotherapy. This regimen is not recommended for further development.", "source": "https://pubmed.ncbi.nlm.nih.gov/25777345/"}
{"doc_id": "292d2c6c3937d1ce8478261c453a595e", "sentence": "Hypertensive rats in separate groups were treated with either candesartan ( 1 mg/kg body weight ) alone or a combination of candesartan ( 1 mg/kg body weight ) and rofecoxib ( 10 mg/kg body weight ) orally and daily for 6 weeks .", "spans": [{"span_id": 0, "text": "candesartan", "start": 62, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "candesartan", "start": 124, "end": 135, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "rofecoxib", "start": 164, "end": 173, "token_start": 29, "token_end": 30}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Effect of rofecoxib on antihypertensive effects of candesartan in experimental models of hypertension. Given the high prevalence of hypertension, concomitant use of nonsteroidal anti-inflammatory drugs and antihypertensive medications is commonly encountered in clinical practice. The present study was designed to study the effect of indomethacin, nimesulide, and rofecoxib on blood pressure (BP) in normotensive and hypertensive rats and also to investigate the effect of rofecoxib on BP control in candesartan-treated hypertensive rats. Male Wistar rats weighing 150-200 g were divided into three groups: control, DOCA-hypertensive, and L-NAME-hypertensive rats. All the rats were given indomethacin (15 mg/kg body weight), nimesulide (20 mg/kg body weight), rofecoxib (10 mg/kg body weight), or vehicle orally and daily for 6 weeks. Hypertensive rats in separate groups were treated with either candesartan ( 1 mg/kg body weight ) alone or a combination of candesartan ( 1 mg/kg body weight ) and rofecoxib ( 10 mg/kg body weight ) orally and daily for 6 weeks . BP measurements were performed using tail cuff method at baseline and 1-week intervals throughout the treatment period. All the three COX inhibitors resulted in increase in BP, but mean change in BP was the highest with rofecoxib. rofecoxib-treated L-NAME-hypertensive rats exhibited a significant increase in mean arterial pressure at 6 weeks (168.3+/-5.7 mmHg) as compared with DOCA-hypertensive rats (128.818+/-7.2 mmHg). Administration of rofecoxib L-NAME-hypertensive rats treated with candesartan resulted in a significant increase in BP. Systolic BP at 0 week (107.0+/-4.2 mmHg) rose to 141.6+/-2.0 mmHg at 6 weeks. Systolic BP at 2, 4, and 6 weeks was significantly higher as compared with (L-NAME+candesartan)- and (rofecoxib+candesartan)-treated group. In conclusion, concomitant use of rofecoxib resulted in poor BP control by candesartan in L-NAME-hypertensive rats.", "source": "https://pubmed.ncbi.nlm.nih.gov/15834454/"}
{"doc_id": "e8f82836baaf9e71816fa84fd14e9a87", "sentence": "The highest weight gain in the cyclophosphamide , methotrexate and fluorouracil group was 2\u00b79 kg ( 5 % ) vs. 0\u00b79 kg ( 1 % ) in the anthracycline-based group .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 31, "end": 47, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "methotrexate", "start": 50, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "fluorouracil", "start": 67, "end": 79, "token_start": 10, "token_end": 11}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Weight change trajectory in women with breast cancer receiving chemotherapy and the effect of different regimens. To investigate the trajectory of weight change in Taiwanese women with breast cancer after starting chemotherapy and the impact of chemotherapy regimens on weight change while controlling for age, menopausal status, body mass index, lymph node involvement and changes in habits of dietary fat intake and exercise. ### background Weight gain after adjuvant chemotherapy in women with breast cancer has negative impact on health outcomes. ### design Longitudinal, clinical observational study. ### methods Weights were repeatedly measured in 147 women with breast cancer stages I-III. Hierarchical linear modelling was used to analyse these longitudinal data. ### results The overall pattern of weight change was a cubic form beginning with a mean of 56\u00b79 kg before chemotherapy. It gradually increased to 59\u00b74 kg at 8\u00b75 months after the first chemotherapy followed by a decrease to 58\u00b75 kg at 21\u00b75 months. During the last 2\u00b75 months, weight increased slightly and never returned to the initial level. After controlling for confounders, steeper weight change was observed among women receiving cyclophosphamide, methotrexate and fluorouracil. The highest weight gain in the cyclophosphamide , methotrexate and fluorouracil group was 2\u00b79 kg ( 5 % ) vs. 0\u00b79 kg ( 1 % ) in the anthracycline-based group . ### conclusion The trajectory of body weight change within two years after chemotherapy shows a trend of gradual ascent, followed by a small decline and a slight increase in the last 2\u00b75 months. The chemotherapy regimen can predict the trend after controlling for other confounders; women on cyclophosphamide, methotrexate and fluorouracil have a steeper weight change. ### Relevance To Clinical Practice Nurses can inform women with breast cancer about the expected changes in body weight after chemotherapy to reduce their uncertainty. Future studies on effective interventions to minimise chemotherapy-induced weight gain are needed.", "source": "https://pubmed.ncbi.nlm.nih.gov/24393441/"}
{"doc_id": "402f6227835ed4a8c7deaebb01994c3f", "sentence": "Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus ( RAD001 ) and alemtuzumab : a Phase I/II study .", "spans": [{"span_id": 0, "text": "everolimus", "start": 94, "end": 104, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "alemtuzumab", "start": 120, "end": 131, "token_start": 14, "token_end": 15}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus ( RAD001 ) and alemtuzumab : a Phase I/II study . Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), and especially those with purine analogue refractory disease or TP53 deletion/mutation, had a poor prognosis prior to the introduction of therapy targeting B cell receptor signaling. The mammalian target of rapamycin (mTOR) inhibitor everolimus has biological activity in CLL and can mobilize CLL cells from the lymphoid tissues into the circulation. In this clinical trial we determined the maximum tolerated dose (MTD) of everolimus together with eight weeks of standard dose subcutaneous alemtuzumab (Phase I) and then evaluated the tolerability and efficacy of therapy of relapsed/refractory CLL with the combination of everolimus and alemtuzumab (Phase II). The maximum tolerated dose of oral everolimus was 2.5\u2009mg three times/week. Therapy with everolimus and alemtuzumab was tolerable, but not sufficiently efficacious (33% partial responses, no complete responses) to recommend further development of the regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/26699397/"}
{"doc_id": "93fc84fbededb827039793d81948c432", "sentence": "Since primary amines similar to that of lisinopril readily form Schiff bases with acetaldehyde , these data suggest that both captopril and lisinopril may act to detoxify the acetaldehyde effect upon plasma , albeit by different mechanisms .", "spans": [{"span_id": 0, "text": "lisinopril", "start": 40, "end": 50, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "captopril", "start": 126, "end": 135, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "lisinopril", "start": 140, "end": 150, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Captopril and lisinopril decrease acetaldehyde effects upon the prothrombin time. captopril, a thiol-containing antihypertensive drug, and lisinopril, an amino-containing antihypertensive drug, will both prolong the prothrombin time (PT) of Level I plasma. Acetaldehyde, a product of ethanol metabolism, also prolongs PT. In a study to examine the interrelationship between hypertension, hemostasis, and alcoholism, an examination of the impact of acetaldehyde on the effects of captopril and lisinopril upon PT was undertaken. It was observed that the pre-mixing of 7.7 x 10(-3) M captopril with 40.6 mM acetaldehyde for 30 min at R.T. prior to the addition to plasma results in a prolongation of PT which is less than that caused by acetaldehyde alone. Successive additions of captopril and acetaldehyde to plasma also yield a PT which is less than that of acetaldehyde alone. These data suggest that captopril may partially inactivate and detoxify the acetaldehyde effect on hemostasis upon interaction to form a thiohemiacetal. captopril may prolong PT by the reduction of the S-S bridges in the coagulation factors. lisinopril behaves similarly to captopril, prolonging PT. Successive additions of lisinopril and acetaldehyde, or pre-mixtures thereof, to plasma result in a lesser prolongation of clotting time relative to acetaldehyde alone. Since primary amines similar to that of lisinopril readily form Schiff bases with acetaldehyde , these data suggest that both captopril and lisinopril may act to detoxify the acetaldehyde effect upon plasma , albeit by different mechanisms .", "source": "https://pubmed.ncbi.nlm.nih.gov/17932766/"}
{"doc_id": "bffb465b1cdd2b90e26ec5367aab27ab", "sentence": "Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin , respectively .", "spans": [{"span_id": 0, "text": "Capecitabine", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "oxaliplatin", "start": 17, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "fluorouracil", "start": 67, "end": 79, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "cisplatin", "start": 84, "end": 93, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma. At present, there is no standard regimen for the treatment of gastroesophageal cancer. docetaxel, cisplatin and fluorouracil (DCF) has been shown to be an effective regimen; however, toxicity is an area of concern in the palliative case setting. Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin , respectively . To reduce the toxicity of DCF while maintaining efficacy, we conducted this study to evaluate the efficacy of docetaxel, oxaliplatin and capecitabine (DOX) combination in advanced gastroesophageal cancer. ### methods Patients with histologically confirmed metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction received docetaxel 25 mg/m2 and oxaliplatin 50 mg/m2 on days 1 and 8 with capecitabine 625 mg/m2 twice daily from day 1-14, in 21-day cycles. The primary endpoint was overall response rate (ORR). ### results Of 21 patients, there were 16 males and 5 females with a median age of 57 years, range 37-80 years. The primary tumor was located at the gastroesophageal junction in 7 patients and in other parts of the stomach in the remaining 14 patients. One patient had locally advanced tumor without distant metastases and 20 patients presented with metastatic disease. Grade 3/4 toxicities included diarrhea (24%), hand-foot syndrome (5%) and febrile neutropenia (5%). The ORR was 29%. The median survival was 8.4 months. At the time of analysis, 5 of the 21 patients (24%) were alive. ### conclusions The DOX combination is tolerable, active and a promising day-care regimen for advanced gastroesophageal cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/20543537/"}
{"doc_id": "fa3bc4b5c7d75d4fc07add3b08193775", "sentence": "To compare cardiopulmonary and sedative effects following administration of dexmedetomidine alone or with butorphanol , methadone , morphine or tramadol in healthy sheep .", "spans": [{"span_id": 0, "text": "dexmedetomidine", "start": 76, "end": 91, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "butorphanol", "start": 106, "end": 117, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "methadone", "start": 120, "end": 129, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "morphine", "start": 132, "end": 140, "token_start": 17, "token_end": 18}, {"span_id": 4, "text": "tramadol", "start": 144, "end": 152, "token_start": 19, "token_end": 20}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 3], "is_context_needed": true}], "paragraph": "Behavioral and cardiopulmonary effects of dexmedetomidine alone and in combination with butorphanol, methadone, morphine or tramadol in conscious sheep.  To compare cardiopulmonary and sedative effects following administration of dexmedetomidine alone or with butorphanol , methadone , morphine or tramadol in healthy sheep . ### Study Design Randomized crossover study. ### animals Six Santa In\u00eas sheep, five females, one male, aged 12-28\u00a0months and weighing 40.1\u00a0\u00b1\u00a06.2\u00a0kg. ### methods Sheep were assigned treatments of dexmedetomidine (0.005\u00a0mg\u00a0kg(-1) ; D); D and butorphanol (0.15\u00a0mg\u00a0kg(-1) ; DB); D and methadone (0.5\u00a0mg\u00a0kg(-1) ; DM); D and morphine (0.5\u00a0mg kg(-1) ; DMO); or D and tramadol (5.0\u00a0mg\u00a0kg(-1) ; DT). All drugs were administered intravenously with at least 7\u00a0days between each treatment. Rectal temperature, heart rate (HR), respiratory rate (fR ), invasive arterial pressure, blood gases and electrolytes were measured prior to administration of drugs (baseline, T0) and every 15\u00a0minutes following drug administration for 120\u00a0minutes (T15-T120). Sedation was scored by three observers blinded to treatment. ### results HR decreased in all treatments and fR decreased in DM at T30 and DMO at T30 and T45. PaCO2 was increased in D, DB and DM compared with baseline, and PaO2 decreased in D at T15 and T45; in DB at T15 to T75; in DM at T15 to T60; in DMO at T15; and in DT at T15, T30 and T75. There was a decrease in temperature in D, DB and DM. An increased pH was measured in D at all time points and in DT at T30-T120. HCO3- and base excess were increased in all treatments compared with baseline. There were no statistical differences in sedation scores. ### Conclusions And Clinical Relevance The combination of dexmedetomidine with butorphanol, methadone, morphine or tramadol resulted in similar changes in cardiopulmonary function and did not improve sedation when compared with dexmedetomidine alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/26848935/"}
{"doc_id": "fe175754297258a1f3caa314f0949acf", "sentence": "We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition ; this phenomenon was associated with altered conductance through Ca\u00b2\u207a and voltage-activated K\u207a ( BK ) channels , and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling .", "spans": [{"span_id": 0, "text": "melatonin", "start": 14, "end": 23, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "all-trans retinoic acid", "start": 44, "end": 67, "token_start": 7, "token_end": 10}, {"span_id": 2, "text": "somatostatin", "start": 72, "end": 84, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "melatonin", "start": 112, "end": 121, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules. melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition ; this phenomenon was associated with altered conductance through Ca\u00b2\u207a and voltage-activated K\u207a ( BK ) channels , and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling . The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/22532966/"}
{"doc_id": "e609fcfa45531012af6f10e72c76a75b", "sentence": "It was concluded that cytosine arabinoside in combination with vincristine and prednisone is an effective but toxic antileukemic regimen which did not produce a major improvement in remission duration .", "spans": [{"span_id": 0, "text": "cytosine arabinoside", "start": 22, "end": 42, "token_start": 4, "token_end": 6}, {"span_id": 1, "text": "vincristine", "start": 63, "end": 74, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "prednisone", "start": 79, "end": 89, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Treatment of adult acute lymphoblastic leukemia with cytosine arabinoside, vincristine, and prednisone. Thirteen adults with acute lymphoblastic leukemia were entered into a protocol in which cytosine arabinoside infusion was added to vincristine and prednisone as remission induction and periodic intensification therapy. Central nervous system prophylaxis consisting of cranial irradiation and intrathecal methotrexate was given, and all patients received continuous oral 6-mercaptopurine and methotrexate as maintenance treatment. Myelotoxicity was severe during induction, with prolonged granulocyte and platelet count nadirs noted. Nine of 13 patients (69%) obtained a complete remission and one (8%) obtained a partial remission. The median duration of complete remission was 38.1 weeks. It was concluded that cytosine arabinoside in combination with vincristine and prednisone is an effective but toxic antileukemic regimen which did not produce a major improvement in remission duration .", "source": "https://pubmed.ncbi.nlm.nih.gov/356988/"}
{"doc_id": "c178c4c3b519362980989cb290ad3e8e", "sentence": "Patients were categorized into 10 groups according to the index OAC ( warfarin , rivaroxaban , dabigatran , apixaban , and edoxaban ) and whether or not they received PPI co-therapy , and were followed up for incidence of major GIB .", "spans": [{"span_id": 0, "text": "warfarin", "start": 70, "end": 78, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "rivaroxaban", "start": 81, "end": 92, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "dabigatran", "start": 95, "end": 105, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "apixaban", "start": 108, "end": 116, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "edoxaban", "start": 123, "end": 131, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Proton Pump Inhibitor Co-Therapy in Patients with Atrial Fibrillation Treated with Oral Anticoagulants and a Prior History of Upper Gastrointestinal Tract Bleeding. The risk of gastrointestinal bleeding (GIB) can be mitigated by proton pump inhibitor (PPI) co-therapy in patients with atrial fibrillation (AF) treated with anticoagulants. We aimed to evaluate the effect of PPIs on the risk of GIB in Asian patients with AF, treated with oral anticoagulants (OACs), and with a prior history of upper GIB. ### methods Using a nationwide claims database, OAC-na\u00efve patients with AF and a history of upper GIB before initiating OAC treatment between January 2010 and April 2018 were included. Patients were categorized into 10 groups according to the index OAC ( warfarin , rivaroxaban , dabigatran , apixaban , and edoxaban ) and whether or not they received PPI co-therapy , and were followed up for incidence of major GIB . ### results Among a total of 42,048 patients, 40% were prescribed PPIs as co-therapy with OACs. Over a median 0.6\u00a0years (interquartile ranges 0.2-1.7\u00a0years) of follow-up, rivaroxaban use without PPIs showed the highest crude incidence of major GIB (2.62 per 100 person-years), followed by the use of warfarin without a PPI (2.20 per 100 person-years). Compared to the patients without PPI use, PPI co-therapy was associated with a significantly lower risk of major GIB, by 40% and 36%, in the rivaroxaban and warfarin groups, respectively. In dabigatran, apixaban, and edoxaban users, PPI co-therapy did not show a significant reduction in the risk of major GIB. ### conclusion Among patients with AF receiving anticoagulant treatment and with a prior history of upper GIB, PPI co-therapy was associated with a significant reduction in the risk of major GIB in patients treated with rivaroxaban and warfarin.", "source": "https://pubmed.ncbi.nlm.nih.gov/33730289/"}
{"doc_id": "9d6fcba2e6520c9c80bdedbaa4495ed7", "sentence": "Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin , etoposide , irinotecan or vincristine in vitro .", "spans": [{"span_id": 0, "text": "Celecoxib", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 84, "end": 95, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "etoposide", "start": 98, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "irinotecan", "start": 110, "end": 120, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "vincristine", "start": 124, "end": 135, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 3], "is_context_needed": false}], "paragraph": "Celecoxib prevents neuroblastoma tumor development and potentiates the effect of chemotherapeutic drugs in vitro and in vivo. Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2-specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. ### Experimental Design Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. ### results Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin , etoposide , irinotecan or vincristine in vitro . In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. ### conclusions celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. celecoxib could also be a potential drug for treatment of minimal residual disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/17289900/"}
{"doc_id": "67c22a91de33a9ba2240f12810ebef2e", "sentence": "In vivo , midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments .", "spans": [{"span_id": 0, "text": "midostaurin", "start": 10, "end": 21, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "rituximab", "start": 113, "end": 122, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Midostaurin potentiates rituximab antitumor activity in Burkitt's lymphoma by inducing apoptosis. An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt's lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells. The PI3K/AKT inhibitor IPI-145 failed to reverse the resistance. In contrast, the pan-PKC inhibitor midostaurin exhibited potent antitumor activity in both original and resistant cells, alone or in combination with rituximab. Notably, midostaurin promoted apoptosis by reducing the phosphorylation of PKC and consequently of downstream Bad, Bcl-2 and NF-\u03baB. Therefore, midostaurin improved rituximab activity by supplementing pro-apoptotic effects. In vivo , midostaurin alone powerfully prolonged the survival of mice bearing the resistant BL cells compared to rituximab alone treatments . Addition of midostaurin to rituximab led to dramatically improved survival compared to rituximab but not midostaurin monotherapy. Our findings call for further evaluation of midostaurin alone or in combination with rituximab in treating resistant BL in particular.", "source": "https://pubmed.ncbi.nlm.nih.gov/30584254/"}
{"doc_id": "f67b8b02b47a8036885907fa7d3afd2b", "sentence": "Treatment of GIST882-R with imatinib in combination with gefitinib , an EGFR inhibitor , partially prevented cell growth , implying that EGFR may be involved in acquisition of secondary imatinib resistance in GIST .", "spans": [{"span_id": 0, "text": "imatinib", "start": 28, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "gefitinib", "start": 57, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "imatinib", "start": 186, "end": 194, "token_start": 29, "token_end": 30}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Augmentation of multiple protein kinase activities associated with secondary imatinib resistance in gastrointestinal stromal tumors as revealed by quantitative phosphoproteome analysis. Mutations in the Kit receptor tyrosine kinase gene (KIT), which result in constitutive activation of the protein (KIT), are causally related to the development of gastrointestinal stromal tumors (GISTs). imatinib, a targeted anticancer drug, exerts a therapeutic effect against GISTs by repressing the kinase activity of KIT. Long-term administration of this drug, however, causes the emergence of imatinib-resistant GISTs. We performed quantitative phosphoproteome analysis using a cell-based GIST model system comprising an imatinib-sensitive GIST cell line (GIST882), GIST882 under treatment with imatinib (GIST882-IM), and secondary imatinib-resistant GIST882 (GIST882-R). Phosphorylated peptides were purified from each cell line using titania-based affinity chromatography or anti-phosphotyrosine immunoprecipitation, and then subjected to LC-MS/MS based quantitative phosphoproteome analysis. Using this method we identified augmentation of the kinase activities of multiple elements of the signal transduction pathway, especially KIT and EGFR. Although, these elements were up-regulated in GIST882-R, no additionally mutated KIT mRNA was found in secondary imatinib-resistant GIST cells. Treatment of GIST882-R with imatinib in combination with gefitinib , an EGFR inhibitor , partially prevented cell growth , implying that EGFR may be involved in acquisition of secondary imatinib resistance in GIST . ### Biological Significance In this study, we performed a quantitative phosphoproteome analysis using a cell culture-based GIST model system. The goal of the study was to investigate the mechanism of acquired resistance in GISTs against imatinib, a molecularly targeted drug that inhibits kinase activity of the KIT protein and that has been approved for the treatment of GISTs. In imatinib-resistant GIST cells, we observed elevated expression of KIT and restoration of its kinase activity, as well as activation of multiple proliferative signaling pathways. Our results indicate that the effects of even so-called 'molecularly targeted' drugs, are broad rather than convergent, and that the mechanisms of action of such drugs during continuous administration are extremely complex.", "source": "https://pubmed.ncbi.nlm.nih.gov/25554490/"}
{"doc_id": "2e01a54adda80b3e1acdce028954a1a4", "sentence": "This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients , providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 79, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "risperidone", "start": 94, "end": 105, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "tamoxifen", "start": 239, "end": 248, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination treatment of tamoxifen with risperidone in breast cancer. tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients , providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer .", "source": "https://pubmed.ncbi.nlm.nih.gov/24886861/"}
{"doc_id": "e94ef24785140b8074e7ae63e5a592e8", "sentence": "Amoxicillin , erythromycin , and levofloxacin at supra-MIC concentrations were very active against planktonic cells of 3 selected strains but lower on biofilm-associated organisms in 2 strains and null against the third .", "spans": [{"span_id": 0, "text": "Amoxicillin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "erythromycin", "start": 14, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "levofloxacin", "start": 33, "end": 45, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Biofilm formation by Streptococcus pneumoniae strains and effects of human serum albumin, ibuprofen, N-acetyl-l-cysteine, amoxicillin, erythromycin, and levofloxacin. Streptococcus pneumoniae ability to produce biofilms may induce persistent infections and difficulties for eradication in vivo. We investigated the ability of 11 pneumococcal strains (serotypes 3, 6B, 9V, 19F, and 23F) to form biofilms on polystyrene plates at 16 and 24 h. The extent of biofilm was greater at 24 h in 10 strains, being the highest magnitude for serotype 3 strains. Human serum albumin at 25,000 microg/mL and ibuprofen at 128 microg/mL significantly reduced biofilm formation in 7 and 5 strains, respectively. Amoxicillin , erythromycin , and levofloxacin at supra-MIC concentrations were very active against planktonic cells of 3 selected strains but lower on biofilm-associated organisms in 2 strains and null against the third . Although N-acetyl-l-cysteine had very little activity against both planktonic and biofilm-forming organisms, when combined with the 3 antibiotics, a slightly enhanced activity against biofilm-embedded organisms in 1 strain and combined with amoxicillin in another one was observed.", "source": "https://pubmed.ncbi.nlm.nih.gov/20638597/"}
{"doc_id": "e3f8061263e9c92e36bbc4142eefa57f", "sentence": "A double-blind , parallel , placebo-controlled study was performed to assess the efficacy of a combination drug product containing the antihistamine , triprolidine , and the sympathomimetic , pseudoephedrine , in the treatment of allergic rhinitis .", "spans": [{"span_id": 0, "text": "triprolidine", "start": 151, "end": 163, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "pseudoephedrine", "start": 192, "end": 207, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "An evaluation of triprolidine and pseudoephedrine in the treatment of allergic rhinitis.  A double-blind , parallel , placebo-controlled study was performed to assess the efficacy of a combination drug product containing the antihistamine , triprolidine , and the sympathomimetic , pseudoephedrine , in the treatment of allergic rhinitis . Allergic rhinitis was defined on the basis of coexistent nasal congestion and an aggregate symptom complex score which exceeded a pre-established value. pseudoephedrine and triprolidine were shown to make distinct and separate contributions to the treatment of allergic rhinitis defined in this manner.", "source": "https://pubmed.ncbi.nlm.nih.gov/7258744/"}
{"doc_id": "cd58d1b74e20986d75608ae49ee926e2", "sentence": "After surgery , 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide ( EC ; 90 and 600 mg/m(2 ) , respectively , \u00d7 four cycles ) , followed by docetaxel ( 100 mg/m(2 ) \u00d7 four cycles ; EC-T ) or epirubicin plus docetaxel ( ET ; 90 and 75 mg/m(2 ) , respectively , \u00d7 four cycles ) , followed by capecitabine ( 1,250 mg/m(2 ) twice a day on days 1 to 14 , \u00d7 four cycles ; ET-X ) ; all regimens were given every 3 weeks .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 65, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "cyclophosphamide", "start": 81, "end": 97, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "docetaxel", "start": 172, "end": 181, "token_start": 31, "token_end": 32}, {"span_id": 3, "text": "epirubicin", "start": 223, "end": 233, "token_start": 43, "token_end": 44}, {"span_id": 4, "text": "docetaxel", "start": 239, "end": 248, "token_start": 45, "token_end": 46}, {"span_id": 5, "text": "capecitabine", "start": 322, "end": 334, "token_start": 64, "token_end": 65}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "NEG", "spans": [3, 4, 5], "is_context_needed": true}], "paragraph": "Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study. capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. ### Patients And Methods Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery , 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide ( EC ; 90 and 600 mg/m(2 ) , respectively , \u00d7 four cycles ) , followed by docetaxel ( 100 mg/m(2 ) \u00d7 four cycles ; EC-T ) or epirubicin plus docetaxel ( ET ; 90 and 75 mg/m(2 ) , respectively , \u00d7 four cycles ) , followed by capecitabine ( 1,250 mg/m(2 ) twice a day on days 1 to 14 , \u00d7 four cycles ; ET-X ) ; all regimens were given every 3 weeks . The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). ### results After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). ### conclusion Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.", "source": "https://pubmed.ncbi.nlm.nih.gov/26416999/"}
{"doc_id": "978592058e063b76a9516013aa601c76", "sentence": "This prospective study recruited 152 patients with locally advanced breast cancer who underwent four-cycle weekly paclitaxel plus carboplatin without trastuzumab .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 114, "end": 124, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "carboplatin", "start": 130, "end": 141, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "trastuzumab", "start": 150, "end": 161, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Association of HER-2 copy number and HER-2/CEP-17 ratio with neoadjuvant taxane-containing chemotherapy sensitivity in locally advanced breast cancer. Aneusomy 17 causes inconsistency in fluorescence in situ hybridization (FISH)-based human epidermal growth factor receptor (HER)-2 status assessment using different algorithms (copy number or the HER-2/centromere enumerator probe 17 [CEP-17] ratio). We investigated the effects of FISH-based HER-2 status assessment and aneusomy 17 on responsiveness to neoadjuvant chemotherapy (NAC). ### Patients And Methods This prospective study recruited 152 patients with locally advanced breast cancer who underwent four-cycle weekly paclitaxel plus carboplatin without trastuzumab . ### results The pathologic complete remission (pCR) rate in the breast and axilla was 24.3% (95% confidence interval [CI], 17.7%-32.0%). Although HER-2 status, assessed by either HER-2/CEP-17 ratio-based FISH or copy number-based FISH, was a predictor of NAC sensitivity, ratio-assessed HER-2 status had a poorer performance in determining patients' responsiveness to NAC (p = .029). Patients who were not HER-2 amplified when assessed using the HER-2/CEP-17 ratio but were HER-2 amplified when assessed using copy number (~5%) were eventually proven to be responsive to NAC, with a pCR rate of 57% (95% CI, 18.4%-90.1%). In contrast, patients who were HER-2 amplified when assessed by the ratio but not HER-2 amplified when assessed using copy number (~3%) were completely irresponsive. Higher HER-2 copy numbers represented increasing chances of a pCR (adjusted odds ratio, 3.09; 95% CI, 1.35-7.08), with an apparent gene-dose effect (p for trend < .001). ### conclusion It is likely that HER-2 copy number but not the HER-2/CEP-17 ratio determines NAC sensitivity. Additional studies to validate our findings are warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/22561335/"}
{"doc_id": "702912841ec686e82c8e3e19682f76d9", "sentence": "High response rate and acceptable toxicity of a combination of rituximab , vinorelbine , ifosfamide , mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse : results of the R-NIMP GOELAMS study .", "spans": [{"span_id": 0, "text": "rituximab", "start": 63, "end": 72, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "vinorelbine", "start": 75, "end": 86, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "ifosfamide", "start": 89, "end": 99, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "mitoxantrone", "start": 102, "end": 114, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "prednisone", "start": 119, "end": 129, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": false}], "paragraph": "High response rate and acceptable toxicity of a combination of rituximab , vinorelbine , ifosfamide , mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse : results of the R-NIMP GOELAMS study . The optimal management of relapsed diffuse large B-cell lymphoma (DLBCL) is not standardized. The Groupe Ouest Est des Leuc\u00e9mies et aAutres Maladies du Sang developed a combination of vinorelbine, ifosfamide, mitoxantrone and prednisone (NIMP) for the treatment of relapsed DLBCL, and assessed its efficacy and safety in association with rituximab (R). This multicentric phase II study included 50 patients with DLBCL in first relapse, aged 18-75 years. Patients received rituximab 375 mg/m\u00b2 day 1, ifosfamide 1000 mg/m\u00b2 days 1-5, vinorelbine 25 mg/m\u00b2 days 1 and 15, mitoxantrone 10 mg/m\u00b2 day 1, and prednisone 1 mg/kg days 1-5, every 28 days for three cycles. Responding patients underwent autologous transplantation or received three additional R-NIMP cycles. All patients were evaluable for toxicity and 49 for response. Centralized pathology review confirmed DLBCL in all cases. Toxicities were mainly haematological with infectious events needing hospitalization in nine cases. Two toxic deaths were observed. After three cycles, 22 patients (44%) achieved complete response/unconfirmed complete response, 11 achieved partial response (24%), 2 had stable disease and 13 progressed. The non-germinal centre B immunophenotype was associated with shorter progression-free survival. in conclusion, the R-NIMP regimen displayed significant activity in relapsed DLBCL, with acceptable toxicity and should be considered a candidate for combination with new agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/23692641/"}
{"doc_id": "de1bf6c32ec082fe4cb33f57d88827ee", "sentence": "A second complete remission was obtained with RFC chemotherapy regimen ( rituximab , fludarabine , and cyclophosphamide ) .", "spans": [{"span_id": 0, "text": "rituximab", "start": 73, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "fludarabine", "start": 85, "end": 96, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "cyclophosphamide", "start": 103, "end": 119, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Bing and neel syndrome. Introduction. We report the case of a Bing and Neel syndrome revealed by an isolated left ptosis. Case Report. a 57-year-old man was followed up since October 2003 for a typical Waldenstr\u00f6m's macroglobulinemia. A first complete remission was obtained with chlorambucil. In August 2004, he relapsed. A second complete remission was obtained with RFC chemotherapy regimen ( rituximab , fludarabine , and cyclophosphamide ) . In October 2009, the patient presented with an isolated left ptosis revealing a Bing and Neel syndrome. The diagnosis was suspected on MRI and confirmed by the detection in the CSF of a monoclonal IgM similar to the one found in the plasma. A quite good partial remission has been obtained after one course of RDHAP (rituximab, dexamethasone, cytarabine, and cisplatin) and 3 courses of RDHOx (rituximab, dexamethasone, cytarabine, and oxaliplatin), in addition to ten intrahectal chemotherapy injections. The treatment was followed by intensification and autologous stem cell transplantation. At D58, the patient died due to a septic shock. Conclusion. BNS is a rare and potentially treatable complication of WM. It should be considered in patients with neurologic symptoms and a history of WM.", "source": "https://pubmed.ncbi.nlm.nih.gov/22988532/"}
{"doc_id": "974b0e10447488e9814e90bc4e274dcc", "sentence": "At a median duration of follow-up of 18.2 months , anastrozole was at least equivalent to tamoxifen in terms of median TTP ( 8.5 and 7.0 months , respectively ; estimated hazard ratio [ tamoxifen relative to anastrozole ] , 1.13 [ lower 95 % confidence level , 1.00 ] ) .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 51, "end": 62, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "tamoxifen", "start": 90, "end": 99, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "tamoxifen", "start": 186, "end": 195, "token_start": 34, "token_end": 35}, {"span_id": 3, "text": "anastrozole", "start": 208, "end": 219, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Two randomized, double-blind trials have compared tamoxifen 20 mg daily and the selective, nonsteroidal aromatase inhibitor anastrozole 1 mg daily as first-line therapy for advanced breast carcinoma (ABC) in postmenopausal women. The trials were prospectively designed to allow for combined data analyses. ### methods The combined study population included 1021 postmenopausal women (median age, 67 years [range, 30-92]) with ABC whose tumors were either estrogen and/or progesterone receptor positive or of unknown receptor status. Primary endpoints were time to progression (TTP), objective response, and tolerability. ### results At a median duration of follow-up of 18.2 months , anastrozole was at least equivalent to tamoxifen in terms of median TTP ( 8.5 and 7.0 months , respectively ; estimated hazard ratio [ tamoxifen relative to anastrozole ] , 1.13 [ lower 95 % confidence level , 1.00 ] ) . In a retrospective subgroup analysis, anastrozole was superior to tamoxifen with respect to TTP (median values of 10.7 and 6.4 months for anastrozole and tamoxifen, respectively, two-sided P = 0.022) in patients with estrogen and/or progesterone receptor positive tumors (60% of combined trial population). In terms of objective response, 29.0% of anastrozole and 27.1% of tamoxifen patients achieved either a complete response (CR) or a partial response (PR). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 57.1% and 52.0% for anastrozole and tamoxifen, respectively. Both anastrozole and tamoxifen were well tolerated. anastrozole led to significantly fewer venous thromboembolic (P = 0.043; not adjusted for multiple comparisons) events, and vaginal bleeding was reported in fewer patients treated with anastrozole than with tamoxifen. ### conclusions In postmenopausal women with hormonally sensitive ABC, anastrozole should be considered as the new standard first-line treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/11745278/"}
{"doc_id": "393ff550cc8686a0aa016fefad4777bc", "sentence": "A favourable response to chemotherapy can be expected in up to 60 % of patients receiving a combination of streptozocin plus doxorubicin , and in up to 40 % of patients receiving dacarbazine .", "spans": [{"span_id": 0, "text": "streptozocin", "start": 107, "end": 119, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "doxorubicin", "start": 125, "end": 136, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "dacarbazine", "start": 179, "end": 190, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Endocrine tumours of the gastrointestinal tract: Chemotherapy. Malignant neuroendocrine tumours are less sensitive to chemotherapy than other epithelial malignancies. If chemotherapy is considered, tumours of pancreatic origin have a higher sensitivity than tumours from the gastrointestinal tract ('carcinoids'). Chemotherapy with streptozocin combinations and with dacarbazine should be considered in patients with progressive malignant neuroendocrine tumours of the pancreas. A favourable response to chemotherapy can be expected in up to 60 % of patients receiving a combination of streptozocin plus doxorubicin , and in up to 40 % of patients receiving dacarbazine . A survival benefit has been shown for streptozocin combinations. Treatment regimens are effective in functioning and non-functioning tumours. The response to treatment cannot be predicted. Poorly differentiated neuroendocrine tumours, independent of their origin, respond to a combination of etoposide plus cisplatin. Chemotherapy is, however, almost ineffective in patients with well-differentiated neuroendocrine tumours originating in the gastrointestinal tract ('carcinoids').", "source": "https://pubmed.ncbi.nlm.nih.gov/16183533/"}
{"doc_id": "fa9ceb85fec23bbd0522dd1f81e97f53", "sentence": "A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B ) and 5-HT(2C ) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine .", "spans": [{"span_id": 0, "text": "fenfluramine", "start": 184, "end": 196, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "fluoxetine", "start": 201, "end": 211, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Behavioural satiety sequence (BSS): separating wheat from chaff in the behavioural pharmacology of appetite. The history of anti-obesity drug development is far from glorious, with transient magic bullets and only a handful of agents currently licensed for clinical use. In view of recent progress in our understanding of the multiplicity of signalling pathways involved in appetite regulation, and the resultant deluge of reports on the anorectic efficacy of novel therapies, it seems timely to stress the need to differentiate treatments that suppress intake by primary means from those that only indirectly achieve this endpoint. The current article reviews the conceptual history of the behavioural satiety sequence (BSS), also known as the behavioural sequence of satiety, post-ingestive satiety, and the postprandial satiety sequence. Early research confirmed that natural satiation, produced by a caloric load on the gut, is associated with a predictable transition from feeding through grooming to resting. Although many less naturalistic manipulations are also capable of reducing food intake, very few do so without disrupting the normal structure of this feeding cycle. Thus, while CCK and d-fenfluramine reduce intake by accelerating but otherwise maintaining the integrity of the BSS, other anorectic interventions disrupt the BSS through response competition (e.g. d-amphetamine), nausea/discomfort (e.g. lithium chloride) and/or interference with taste-mediated positive feedback (e.g. quinine adulteration of the diet). A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B ) and 5-HT(2C ) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine . Recent BSS analyses have also identified rather selective anorectic profiles for the dual noradrenaline and 5-HT reuptake inhibitor sibutramine, the orexin-1 receptor antagonist SB-334867, and the broad spectrum opioid receptor antagonist naloxone. However, similar analyses have offered little/no support for the anorectic potential of the gut peptide PYY(3-36) while the acute anorectic efficacy of cannabinoid CB1 receptor antagonist/inverse agonists appears largely to be secondary to response competition. In contrast, studies with low-dose combinations of naloxone and CB1 receptor antagonist/inverse agonists have very recently confirmed the potential of drug polytherapies not only in appetite suppression but also in attenuating/eliminating unwanted side-effects. In sum, as BSS analysis offers a reliable means of differentiating the wheat (primary anorectics) from the chaff (secondary anorectics), it should form an integral part of early phase testing in any anti-obesity drug screening programme.", "source": "https://pubmed.ncbi.nlm.nih.gov/20214921/"}
{"doc_id": "3333180a9b1fedb5e1a21a31df3b039a", "sentence": "Pilocarpine also induced secretion at a concentration as low as 1 \u03bcM and was the most powerful secretagogue at 10 \u03bcM. Secretion was induced by carbachol at 0.1 \u03bcM , with maximum secretion at 1.0 \u03bcM.", "spans": [{"span_id": 0, "text": "Pilocarpine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "carbachol", "start": 143, "end": 152, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Cevimeline-induced monophasic salivation from the mouse submandibular gland: decreased Na+ content in saliva results from specific and early activation of Na+/H+ exchange. cevimeline and pilocarpine are muscarinic agonists used clinically to treat dry mouth. In this study, we explored fluid secretion from mouse submandibular glands to determine the mechanism of cevimeline, pilocarpine, and an experimentally used agent carbachol. cevimeline evoked almost the same amount of secretion at concentrations from 30 \u03bcM to 1 mM. Pilocarpine also induced secretion at a concentration as low as 1 \u03bcM and was the most powerful secretagogue at 10 \u03bcM. Secretion was induced by carbachol at 0.1 \u03bcM , with maximum secretion at 1.0 \u03bcM. cevimeline induced monophasic secretion at all concentrations tested, whereas higher concentrations of pilocarpine and carbachol induced secretion with variable kinetics, i.e., an initial transient high flow rate, followed by decreased secretion after 2 to 3 min. In the presence of an epithelial Na(+) channel blocker, amiloride, neither carbachol nor pilocarpine affected the Na(+) level of secreted saliva; however, it significantly increased the Na(+) content of cevimeline-induced saliva. The intracellular Ca(2+) response of acinar cells was almost identical among all three agents, although recovery after drug removal was slower for cevimeline and pilocarpine. A profound decrease in intracellular pH was observed during pilocarpine and carbachol treatment, whereas intracellular acidification induced by cevimeline was only seen in the presence of a Na(+)/H(+) exchange inhibitor. When external HCO(3)(-) was removed, cevimeline-induced saliva significantly decreased. These findings suggest that cevimeline specifically activates Na(+)/H(+) exchange and may promote Na(+) reabsorption by stabilizing epithelial sodium channel activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/21239510/"}
{"doc_id": "342b18aa94a0107a5f0487598f751b34", "sentence": "This phase II study was conducted to establish whether induction chemotherapy with carboplatin ( CBDCA ) and paclitaxel ( PTX ) plus bevacizumab prior to surgery reduces the risk of progression .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 83, "end": 94, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "paclitaxel", "start": 109, "end": 119, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "bevacizumab", "start": 133, "end": 144, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase II trial of induction chemotherapy with carboplatin and paclitaxel plus bevacizumab in patients with stage IIIA to IV nonsquamous non-small cell lung cancer. Surgery remains the best curative treatment option for non-small cell lung cancer (NSCLC), but is of benefit only to patients with localized disease. A meta-analysis showed a significant beneficial effect of induction chemotherapy on survival, but there is still no clear evidence. This phase II study was conducted to establish whether induction chemotherapy with carboplatin ( CBDCA ) and paclitaxel ( PTX ) plus bevacizumab prior to surgery reduces the risk of progression . ### methods The subjects of this study were 29 patients with treatment-naive nonsquamous NSCLC (clinical stages IIIA to IV). Patients received PTX (200\u00a0mg/m ### results The overall response rate was 72.4%. Of the 29 patients, ten underwent surgery after the induction chemotherapy and complete resection was achieved in 7 (70%). The median progression-free-survival (PFS) time and the 3-year PFS rate were 0.92\u00a0years and 16.2%, respectively. The median overall survival (OS) time and the 3-year OS rate were 1.96\u00a0years and 44.9%, respectively. ### conclusion Combined modality therapy with surgery after induction chemotherapy with CBDCA and PTX plus bevacizumab is clinically feasible and tolerable for patients with unknown or negative molecular profiles.", "source": "https://pubmed.ncbi.nlm.nih.gov/30826861/"}
{"doc_id": "8caeec4c972d1568c6153dc1fac3df09", "sentence": "In women of childbearing potential , valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage .", "spans": [{"span_id": 0, "text": "valproate", "start": 37, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "levetiracetam", "start": 71, "end": 84, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "lamotrigine", "start": 89, "end": 100, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Treatment options in juvenile myoclonic epilepsy. Juvenile myoclonic epilepsy (JME) is characterized by excellent response to treatment, if diagnosed correctly. Lifestyle advice is an integral part of the treatment of JME; it should include recommendations on avoidance of common triggers such as sleep deprivation and alcohol excess and emphasis on the importance of compliance with medication. The drug of first choice in the treatment of JME is sodium valproate, which has a response rate of up to 80%. Valproate should be avoided in women of childbearing age because of significantly increased risks of fetal malformations and neurodevelopmental delay. levetiracetam or lamotrigine are alternative first-line options if valproate is contraindicated. With limited data from trials to support either of these drugs, the choice should take into account comorbidity factors and patient priorities. Because of its low side effect profile, excellent tolerability, and lack of interactions with other drugs, levetiracetam is our preferred alternative first-line agent. lamotrigine is another first-line option but may exacerbate myoclonus. The failure of valproate or failure of two first-line antiepileptic drugs suggests that combination therapy is indicated. Drug interactions and the patient's gender, age, and comorbidities need to be considered. levetiracetam, lamotrigine, and valproate are suitable adjuncts, with a synergistic effect reported from the combination of valproate and lamotrigine. clonazepam is a useful adjunct for myoclonus and can be used in combination with lamotrigine to avoid lamotrigine's myoclonic effects. In women of childbearing potential , valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage . topiramate is a cost-effective alternative monotherapy, but because of its poor tolerability, we recommend it as add-on treatment only. zonisamide should remain a second-line adjunct in the treatment of JME, owing to the lack of supportive data. Phenobarbital is the most cost-effective drug and can be used to control the seizures of JME when antiepileptic drugs are limited or too costly. carbamazepine, oxcarbazepine, and phenytoin can exacerbate absences and myoclonus and are therefore contraindicated, although they can improve control of tonic-clonic seizures when these are refractory to other medication. gabapentin, pregabalin, tiagabine, and vigabatrin are contraindicated and can worsen seizures. (tiagabine and vigabatrin have been reported to induce absence status epilepticus.) Surgical alternatives in refractory cases are rarely contemplated but may include vagus nerve stimulation and callosotomy. Deep brain stimulation is an experimental technique that may prove useful in managing refractory cases of JME.", "source": "https://pubmed.ncbi.nlm.nih.gov/21494841/"}
{"doc_id": "f257c53b718d4eaaa73be8c3ff25c60d", "sentence": "Patients with clinically localized , intermediate- or high-grade non-Hodgkin 's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 169, "end": 185, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "doxorubicin", "start": 188, "end": 199, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "vincristine", "start": 202, "end": 213, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "prednisone", "start": 220, "end": 230, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma.  Patients with clinically localized , intermediate- or high-grade non-Hodgkin 's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) . Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. ### methods We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone. ### results Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). ### conclusions Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/9647875/"}
{"doc_id": "8b8d94ebd51dba1ac76a5865fda14eb7", "sentence": "To evaluate the effects of a fixed combination of olmesartan/amlodipine compared with olmesartan or amlodipine alone on some parameters of endothelial damage in diabetic , hypertensive patients .", "spans": [{"span_id": 0, "text": "olmesartan", "start": 86, "end": 96, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "amlodipine", "start": 100, "end": 110, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Olmesartan Combined With Amlodipine on Oxidative Stress Parameters in Type 2 Diabetics, Compared With Single Therapies: A Randomized, Controlled, Clinical Trial.  To evaluate the effects of a fixed combination of olmesartan/amlodipine compared with olmesartan or amlodipine alone on some parameters of endothelial damage in diabetic , hypertensive patients .We enrolled 221 patients; 74 were randomized to olmesartan 20\u200amg, 72 to amlodipine 10\u200amg, and 75 to olmesartan/amlodipine fixed combination 20/5\u200amg for 12 months. We assessed blood pressure monthly; in addition, we also assessed at baseline, and after 6 and 12 months, the following parameters: lipoprotein (a), myeloperoxidase (MPO), isoprostanes, and paraoxonase-1 (PON-1). Blood pressure values obtained with fixed olmesartan/amlodipine combination were significantly lower than those reached with single monotherapies. There was a reduction of lipoprotein (a), and isoprostanes levels with olmesartan/amlodipine fixed combination, both compared with baseline, and with single monotherapies. On the other hand, there was an increase of PON-1 with fixed olmesartan/amlodipine combination, both compared with baseline, and with single drugs. All treatments reduced MPO compared with baseline; however, in group-to-group comparison, MPO reduction was greater with olmesartan/amlodipine fixed combination. Fixed combination of olmesartan/amlodipine was more effective than single monotherapies in reducing oxidative stress, especially in increasing PON-1, and reducing isoprostanes levels in diabetic and hypertensive patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/27043671/"}
{"doc_id": "8ae99858bbece53f14785ea1295dd424", "sentence": "Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer ( NSCLC ) than that of both agents in monotherapy .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 90, "end": 101, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "docetaxel", "start": 107, "end": 116, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study.  Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer ( NSCLC ) than that of both agents in monotherapy . ### methods This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m(2) (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m(2) (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. ### results Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1-6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29-59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3-4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3-4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). ### conclusion gemcitabine 1,000 mg/m(2) on days 1 and 8 in combination with docetaxel 85 mg/m(2) on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/17273825/"}
{"doc_id": "b2f45e953ebd8acc0d2d99a6ed60565c", "sentence": "The use of HDCT-SCT in CNS metastases needs to be carefully considered , possibly by adding thiotepa or topotecan to improve tumor control .", "spans": [{"span_id": 0, "text": "thiotepa", "start": 92, "end": 100, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "topotecan", "start": 104, "end": 113, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Stem-Cell Therapy Following High-Dose Chemotherapy in Advanced Retinoblastoma: A Systematic Review. To analyze the risk and benefit of high-dose chemotherapy followed by stem cell transplantation (HDCT-SCT) treatment in patients with advanced retinoblastoma. ### design Systematic review. ### methods A comprehensive literature search from 4 online databases, including PubMed, Scopus, EBSCO, and Cochrane was done for original studies evaluating the use of HDCT followed by SCT in the treatment of patients with advanced retinoblastoma. The last search was performed on April 15, 2020. ### results A total of 35 studies consisting of 160 patients were considered suitable for inclusion. After HDCT-SCT treatment, 108/160 (67.5%) patients were alive with no evidence of disease at the last follow-up. The incidence of secondary malignancy in our data was also relatively low, which was 16/160 (10%) patients. The side effects were mainly hematological and gastrointestinal toxicities. The prognosis for metastatic cases especially the one to the central nervous system (CNS) remains poor, as shown in our data that 22 of 44 (50%) patients died due to the evidence of disease, and 12 of 44 (27%) patients acquired CNS relapse and died. ### conclusions HDCT-SCT is a promising treatment option in patients with advanced retinoblastoma. The use of HDCT-SCT in CNS metastases needs to be carefully considered , possibly by adding thiotepa or topotecan to improve tumor control . Further randomized clinical trials are needed to draw firm conclusion regarding its safety and efficacy.", "source": "https://pubmed.ncbi.nlm.nih.gov/33481395/"}
{"doc_id": "8030e5249393be52f9d124dfc63acd8d", "sentence": "Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors ( Cetuximab , Panitumumab , Zalutumumab ) , EGFR tyrosine kinase inhibitors ( Gefitinib , Erloitinib ) , VEGFR inhibitors ( Bevacizumab , Vandetanib ) , and various inhibitors of , e.g. , Src-family kinase , PARP , proteasome , mTOR , COX , and heat shock protein .", "spans": [{"span_id": 0, "text": "Cetuximab", "start": 109, "end": 118, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "Panitumumab", "start": 121, "end": 132, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "Zalutumumab", "start": 135, "end": 146, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "Gefitinib", "start": 185, "end": 194, "token_start": 28, "token_end": 29}, {"span_id": 4, "text": "Bevacizumab", "start": 231, "end": 242, "token_start": 36, "token_end": 37}, {"span_id": 5, "text": "Vandetanib", "start": 245, "end": 255, "token_start": 38, "token_end": 39}], "rels": [], "paragraph": "Targeted therapy in head and neck cancer. Head and neck squamous cell carcinoma (HNSCC) of multi-factorial etiopathogenesis is rising worldwide. Treatment-associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies. Molecular targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. In an attempt to improve outcomes in HNSCC, targeted therapeutic strategies have been developed. These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis. Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches. Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors ( Cetuximab , Panitumumab , Zalutumumab ) , EGFR tyrosine kinase inhibitors ( Gefitinib , Erloitinib ) , VEGFR inhibitors ( Bevacizumab , Vandetanib ) , and various inhibitors of , e.g. , Src-family kinase , PARP , proteasome , mTOR , COX , and heat shock protein . Moreover, targeted molecular therapy can also act as a complement to other existing cancer therapies. Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control, without exacerbating the treatment related toxicities. Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use, whereas remainder exhibits mixed result and necessitates further studies. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/22373581/"}
{"doc_id": "782510b8d68226471251395f40f1440b", "sentence": "We performed a retrospective analysis of 114 severely head injured patients who were admitted to the neurocritical care unit of Level 1 trauma center and who received vasopressors ( phenylephrine , norepinephrine , dopamine , vasopressin or epinephrine ) to increase blood pressure", "spans": [{"span_id": 0, "text": "phenylephrine", "start": 182, "end": 195, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "vasopressin", "start": 226, "end": 237, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "epinephrine", "start": 241, "end": 252, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Vasopressor use and effect on blood pressure after severe adult traumatic brain injury. We describe institutional vasopressor usage, and examine the effect of vasopressors on hemodynamics: heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygenation (PbtO(2)), and jugular venous oximetry (SjVO(2)) in adults with severe traumatic brain injury (TBI). ### methods We performed a retrospective analysis of 114 severely head injured patients who were admitted to the neurocritical care unit of Level 1 trauma center and who received vasopressors ( phenylephrine , norepinephrine , dopamine , vasopressin or epinephrine ) to increase blood pressure ### results phenylephrine was the most commonly used vasopressor (43%), followed by norepinephrine (30%), dopamine (22%), and vasopressin (5%). Adjusted for age, gender, injury severity score, vasopressor dose, baseline blood pressure, fluid administration, propofol sedation, and hypertonic saline infusion, phenylephrine use was associated with 8 mmHg higher mean arterial pressure (MAP) than dopamine (P = 0.03), and 12 mmHg higher cerebral perfusion pressure (CPP) than norepinephrine (P = 0.02) during the 3 h after vasopressor start. There was no difference in ICP between the drug groups, either at baseline or after vasopressor treatment. ### conclusions Most severe TBI patients received phenylephrine. Patients who received phenylephrine had higher MAP and CPP than patients who received dopamine and norepinephrine, respectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/20878264/"}
{"doc_id": "66de547f7916f338742dbd5bdb9fea53", "sentence": "While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20 % , the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 171, "end": 181, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "oxaliplatin", "start": 218, "end": 229, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "5-fluorouracil/folinic", "start": 187, "end": 209, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "5-fluorouracil/folinic", "start": 235, "end": 257, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 3], "is_context_needed": false}], "paragraph": "FOLFOX/FOLFIRI pharmacogenetics: the call for a personalized approach in colorectal cancer therapy.  While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20 % , the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival . However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/25132748/"}
{"doc_id": "ad310a73917f2a65c49f1c5740a1b604", "sentence": "Chemotherapy was given in 405 of 410 treatment periods with dacarbazine , fotemustine , vindesine , carboplatin and temozolomide in different schedules .", "spans": [{"span_id": 0, "text": "dacarbazine", "start": 60, "end": 71, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "carboplatin", "start": 100, "end": 111, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "temozolomide", "start": 116, "end": 128, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Organ- and treatment-specific local response rates to systemic and local treatment modalities in stage IV melanoma. Metastatic melanoma shows different local response rates in organs to systemic or local treatment modalities. Whereas skin, soft tissue, lymph node and lung metastases seem to have better local response rates, the local response of metastases localized in the liver, brain and bone seems to be low. ### objectives The organ-specific response rate, local response rate of each therapeutic measure and survival of 68 patients with stage IV disease were evaluated. ### methods Four hundred and ten treatment periods (1-18 per patient) in 17 different organs of 43 men and 25 women (mean age 55 years, range 19-79) with measurable, widespread, surgically incurable disease were analysed. Chemotherapy was given in 405 of 410 treatment periods with dacarbazine , fotemustine , vindesine , carboplatin and temozolomide in different schedules . Local treatment modalities comprising radiotherapy, gamma knife radiosurgery and local hyperthermia were given in 71 of 410 treatment periods. ### results Local response (complete or partial local remission) was achieved in 52 treatment periods (12.7%). When local treatment modalities, either combined with systemic therapy or not, were compared with systemic therapeutic modalities alone, a local response of 24% was achieved with local measures, compared with 10% in systemic treatment only (P = 0.003). When a spontaneous remission rate of less than 5% is considered, however, local as well as systemic treatments had a significant effect (P < 0.001). Organ-specific response rates to local therapies showed no statistically significant differences between the various organs involved. When systemic treatments without local measures were taken into account, lung metastases, cutaneous/subcutaneous metastases and adrenal metastases performed significantly better than liver metastases. When different treatment modalities were considered, there was no significant difference between the three local measures applied (radiotherapy, gamma knife radiosurgery and hyperthermia). Among the systemic therapies, dacarbazine high dose and carboplatin monochemotherapy were superior to combined regimens using fotemustine. A local response, irrespective of the mode of therapy, was significantly associated with longer survival (median 16 months) compared with no local response or local progressive disease (median 7 months; P < 0.0001). When the first treatment period of each patient was considered, local response was no longer a significant predictor. ### conclusions The study shows that local therapeutic measures are superior in inducing a local response than systemic therapies alone. Induction of remission may be associated with longer survival. Chemotherapy, despite limited local response rates, is still statistically superior to an estimated spontaneous remission rate.", "source": "https://pubmed.ncbi.nlm.nih.gov/16225601/"}
{"doc_id": "c4e685add5c386bede07d3d0e7c7d983", "sentence": "[ Effect of nedaplatin , 5-FU , and leucovorin combined with radiation therapy in unresectable esophageal carcinoma ] .", "spans": [{"span_id": 0, "text": "nedaplatin", "start": 12, "end": 22, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "leucovorin", "start": 36, "end": 46, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "5-FU", "start": 25, "end": 29, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[ Effect of nedaplatin , 5-FU , and leucovorin combined with radiation therapy in unresectable esophageal carcinoma ] . A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/12795101/"}
{"doc_id": "77936ab1257411c5c8d55a4b43f4afca", "sentence": "After 5 years , approximately 30.8 % of etanercept patients and 68.8 % of monoclonal antibody patients ( adalimumab 71.2 % ; infliximab 67.2 % ) were still being treated .", "spans": [{"span_id": 0, "text": "etanercept", "start": 40, "end": 50, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "adalimumab", "start": 105, "end": 115, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "infliximab", "start": 125, "end": 135, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Psoriatic arthritis treated by anti-TNFs: a monocentric trial of 102 cases in Auvergne, France. While several registries have already evaluated the retention of anti-TNF therapy in psoriatic arthritis (PsA), they sometimes reach divergent conclusions. Our study therefore sought to assess therapeutic retention rates and predictive factors of response in a patient cohort from Auvergne, France, followed up in routine clinical practice. ### methods Medical records of all PsA patients treated from 2002 to May 2015 were analysed. PsA diagnosis was established based on the CASPAR criteria. ### results In total, 102 patients were analysed, comprising 62 men (44.6\u00b112.6 years) and 40 women (37.8\u00b113.4). Mean PsA evolution was 2.7 years (0.8-11.2). The most common forms were peripheral (47/102, 45.1%) and mixed (46/102, 46.1%) PsA. The anti-TNF treatment initiated was etanercept in 47 cases (45.2%), adalimumab in 29 (27.9%), infliximab in 20 (19.2%), and golimumab in six [5.8%]. In 28 cases (27.4%), anti-TNF was associated with methotrexate (MTX). Overall, the median duration of anti-TNF retention was 76.5 months. The hazard ratios (HR) for treatment cessation did not significantly differ between the etanercept and monoclonal antibody groups (HR=1.35[0.96-1.93], p=0.08). After 5 years , approximately 30.8 % of etanercept patients and 68.8 % of monoclonal antibody patients ( adalimumab 71.2 % ; infliximab 67.2 % ) were still being treated . Combining with MTX did not prolong the overall retention rate (HR=0.85[0.37-1.96], p=0.71). Tobacco use was predictive of discontinuation (p=0.03). ### conclusions Our study demonstrates good anti-TNF treatment retention in PsA patients, as well as confirming the deleterious effect of smoking while providing no argument in favour of combined treatment with MTX to improve maintenance.", "source": "https://pubmed.ncbi.nlm.nih.gov/27607233/"}
{"doc_id": "bcf8beb68f7f3a805ddcdc34243375e9", "sentence": "( 4 mg/day ) ; in group 3 , 69 patients administered metformin ( 1,000 mg/day ) and rosiglitazone ( 4 mg/day ) for 6 months ,", "spans": [{"span_id": 0, "text": "metformin", "start": 53, "end": 62, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "rosiglitazone", "start": 84, "end": 97, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial. To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance. ### design Prospective randomized controlled trail. ### setting Tertiary teaching hospital. ### Patient S Obese Chinese women (body mass index [BMI] \u226525 kg/m ### Intervention S In group 1, 68 patients administered metformin (1,500 mg/day); in group 2, 67 patients administered rosiglitazone ( 4 mg/day ) ; in group 3 , 69 patients administered metformin ( 1,000 mg/day ) and rosiglitazone ( 4 mg/day ) for 6 months , all with the same diet and regular exercise lifestyle recommendation. ### Main Outcome Measure S Average menstrual interval, anthropometric measurements, androgen-related parameters, and metabolic features of insulin, carbohydrates, and lipids, with intention-to-treat analysis. ### Result S The baseline parameters showed no statistically significant differences. After the 6-month treatment, most participants showed an improved menstrual pattern. There were statistically significant decreases in acne scores, weight, BMI, waist circumference, waist-to-hip ratio, and serum testosterone. The metabolic indexes of insulin, carbohydrates, and lipids were improved obviously compared with the baseline in each group. Among the three groups, the patients administered 1,500 mg/day metformin experienced greater reductions in weight. However, the rosiglitazone users (alone or combined with metformin) showed a more notable decline in total cholesterol and triglyceride levels. ### Conclusion S Considering the benefits of metformin on weight loss, high-dose metformin (1,500 mg/day) along with lifestyle modification should be recommended for obese, insulin-resistant women with PCOS. rosiglitazone alone or combined with low-dosage metformin plus lifestyle modification should be considered for the women with abnormal lipid profiles. ### Clinical Trial Registration Number ChiCTR-TRC-13003642 (Chinese Clinical Trial Registry).", "source": "https://pubmed.ncbi.nlm.nih.gov/31718828/"}
{"doc_id": "080a1f6daab8cdd048d02a1e2eaf5a0d", "sentence": "In the intention-to-treat analysis , 57 % of patients that received tenecteplase and 53 % of patients that received alteplase reached good functional outcome ( modified Rankin Scale score of 0 - 1 ) at 3 months ( odds ratio , 1.19 ; 95 % CI , 0.68 - 2.10 ) .", "spans": [{"span_id": 0, "text": "tenecteplase", "start": 68, "end": 80, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "alteplase", "start": 116, "end": 125, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Background and Purpose- Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke. Methods- The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase. Results- The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2-6). In the intention-to-treat analysis , 57 % of patients that received tenecteplase and 53 % of patients that received alteplase reached good functional outcome ( modified Rankin Scale score of 0 - 1 ) at 3 months ( odds ratio , 1.19 ; 95 % CI , 0.68 - 2.10 ) . The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26-2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65-2.37). Conclusions- tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.", "source": "https://pubmed.ncbi.nlm.nih.gov/30602354/"}
{"doc_id": "a2068802121405329956c2ab8aeac3ce", "sentence": "The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy .", "spans": [{"span_id": 0, "text": "dexamethasone", "start": 29, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "ethinyl", "start": 47, "end": 54, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Congenital Adrenal Hyperplasia due to 17-alpha-hydoxylase/17,20-lyase Deficiency Presenting with Hypertension and Pseudohermaphroditism: First Case Report from Oman. This is the first report of congenital adrenal hyperplasia (CAH) due to combined 17\u03b1-hydroxylase/17,20 lyase deficiency in an Omani patient who was initially treated for many years as a case of hypertension. CAH is an uncommon disorder that results from a defect in steroid hormones biosynthesis in the adrenal cortex. The clinical presentation depends on the site of enzymatic mutations and the types of accumulated steroid precursors. A 22-year-old woman who was diagnosed to have hypertension since the age of 10 years who was treated with anti-hypertensive therapy was referred to the National Diabetes and Endocrine Centre, Royal Hospital, Oman. The patient also had primary amenorrhea and features of sexual infantilism. Full laboratory and radio-imaging investigations were done. Adrenal steroids, pituitary function and karyotyping study were performed and the diagnosis was confirmed by molecular mutation study. Laboratory investigations revealed adrenal steroids and pituitary hormones profile in addition to 46XY karyotype that are consistent with the diagnosis of CAH due to 17\u03b1-hydroxylase deficiency. Extensive laboratory workup revealed low levels of serum cortisol (and its precursors 17\u03b1-hydroxyprogesterone and 11-deoxycortisol), adrenal androgens (dehydroepiandrosterone sulfate and androstenedione), and estrogen (estradiol); and high levels of mineralocorticoids precursors (11-deoxycorticosterone and corticosterone) with high levels of ACTH, FSH and LH. Mutation analysis revealed CYP17A1-homozygous mutation (c.287G>A p.Arg96Gln) resulting in the complete absence of 17\u03b1-hydroxylase/17,20-lyase activity. The patient was treated with dexamethasone and ethinyl estradiol with cessation of anti-hypertensive therapy . A review of the literature was conducted to identify previous studies related to this subtype of CAH. This is the first biochemically and genetically proven case of CAH due to 17\u03b1-hydroxylase/17,20-lyase deficiency in Oman and in the Arab World described in the literature.", "source": "https://pubmed.ncbi.nlm.nih.gov/24498484/"}
{"doc_id": "b951d4bad97758b8d64e9f2a728d3f9a", "sentence": "Exposure of bss1 to clinically-used antiepileptic drugs ( phenytoin or gabapentin ) significantly reduces synchrony .", "spans": [{"span_id": 0, "text": "phenytoin", "start": 58, "end": 67, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "gabapentin", "start": 71, "end": 81, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Calcium Imaging of Neuronal Activity in Drosophila Can Identify Anticonvulsive Compounds. Although there are now a number of antiepileptic drugs (AEDs) available, approximately one-third of epilepsy patients respond poorly to drug intervention. The reasons for this are complex, but are probably reflective of the increasing number of identified mutations that predispose individuals to this disease. Thus, there is a clear requirement for the development of novel treatments to address this unmet clinical need. The existence of gene mutations that mimic a seizure-like behaviour in the fruit fly, Drosophila melanogaster, offers the possibility to exploit the powerful genetics of this insect to identify novel cellular targets to facilitate design of more effective AEDs. In this study we use neuronal expression of GCaMP, a potent calcium reporter, to image neuronal activity using a non-invasive and rapid method. Expression in motoneurons in the isolated CNS of third instar larvae shows waves of calcium-activity that pass between segments of the ventral nerve cord. Time between calcium peaks, in the same neurons, between adjacent segments usually show a temporal separation of greater than 200 ms. Exposure to proconvulsants (picrotoxin or 4-aminopyridine) reduces separation to below 200 ms showing increased synchrony of activity across adjacent segments. Increased synchrony, characteristic of epilepsy, is similarly observed in genetic seizure mutants: bangsenseless1 (bss1) and paralyticK1270T (paraK1270T). Exposure of bss1 to clinically-used antiepileptic drugs ( phenytoin or gabapentin ) significantly reduces synchrony . In this study we use the measure of synchronicity to evaluate the effectiveness of known and novel anticonvulsive compounds (antipain, isethionate, etopiside rapamycin and dipyramidole) to reduce seizure-like CNS activity. We further show that such compounds also reduce the Drosophila voltage-gated persistent Na+ current (INaP) in an identified motoneuron (aCC). Our combined assays provide a rapid and reliable method to screen unknown compounds for potential to function as anticonvulsants.", "source": "https://pubmed.ncbi.nlm.nih.gov/26863447/"}
{"doc_id": "c01c2daec942afc34c5c4f3a1dafef29", "sentence": "When compared with the combination of amphotericin B plus flucytosine , fluconazole was similarly effective in early treatment of acute and subacute disseminated candidiasis .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 38, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "flucytosine", "start": 58, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "fluconazole", "start": 72, "end": 83, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Effects of preventive, early, and late antifungal chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. To investigate the potential use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, its in vivo antifungal activity was studied in three models of disseminated candidiasis in persistently granulocytopenic rabbits: acute, subacute, and chronic disseminated candidiasis. fluconazole was compared with the combination of amphotericin B and flucytosine for preventive, early, and late treatment of disseminated candidiasis, depending on the model. fluconazole was most effective when used for preventive or early treatment of acute and subacute disseminated candidiasis. When compared with the combination of amphotericin B plus flucytosine , fluconazole was similarly effective in early treatment of acute and subacute disseminated candidiasis . When treatment was delayed 6 days after established infection, fluconazole was less active in clearing tissues in comparison with its activity in preventive and early treatment. The combination of amphotericin B plus flucytosine, however, was significantly more active than fluconazole in treatment of chronic disseminated candidiasis in all tissues. In summary, fluconazole was most effective against disseminated candidiasis in persistently granulocytopenic rabbits when used for prevention or early treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/2138654/"}
{"doc_id": "f4198d736bd1ac7d37b16e95d79eb3a8", "sentence": "Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside , vincristine , and prednisone ( ROAP ) .", "spans": [{"span_id": 0, "text": "rubidazone", "start": 97, "end": 107, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "cytosine arabinoside", "start": 112, "end": 132, "token_start": 18, "token_end": 20}, {"span_id": 2, "text": "vincristine", "start": 135, "end": 146, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "prednisone", "start": 153, "end": 163, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside , vincristine , and prednisone ( ROAP ) . We administered a combination of rubidazone, cytosine arabinoside, vincristine, and prednisone (ROAP) to 91 patients with acute myelogenous leukemia who were 50 yr of age or older. These patients had been identified in previous studies to be a group with a relatively poor prognosis. One-third of the patients had an antecedent hematologic disorder prior to treatment. Forty patients (48%) obtained a complete hematologic and clinical remission. A history of an antecedent hematologic disorder, male sex, and absence of Auer rods were adverse factors for achieving remission in this older population. More than half of the patients achieved remission in one course. The major cause of failure to obtain a remission was death due to infection, 40% of which were caused by fungi. Resistance to chemotherapy, although uncommon, was noted more frequently in patients with an antecedent hematologic disorder. Univariate and multivariate prognostic factor analysis was used to compare these patients with a historical control group treated with a program in which adriamycin was used instead of rubidazone (AdOAP). No significant difference in remission rate was detected. Cyclocytidine was used as a maintenance agent in this study, and while the median remission duration was only 37 wk, 30% of patients are expected to be in remission for 2 yr. Chemotherapy programs combining an anthracycline with cytosine arabinoside, given to older patients in similar fasion to younger patients will achieve remissions in one-half of a group of older patients. These remissions are of comparable quality to those of younger patients. Mathematical models derived from analysis of prognostic factors are of use in identifying patients likely to fail these programs who are in need of innovative approaches to treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/6942848/"}
{"doc_id": "fdcac5bfcc99b822df604cef2bffb127", "sentence": "Patients progressing after first-line chemotherapy are treated with docetaxel , pemetrexed or erlotinib .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 68, "end": 77, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "pemetrexed", "start": 80, "end": 90, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "erlotinib", "start": 94, "end": 103, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Chemotherapy of advanced non-small cell lung cancer. Patients with advanced NSCLC receive palliative chemotherapy with platinum-based doublets. Cisplatin-based doublets are preferred in patients with good performance status, whereas carboplatin-based protocols are preferred in patients with impaired organ functions (kidney, heart). Customized chemotherapy appears promising but still remains experimental. Improvements of the outcome of first-line chemotherapy have been achieved by the addition of cetuximab in patients with EGFR-positive NSCLC and of bevacizumab in selected patients with non-squamous cell NSCLC. The optimal combination of chemotherapy with targeted therapies remains a challenge. Maintenance therapy and early second-line chemotherapy might improve outcome but are not yet considered as standard treatments. Patients progressing after first-line chemotherapy are treated with docetaxel , pemetrexed or erlotinib . Finally, the efficacy of new anticancer treatments should be assessed by several clinical endpoints with overall survival remaining the most important endpoint in patients with advanced NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/19955802/"}
{"doc_id": "6c805952d028fae25b74c03c73e50488", "sentence": "To compare the therapeutic effect of \u03b1(2 ) and \u03b1(4 ) integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate , 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 131, "end": 143, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "5-aminosalicylic acid", "start": 146, "end": 167, "token_start": 21, "token_end": 23}, {"span_id": 2, "text": "azathioprine", "start": 172, "end": 184, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effective treatment of mouse experimental colitis by alpha 2 integrin antibody: comparison with alpha 4 antibody and conventional therapy.  To compare the therapeutic effect of \u03b1(2 ) and \u03b1(4 ) integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate , 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model . ### methods Colitis was induced in balb/c mice with 2.5-3.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. ### results Treatment with anti-\u03b1(2) antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-\u03b1(2) antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-\u03b1(2) antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1\u03b2 at the mRNA level, while the anti-\u03b1(2) antibody group displayed decreased protein expression of iNOS and IL-1\u03b2. ### conclusions Specific blocking of extravascular trafficking of leucocytes with \u03b1(2)-antibodies could be a new beneficial drug target in inflammatory bowel disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/23009282/"}
{"doc_id": "543d288140376a20b71334d3c0ffcfcf", "sentence": "Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 35, "end": 46, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "paclitaxel", "start": 107, "end": 117, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "paclitaxel", "start": 173, "end": 183, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "gemcitabine", "start": 207, "end": 218, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis. paclitaxel, the first member of taxanes, is one of the most active chemotherapeutic agents developed in the last decade for the treatment of advanced breast cancer and many other types of solid tumors. The promising clinical activity of paclitaxel has also promoted considerable interest in combining this drug with other anti-tumor agents. In this study, we assessed the cytotoxic interaction between paclitaxel and gemcitabine administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, DNA fragmentation, and flow cytometric analyses, we found that gemcitabine could significantly antagonize the cytotoxic effects of paclitaxel when tumor cells were exposed to the two drugs simultaneously or exposed to gemcitabine before paclitaxel. However, there was little antagonistic interaction observed when paclitaxel was administered before gemcitabine. Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine . In addition, biochemical examinations revealed that pretreatment or cotreatment of gemcitabine inhibited paclitaxel-induced IkappaBalpha degradation and bcl-2 phosphorylation that are believed to play critical roles in the signal pathways leading to apoptotic cell death. These results indicate that the interaction between paclitaxel and gemcitabine is highly schedule dependent. Exposure of tumor cells to gemcitabine before paclitaxel or two drugs simultaneously could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to paclitaxel followed by gemcitabine.", "source": "https://pubmed.ncbi.nlm.nih.gov/16855376/"}
{"doc_id": "d4af3bd7f0037132c5d1b2c3bd96e0c4", "sentence": "Standard anticonvulsants such as phenytoin , the barbiturates , carbamazepine , and the succinimides have been ineffective .", "spans": [{"span_id": 0, "text": "phenytoin", "start": 33, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "carbamazepine", "start": 64, "end": 77, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Treatment of infantile spasms. To summarize and evaluate the literature regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms. ### Data Sources A literature search of articles from January 1966 to July 1993 using MEDLINE, EM-Base, and Current Concepts/Life Sciences, as well as bibliographies of relevant articles. ### Study Selection All identified original and review publications regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms were reviewed. Emphasis was placed on original studies published since 1975. ### Data Extraction Data from published research were extracted and evaluated according to study design, sample size, dosing regimen, outcome measures, and treatment efficacy and safety. ### Data Synthesis Infantile spasms constitute a rare epileptic syndrome with a poor long-term prognosis for normal intellectual development. The spasms are characterized by a brief symmetric contraction of the muscles of the neck, trunk, and/or extremities, often occurring in a series of 2 to more than 100 spasms during a single episode. The disorder is age-specific, with the peak onset of symptoms occurring between 2 and 8 months of age. Spasms of no identifiable cause in infants with normal development prior to the onset of infantile spasms are classified as cryptogenic or idiopathic, whereas those with an identifiable cause are classified as symptomatic. Long-term prognosis is best in cryptogenic cases, with 30-70 percent attaining normal intellect compared with 5-19 percent in symptomatic cases. The etiology and pathophysiology are not well understood. Recent theory postulates that infantile spasms may be caused by an excess of corticotropin-releasing hormone activity during infancy. The suspected association between the whole-cell pertussis vaccine and infantile spasms is coincidental. Few well-designed, prospective, controlled clinical trials for the treatment of infantile spasms have been conducted. ### conclusions Standard anticonvulsants such as phenytoin , the barbiturates , carbamazepine , and the succinimides have been ineffective . Of the anticonvulsants, only the benzodiazepines, valproic acid, and vigabatrin have shown efficacy in reducing spasm frequency and severity. Hormonal therapy with adrenocorticotropic hormone (ACTH) and/or prednisone has been the most frequently studied treatment modality and appears to be the most effective. Hormonal therapy achieves complete spasm control in 50-75 percent of infants within four weeks of initiation. Opinions differ regarding the relative efficacy between ACTH and prednisone, the need for early initiation of hormonal treatment, and the benefits of high dosages of ACTH (> 40 units/d). No treatment has been shown conclusively to improve the long-term intellectual development of these infants. Neurosurgery may be the treatment of choice in select cases when a localized central nervous system abnormality can be demonstrated. Well-designed, blind, prospective clinical trials are needed to answer definitively many lingering questions regarding the treatment of infantile spasms.", "source": "https://pubmed.ncbi.nlm.nih.gov/7919570/"}
{"doc_id": "6ae0095c9a8f6cbc8960a54c0af639de", "sentence": "Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.", "spans": [{"span_id": 0, "text": "curcumin", "start": 35, "end": 43, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "doxorubicin", "start": 100, "end": 111, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells. Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin, a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore. ### methods A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, I\u03baB\u03b1 and NF\u03baB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently. ### results Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as I\u03baB\u03b1. Phosphorylated I\u03baB\u03b1 preceded release of NF\u03baB. Phospho-Akt, NF\u03baB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis. ### conclusion Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/33773562/"}
{"doc_id": "eac9584c2367a897c3d5f005ad38e353", "sentence": "Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma .", "spans": [{"span_id": 0, "text": "Daratumumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "Lenalidomide", "start": 17, "end": 29, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "Dexamethasone", "start": 34, "end": 47, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma . lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. ### methods We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. ### results At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10 ### conclusions Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).", "source": "https://pubmed.ncbi.nlm.nih.gov/31141632/"}
{"doc_id": "ad06d06e0a0caf1864998ab4d0c1f297", "sentence": "Noninferiority was concluded if the lower limit of the 2-sided 95 % CI for the difference ( doripenem minus meropenem ) in the proportion of patients classified as clinical cures was > or=-15 % .", "spans": [{"span_id": 0, "text": "doripenem", "start": 92, "end": 101, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "meropenem", "start": 108, "end": 117, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Complicated intra-abdominal infections (cIAIs) require surgical intervention and empiric antibacterial therapy. doripenem, a broad-spectrum carbapenem, provides coverage of key gram-negative and -positive aerobes and anaerobes encountered in cIAI. ### objective This study was designed to compare the efficacy and safety profile of doripenem and meropenem in hospitalized adult patients with cIAI. ### methods In this prospective, multicenter, doubleblind, noninferiority study, hospitalized adults with cIAI were randomly assigned to receive doripenem 500 mg IV q8h or meropenem 1 g IV q8h. After a minimum of 9 doses and adequate clinical improvement (relative to before the start of IV study drug, decreased body temperature and white blood cell count, improved or absent signs and symptoms of cIAI, and return of normal bowel function), patients could be switched to oral amoxicillin/clavulanate. Antibacterial therapy (IV plus subsequent oral) was given for a total of 5 to 14 days. The coprimary efficacy end points were the clinical cure rate (complete resolution or significant improvement of signs or symptoms of the index infection) in patients microbiologically evaluable (>or=1 baseline pathogen isolated from an intra-abdominal culture that was susceptible to both IV study drug therapies) at the test-of-cure (TOC) visit (21-60 days after the completion of study drug therapy) and the clinical cure rate in the microbiological modified intent-to-treat (mMITT) population (a bacterial pathogen identified at baseline, regardless of its susceptibility to the study drug). Noninferiority was concluded if the lower limit of the 2-sided 95 % CI for the difference ( doripenem minus meropenem ) in the proportion of patients classified as clinical cures was > or=-15 % . ### results A total of 476 patients were enrolled. The microbiologically evaluable population (319 patients) was 62.7% male and 67.7% white, with a mean age and weight of 46.7 years and 77.2 kg, respectively. In this population, doripenem and meropenem were associated with clinical cure rates at the TOC visit of 85.9% and 85.3%, respectively. The corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%); this difference was not statistically significant. Similarly, in the mMITT population (385 patients), the clinical cure rates were 77.9% and 78.9%, respectively, and the corresponding 1.0% treatment difference was not statistically significant (95% CI, -9.7% to 7.7%). Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site). Microbiological eradication rates for common pathogens isolated at study entry were not significantly different between the 2 treatment groups. doripenem was well tolerated in the population studied. In the intent-to-treat population (471 patients), 83.0% and 78.0% of patients experienced >or=1 adverse event (AE) and 13.2% and 14.0% experienced >or=1 serious AE in the doripenem and meropenem treatment arms, respectively. In the doripenem and meropenem treatment arms, AEs resulted in study drug discontinuation in 5.1% and 2.1% of patients and death in 2.1% and 3.0% of patients, respectively. ### conclusions The present study found that doripenem (500 mg q8h) was effective in the treatment of cIAI, was therapeutically noninferior to meropenem (1 g q8h), with a safety profile not significantly different from that of meropenem in this selected population of patients with cIAI.", "source": "https://pubmed.ncbi.nlm.nih.gov/18555934/"}
{"doc_id": "a6b383436a2def1c9d1067bc8d6224bd", "sentence": "We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 156, "end": 165, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "pembrolizumab", "start": 169, "end": 182, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. : Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab . A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments. ### Implications For Practice Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types.", "source": "https://pubmed.ncbi.nlm.nih.gov/27401894/"}
{"doc_id": "1907ac711e449549c62aa9eaa1332cb9", "sentence": "Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 29, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "paclitaxel", "start": 45, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "lonafarnib", "start": 72, "end": 82, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV . This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS). ### Patients And Methods We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy. ### results 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)). ### conclusion The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.", "source": "https://pubmed.ncbi.nlm.nih.gov/22564713/"}
{"doc_id": "414a3e5812a4517cf6870ce0c8570e17", "sentence": "One subject who received oxaprozin for 12 days and , in addition , aspirin for the last five days developed a rash that subsided after both drugs were discontinued ; one subject treated with aspirin experienced tinnitus .", "spans": [{"span_id": 0, "text": "oxaprozin", "start": 25, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "aspirin", "start": 67, "end": 74, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "aspirin", "start": 191, "end": 198, "token_start": 34, "token_end": 35}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Effects of oxaprozin alone or in combination with aspirin on hemostasis and plasma protein binding. oxaprozin, a new nonsteroidal antiinflammatory agent, was studied alone and in combination with aspirin for its effects on hemostasis and protein binding in 10 healthy adults. When both oxaprozin and aspirin were given separately for seven days and in combination for five days, both drugs prolonged bleeding time and inhibited collagen- and epinephrine-induced platelet aggregation to a similar degree. The effects of the combination of oxaprozin and aspirin were not additive. The data from the protein binding study showed that oxaprozin was more than 99 per cent bound to plasma proteins. aspirin displaced oxaprozin from its binding sites. As a result, the rate of plasma clearance of oxaprozin significantly increased from 20 to 26 ml/min/kg (P less than 0.05), and the plasma half-life decreased from 45 to 40 hours. Platelet count and the humoral clotting mechanism were not affected by either drug alone or in combination. There was no clinical evidence of bleeding. One subject who received oxaprozin for 12 days and , in addition , aspirin for the last five days developed a rash that subsided after both drugs were discontinued ; one subject treated with aspirin experienced tinnitus . These data suggest that oxaprozin, like aspirin and other nonsteroidal antiinflammatory drugs, should be used with caution when administered to patients who have suffered trauma, who undergo surgery, or who have known defects in hemostasis.", "source": "https://pubmed.ncbi.nlm.nih.gov/6863578/"}
{"doc_id": "85712f0944108b11c6b5f2c0e8251f98", "sentence": "To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis ( MDRTB ) after undergoing solid organ transplantation .", "spans": [{"span_id": 0, "text": "pyrazinamide", "start": 74, "end": 86, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "levofloxacin", "start": 91, "end": 103, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population.  To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis ( MDRTB ) after undergoing solid organ transplantation . ### design Retrospective analysis. ### setting Community outpatient clinic. ### patients Forty-eight recipients of solid organ transplants beginning prophylaxis for MDRTB during August 1999 after possible exposure to a single index case of multidrug-resistant Mycobacterium tuberculosis within our community ### intervention Prophylaxis consisted of pyrazinamide 30 mg/kg/day plus levofloxacin 500 mg/day, administered for 1 year. ### Measurements And Main Results Thirteen (27.1%) of the 48 patients completed therapy; 27 (56.3%) discontinued therapy within 4 months due to adverse drug events. Gastrointestinal intolerance was the major adverse event resulting in early discontinuation. ### conclusion Prophylaxis of MDRTB with levofloxacin and pyrazinamide was associated with limited tolerability due to the high frequency of adverse events. While we search for a better tolerated prophylactic regimen, close monitoring for adverse reactions is recommended.", "source": "https://pubmed.ncbi.nlm.nih.gov/12066961/"}
{"doc_id": "e13b097056767107755caa524612eabc", "sentence": "Additive effect of the combination of griseofulvin and ketoconazole against Microsporum canis in vitro .", "spans": [{"span_id": 0, "text": "griseofulvin", "start": 38, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "ketoconazole", "start": 55, "end": 67, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Additive effect of the combination of griseofulvin and ketoconazole against Microsporum canis in vitro . The susceptibility of 28 strains of Microsporum canis to griseofulvin, to ketoconazole and to a combination of both antifungal drugs was determined. griseofulvin proved to be more active than ketoconazole. The combination of both antifungal agents was found to exert an additive effect.", "source": "https://pubmed.ncbi.nlm.nih.gov/2608097/"}
{"doc_id": "78699e90df5077a96bf93983a2dc5f1e", "sentence": "Aprepitant plus ondansetron may increase acute-CR , may have benefit regarding CINV 's effect on QoL , and is safe for 5-day temozolomide compared to ondansetron .", "spans": [{"span_id": 0, "text": "Aprepitant", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "ondansetron", "start": 16, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "temozolomide", "start": 125, "end": 137, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "ondansetron", "start": 150, "end": 161, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide. CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. ### methods One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200\u00a0mg/m ### results Patients were 61% male, 97% white, 48% with KPS >\u200990%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p\u2009=\u20090.056). Treatment-related toxicities were mild or moderate in severity. ### conclusions Aprepitant plus ondansetron may increase acute-CR , may have benefit regarding CINV 's effect on QoL , and is safe for 5-day temozolomide compared to ondansetron . This study provides no evidence that aprepitant increases CC rate over ondansetron alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/31440823/"}
{"doc_id": "04b11f4bbe48e806b7a55b77e37e351a", "sentence": "Finally , a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide , which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function .", "spans": [{"span_id": 0, "text": "lenalidomide", "start": 128, "end": 140, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "daratumumab", "start": 249, "end": 260, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis. Also in an ex vivo setting, IPH2102 synergistically improved daratumumab-dependent lysis of primary myeloma cells in bone marrow mononuclear cells (n=21), especially in patients carrying the Fc\u03b3RIIIa-158F allele or the Fc\u03b3RIIa-131R allele, who bind IgG1 with lower affinity than patients carrying the Fc\u03b3RIIIa-158V allele or the Fc\u03b3RIIa-131H allele. Finally , a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide , which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function .", "source": "https://pubmed.ncbi.nlm.nih.gov/25510242/"}
{"doc_id": "f3d33152454e31c6b54af84d22ec03f9", "sentence": "Both liposomal doxorubicin ( LD ) and docetaxel ( D ) have a broad range of activity against solid tumors , including advanced pancreatic cancer ( APC ) , as single agents , while their combination has produced encouraging response rates in the treatment of several malignancies .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 15, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "docetaxel", "start": 38, "end": 47, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A phase-II study of liposomal doxorubicin and docetaxel in patients with advanced pancreatic cancer.  Both liposomal doxorubicin ( LD ) and docetaxel ( D ) have a broad range of activity against solid tumors , including advanced pancreatic cancer ( APC ) , as single agents , while their combination has produced encouraging response rates in the treatment of several malignancies . We have conducted a Phase-II study in order to evaluate the tolerance and efficacy of their combination as front-line treatment in patients with APC. ### Patients And Methods Twenty-one chemotherapy-na\u00efve patients with unresectable, locally-advanced or metastatic pancreatic cancer were enrolled. These included 16 males and 5 females with median age 66 years (range 57-80). Performance status (PS) was 0 (n = 10 pts), 1 (n = 7 pts) and 2 (n = 4 pts). D (80 mg/m2), and LD (30 mg/m2) were administered on day 1, every 3 weeks. RhG-CSF s.c. was given to all patients. At the time of analysis, all included patients were evaluated for toxicity and for response. ### results A total of 92 cycles were administered (4.38 cycles/patient). Partial response was achieved in 6 patients, with a median duration of response of 3 months. Stable disease was observed in 7 patients and progressive disease in 8 patients. The median duration of survival was 10 months (95% CI, 6-14 months) and the actuarial 1-year survival rate was 33.33%. With regard to toxicity, grades 3,4 neutropenia occurred in 8 (38%) patients and grades 3,4 thrombocytopenia in 4 (19%) patients. Non-hematological toxicity was recorded in 15 (71%) patients: grades 3,4 diarrhea (3 pts, 14%), hypersensitivity reactions (3 pt, 14%), grade 2 neurotoxicity (6 pts, 29%) and palmar-plantar erythrodysesthesia (9 pts, 43%). ### conclusion The doxorubicin and docetaxel combination was well-tolerated by these poor prognosis patients. Although both drugs have a marginal activity in pancreatic cancer, most patients experienced significant clinical improvement, with acceptable toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/12552960/"}
{"doc_id": "457ab486b502454d826a4ff1764c5a89", "sentence": "Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer .", "spans": [{"span_id": 0, "text": "ranitidine", "start": 20, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "lansoprazole", "start": 34, "end": 46, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer . The aim of this study was to verify the efficacy--in the cure of duodenal ulcer associated H. pylori infection--of ranitidine 300 mg taken late in the evening or lansoprazole 30 mg taken before breakfast, coupled with clarithromycin and metronidazole. ### methods Eighty patients with endoscopically proven active duodenal ulcer were randomized to take ranitidine or lansoprazole for 4-8 wk, together with clarithromycin 250 mg b.i.d. and metronidazole 500 mg b.id. for the first 2 wk. Endoscopic controls, as well as histological and urease tests for H. pylori, were performed at entry and after 4 and 8 wk. ### results According to intent-to-treat analysis, ulcers were healed after 4 wk in 36/40 patients (90%) with ranitidine and in 38/40 (95%) with lansoprazole. After 8 wk, the healing percentage with ranitidine and lansoprazole was 97% (39/40) and 95% (38/40), respectively. H. pylori was eradicated in 85% of the patients taking ranitidine and in 90% of those taking lanzoprazole. Side effects were reported in 25% of the patients in both groups. ### conclusions Our results confirm that the combination of ranitidine, clarithromycin, and metronidazole can be considered an alternative to proton pump inhibitors in terms of clinical efficacy and economy.", "source": "https://pubmed.ncbi.nlm.nih.gov/9128316/"}
{"doc_id": "2ee98ff750189143f9fb1bb9c9fb70ff", "sentence": "A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats .", "spans": [{"span_id": 0, "text": "cimetidine", "start": 25, "end": 35, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "L-carnitine", "start": 40, "end": 51, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats . Myoglobinuric acute renal failure is the most important life threatening complication of rhabdomyolysis. Iron, free radicals, nitric oxide and cytochrome p450 are involved in the pathogenesis of mARF. The aim of this study is to compare the effect of cimetidine, l-carnitine and both agents together on mARF in rats. Forty rats were divided into 5 groups; group I: control rats, group II: myoglobinuric ARF rats, group III: mARF rats received l-carnitine (200mg/kg, i.p.), group IV: mARF rats received cimetidine (150mg/kg i.p.) and group V: mARF rats received both agents together. 48h after glycerol injection, systolic blood pressure was measured. Urine and blood samples were collected to evaluate urine volume, GFR, BUN, creatinine, K, Na, serum creatine kinase, NO and glutathione levels. Kidney specimens were taken to investigate renal cytochrome p450 and for histological examinations. cimetidine treatment significantly decreased creatinine, BUN, K, Na, SBP and creatine kinase and increased GFR and urine volume compared to group II. l-carnitine exerted similar changes except for the effect on K and GFR. NO was significantly decreased, while renal glutathione and cytochrome p450 were significantly increased in groups treated with l-carnitine or cimetidine as compared to group II. Combined treatment further improved renal functions, creatine kinase, oxidative stress parameters and SBP as compared to each therapy alone. The histological changes confirmed the biochemical findings. cimetidine and l-carnitine have protective effects - almost equally - against mARF. Using both agents together, minimises the renal injury.", "source": "https://pubmed.ncbi.nlm.nih.gov/25930980/"}
{"doc_id": "c621f4b107fb4febd9bfe51738cd297d", "sentence": "Importantly , MAPK and/or MTOR complex1 ( MTORC1 ) activity were upregulated in AML cells made resistant to several FLT3 inhibitors , including crenolanib , quizartinib , or sorafenib .", "spans": [{"span_id": 0, "text": "crenolanib", "start": 144, "end": 154, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "quizartinib", "start": 157, "end": 168, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "sorafenib", "start": 174, "end": 183, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia. Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly , MAPK and/or MTOR complex1 ( MTORC1 ) activity were upregulated in AML cells made resistant to several FLT3 inhibitors , including crenolanib , quizartinib , or sorafenib . These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.", "source": "https://pubmed.ncbi.nlm.nih.gov/33375770/"}
{"doc_id": "d39a99792670b3843d6e896df08acb30", "sentence": "We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts .", "spans": [{"span_id": 0, "text": "varenicline", "start": 18, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "nicotine", "start": 42, "end": 50, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit: a randomized placebo-controlled trial. nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking. We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts . ### methods This randomized, placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month. Participants used varenicline (2 mg/day) or placebo for 2-8 weeks plus received brief counseling on methods to reduce cigarettes/day. The primary measure was the incidence of a quit attempt within 6 months of study entry. Secondary measures were point prevalence abstinence, motivation to stop smoking, and reduction in cigarettes/day. ### results varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site (73% vs. 41%; p < .001) but not at the Vermont site (45% vs. 51%; p = .45). varenicline increased most other measures of quit attempts, motivation and abstinence, independent of site. The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day, dependence, craving, and cigarette satisfaction. varenicline had a greater effect on quit attempts in less-dependent smokers, in minority smokers, and in those who had less prior cessation or reduction activity. Adverse events were minimal. ### conclusions varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site. This appeared to be due to decreasing cigarettes/day and level of dependence.", "source": "https://pubmed.ncbi.nlm.nih.gov/21652735/"}
{"doc_id": "666c22926567c3b45e26c9e0effa533e", "sentence": "However , combination of pioglitazone and sulfasalazine has shown greater efficacy .", "spans": [{"span_id": 0, "text": "pioglitazone", "start": 25, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "sulfasalazine", "start": 42, "end": 55, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Comparative evaluation of different doses of PPAR-\u03b3 agonist alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats. Inflammatory bowel disease (IBD) is an idiopathic, chronic inflammatory condition, which affects the gastrointestinal tract and has no curative treatment. The present study aimed to investigate the effect of different doses of pioglitazone alone and in combination with sulfasalazine in TNBS (trinitrobenzenesulfonic acid)-induced inflammatory bowel disease (IBD) in rats. ### methods A total of 36 animals were included in the study. Animals were divided into five groups (n = 6): group I--vehicle (ethanol), group II--TNBS + ethanol, group IIIA--TNBS + pioglitazone (15 mg/kg), group IIIB--TNBS + pioglitazone (30 mg/kg), group IV--TNBS + sulfasalazine (360 mg/kg), group V--TNBS + sulfasalazine (360 mg/kg) + pioglitazone (least effective dose found in group III). Group III was divided into two subgroups, namely IIIA and IIIB, on the basis of different doses of pioglitazone used. After completion of two weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay and TNF-\u03b1 estimation. ### results All the drug-treated groups showed both gross morphological and microscopic score either 1 or 2. None of them showed score of > 2 on both gross and microscopic morphological examination. Both MDA levels and MPO activity were significantly reduced in the drug-treated groups, with maximum reduction seen in the combination group. TNF-\u03b1 was reduced in pioglitazone group. It was highly reduced in sulfasalazine group (group V) as compared to TNBS group thereby indicating that pioglitazone is protective in TNBS-induced inflammatory bowel disease. ### conclusion The present study showed reduction in lipid peroxidation, malondialdehyde levels and TNF-\u03b1 levels in pioglitazone-treated group and hence, there was significant improvement in gross and microscopic features, too. However , combination of pioglitazone and sulfasalazine has shown greater efficacy .", "source": "https://pubmed.ncbi.nlm.nih.gov/24145089/"}
{"doc_id": "2818609aab66d157161aa1f06d272dd5", "sentence": "At time 2 , genotypic resistance to zidovudine was found in 11 out of 12 cases ( 41L : two cases ; 41L , 215Y : six cases ; 41L , 210W , 215Y : two cases ; M41L , D67N , L210W , T215Y : one case ) with a mean 18.9 + /- 8.8-fold increase in the IC50 to zidovudine and 1.4 + /- 0.4-fold to stavudine", "spans": [{"span_id": 0, "text": "zidovudine", "start": 36, "end": 46, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "zidovudine", "start": 252, "end": 262, "token_start": 61, "token_end": 62}, {"span_id": 2, "text": "stavudine", "start": 288, "end": 297, "token_start": 68, "token_end": 69}], "rels": [], "paragraph": "Phenotypic and genotypic resistance to nucleoside reverse transcriptase inhibitors in HIV-1 clinical isolates. To assess phenotypic and genotypic cross-resistance to nucleoside reverse transcriptase inhibitors in patients treated with a combination including zidovudine, who were switched to a combination including stavudine. ### methods We analysed 24 clinical HIV-1 isolates from 12 patients before and several months after therapeutic switching. Plasma HIV-1 RNA was measured using quantitative polymerase chain reaction (Roche). Genotypic resistance was measured by sequencing the reverse transcriptase gene from plasma HIV-1 RNA. Phenotypic resistance was measured using a recombinant assay (Virco). ### results Patients were treated with a combination including zidovudine for a mean (+/- SEM) period of 21.8 +/- 3.5 months and had a plasma viral load of 4.1 +/- 0.2 log HIV-1 RNA copies/mL (time 1). After a mean period of 19.3 +/- 1.6 months following the therapeutic change, the plasma viral load was 3.6 +/- 0.1 log copies/mL (time 2). At time 1, genotypic resistance to zidovudine was found in all cases (41L: four cases; 41L, 215Y: five cases; 41L, 210W, 215Y: two cases; K70R: one case) with a mean 6.6 +/- 1.6-fold increase in the median inhibitory concentration (IC50) to zidovudine and 1.7 +/- 0.4-fold to stavudine. At time 2 , genotypic resistance to zidovudine was found in 11 out of 12 cases ( 41L : two cases ; 41L , 215Y : six cases ; 41L , 210W , 215Y : two cases ; M41L , D67N , L210W , T215Y : one case ) with a mean 18.9 + /- 8.8-fold increase in the IC50 to zidovudine and 1.4 + /- 0.4-fold to stavudine ### conclusions In this clinical series of patients with suboptimal control of plasma HIV-1 RNA using a combination including zidovudine, the presence of zidovudine-related mutations was associated with a decreased phenotypic sensitivity to this drug. Despite persistent HIV-1 replication, switching to stavudine was associated with a further decrease in phenotypic sensitivity to zidovudine but not to stavudine after 19 months. These data suggest that stavudine remains a possible option in zidovudine-experienced patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/11737402/"}
{"doc_id": "c000680082dd039500d99d2aaec21834", "sentence": "Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin , 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis .", "spans": [{"span_id": 0, "text": "Sorafenib", "start": 18, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "Oxaliplatin", "start": 82, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "5-Fluorouracil", "start": 96, "end": 110, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "Leucovorin", "start": 115, "end": 125, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin , 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis . sorafenib is recommended for the first-line treatment of advanced hepatocellular carcinoma (HCC). However, the median progression-free survival (PFS) of patients with HCC and major portal vein tumor thrombosis treated with sorafenib monotherapy is no more than 3\u00a0months. A prospective single-arm phase II study was conducted to determine whether adding hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin to sorafenib could improve on these results. ### methods Thirty five patients were treated with sorafenib 400\u00a0mg orally twice a day, oxaliplatin 85\u00a0mg/m ### results The 3-, 6-, and 12-month PFS rates were 82.9, 51.4, and 22.9%, respectively. The median PFS and overall survival was 6.7 and 13.2\u00a0months, respectively. The objective response rate was 40%, and the disease control rate was 77.1% by RECIST criteria. Five (14.3%) patients achieved conversion to complete resection after the study treatment, and one of them experienced a pathological complete response. Treatment-related deaths did not occur. Grade 3-4 toxicities consisted of increases in aspartate aminotransferase (31.4%), hand-foot syndrome (17.1%), thrombocytopenia (14.3%), and neutropenia (8.6%). ### conclusions The combination treatment met the pre-specified end point of a 3-month progression free survival rate exceeding 65% and was clinical tolerable. The merits of this approach need to be established with a phase III trial. Clinical trial number http://ClinicalTrials.gov (No. NCT02981498).", "source": "https://pubmed.ncbi.nlm.nih.gov/29327075/"}
{"doc_id": "238e1815e2b060ff8c3b2f516404af28", "sentence": "Sprague-Dawley male rats were treated with levodopa ( LD ) , betaine ( Bet ) , levodopa plus betaine ( LD/Bet ) , levodopa plus benserazide ( LD/Ben ) , levodopa plus betaine-benserazide ( LD/Bet-Ben ) , and the controls with vehicle for 10 consecutive days , orally .", "spans": [{"span_id": 0, "text": "levodopa", "start": 43, "end": 51, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "betaine", "start": 61, "end": 68, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "levodopa", "start": 79, "end": 87, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "betaine", "start": 93, "end": 100, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "levodopa", "start": 114, "end": 122, "token_start": 23, "token_end": 24}, {"span_id": 5, "text": "benserazide", "start": 128, "end": 139, "token_start": 25, "token_end": 26}, {"span_id": 6, "text": "levodopa", "start": 153, "end": 161, "token_start": 30, "token_end": 31}, {"span_id": 7, "text": "betaine-benserazide", "start": 167, "end": 186, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [4, 5], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3, 6, 7], "is_context_needed": true}], "paragraph": "Betaine protects cerebellum from oxidative stress following levodopa and benserazide administration in rats. The aim of the present study was to evaluate antioxidant and methyl donor effects of betaine in cerebellum following levodopa and benserazide administration in rats. ### Materials And Methods Sprague-Dawley male rats were treated with levodopa ( LD ) , betaine ( Bet ) , levodopa plus betaine ( LD/Bet ) , levodopa plus benserazide ( LD/Ben ) , levodopa plus betaine-benserazide ( LD/Bet-Ben ) , and the controls with vehicle for 10 consecutive days , orally . ### results Treatment of rats with LD and benserazide significantly increased total homocysteine in plasma of the LD/Ben group when compared to the other groups. Lipid peroxidation of cerebellum increased significantly in LD-treated rats when compared to the other groups. In contrast, glutathione peroxidase activity and glutathione content in cerebellum were significantly higher in the betaine-treated rats when compared to the LD and LD/Ben groups. Serum dopamine concentration increased significantly in LD-treated rats in comparison with the LD/Ben group. LD/Bet-treated rats also demonstrated significantly higher dopamine levels when compared to the LD/Ben group. ### conclusion We observed valuable effects of Bet in combination with LD and benserazide, which routinely were used for Parkinson's disease (PD) treatment, in experimentally-induced oxidative stress and hyperhomocysteinemia in rats. Therefore, it seems that Bet is a vital and promising agent regarding PD for future clinical trials in humans.", "source": "https://pubmed.ncbi.nlm.nih.gov/26730328/"}
{"doc_id": "67d41e07c43f910f0d11c74aee20802b", "sentence": "We designed a phase I trial to determine the maximum-tolerated dose ( MTD ) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies .", "spans": [{"span_id": 0, "text": "Cixutumumab", "start": 127, "end": 138, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "temsirolimus", "start": 159, "end": 171, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose ( MTD ) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies . A 3 + 3 Phase I design was chosen. Temsirolimus and cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34-72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.", "source": "https://pubmed.ncbi.nlm.nih.gov/23605083/"}
{"doc_id": "9579ba27f569c40ef0d7c0cb5560f8a8", "sentence": "Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole , 31 % received itraconazole alone , and 7 % received an amphotericin B-containing product only .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 66, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "itraconazole", "start": 112, "end": 124, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "itraconazole", "start": 141, "end": 153, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "amphotericin", "start": 182, "end": 194, "token_start": 27, "token_end": 28}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. To our knowledge, an institutional review of systemic histoplasmosis has not been conducted in the United States since the major outbreaks in Indianapolis in 1978-4982. We conducted a retrospective review of all patients with systemic histoplasmosis diagnosed at Mayo Clinic over a 15-year period. The case definitions employed were based on an international consensus statement by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG). One hundred eleven patients with systemic histoplasmosis were identified between January 1, 1991, and December 31, 2005. Of these, 78 patients had disseminated histoplasmosis and 55 patients had Histoplasma capsulatum fungemia. The mean age of patients was 55 years, 66% were male, and 98% were white. Fifty-nine percent of patients were immunocompromised. Fever was the most frequently reported symptom (63%), followed by respiratory complaints (43%) and weight loss (37%). The peripheral white blood cell count was <3000 cells/mm in 28%, hemoglobin was <10 g/dL in 29%, and platelet count was <150,000 cells/mm in 41% of patients. Liver enzymes were elevated (alanine aminotransferase >60 U/L in 39%, aspartate aminotransferase >60 U/L in 27%), alkaline phosphatase was >200 U/L in 55%, and albumin was <3.5 g/dL in 70%. Serologic and histopathologic examinations were each positive in 75% of cases, Histoplasma urine antigen screening was positive in 80%, and H. capsulatum was culture positive in 84%. Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole , 31 % received itraconazole alone , and 7 % received an amphotericin B-containing product only . Another 13% of patients did not receive antifungal treatment, and the remaining 2% did not have treatment data available. Sixty percent of patients required hospitalization, and in hospital mortality was 6% with a median survival time of 61 days. The relapse rate was 9%, with a median relapse-free survival of 857 days. Systemic histoplasmosis should be suspected in patients who have lived in endemic areas with fever, bone marrow suppression, and elevated hepatic enzymes, particularly if they are immunocompromised. Evaluation including a combination of Histoplasma serologic screening, urine antigen assay, and fungal culture will secure the diagnosis in most cases.", "source": "https://pubmed.ncbi.nlm.nih.gov/17505255/"}
{"doc_id": "9258ab4aee8b8684decb3d3c05c37ba1", "sentence": "From August 2008 to May 2011 , consecutive chemo-na\u00efve patients with stage IV non-squamous non-small cell lung cancer ( NSCLC ) received pemetrexed 500mg/m(2 ) , oxaliplatin 100mg/m(2 ) and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles , in the outpatient setting .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 137, "end": 147, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "oxaliplatin", "start": 162, "end": 173, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "bevacizumab", "start": 190, "end": 201, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Pemetrexed, oxaliplatin and bevacizumab as first-line treatment in patients with stage IV non-small cell lung cancer. oxaliplatin has less haematological toxicity than cisplatin and carboplatin. The combination of pemetrexed, oxaliplatin and bevacizumab appeared well tolerated and active as second- or third-line treatment in a previous phase II study. Its role as first-line therapy remains to define. ### Patients And Methods From August 2008 to May 2011 , consecutive chemo-na\u00efve patients with stage IV non-squamous non-small cell lung cancer ( NSCLC ) received pemetrexed 500mg/m(2 ) , oxaliplatin 100mg/m(2 ) and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles , in the outpatient setting . Maintenance therapy including pemetrexed and bevacizumab was given to patients with non-progressive disease. The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, progression-free survival (PFS) and overall survival (OS). ### results Thirty-eight patients (50% males, median age: 55 years, range 38-76) received a total of 199 cycles (median per patient: 6, range 2-6), plus 98 cycles of maintenance therapy. Twenty patients (52.6%) had a PS of 2, and 6 (15.8%) had brain metastases. The most frequent toxicities were hypertension (all grades: 42.1%) and peripheral neuropathy (grade 2-3: 21.1%). Haematological toxicities included grade 4 neutropenia, grade 3 anaemia and thrombopenia (5.3% each). Neither febrile neutropenia nor arterial thrombo-embolic event occurred. The objective response rate was 55.3% (95%CI: 39.5-71.1). The median PFS and OS were 6.2 (95%CI: 5.4-9.0) and 14.6 (95%CI: 9.8-19.5) months, respectively. ### conclusions In this single centre experience, the combination of pemetrexed, oxaliplatin and bevacizumab was well tolerated and had promising activity as first-line therapy in unselected patients with stage IV non-squamous NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/22364783/"}
{"doc_id": "dc679fbc5a8701077814b90e659e7955", "sentence": "To determine if antiseptic central venous catheters impregnated with silver sulfadiazine and chlorhexidine ( antiseptic ) reduce bacterial adherence and biofilm formation without producing local or systemic toxicity .", "spans": [{"span_id": 0, "text": "sulfadiazine", "start": 76, "end": 88, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "chlorhexidine", "start": 93, "end": 106, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Decreased bacterial adherence and biofilm formation on chlorhexidine and silver sulfadiazine-impregnated central venous catheters implanted in swine.  To determine if antiseptic central venous catheters impregnated with silver sulfadiazine and chlorhexidine ( antiseptic ) reduce bacterial adherence and biofilm formation without producing local or systemic toxicity . ### design Prospective, randomized, controlled trial. ### setting Experimental laboratory in a university teaching hospital. ### subjects Ten outbred New Hampshire pigs. ### interventions Nonimpregnated (control) and antiseptic-impregnated catheters were inserted intravascularly into swine for 7 days. After explantation, the catheters were assessed for bacterial adherence and biofilm formation, and the surrounding tissue was assessed for signs of toxicity. Before retrieval, systemic concentrations of antimicrobials were determined. ### Measurements And Main Results Sequential roll plate and centrifuging were used to detect moderately and tightly adherent bacteria on the outer and luminal surfaces of the catheter. The presence of biofilm was detected by scanning electron microscopy. Tissues surrounding the catheters were examined histopathologically; systemic concentrations of chlorhexidine, sulfadiazine, and silver were determined by atomic absorption and high-performance liquid chromatography. As compared with the controls, antiseptic catheters had significantly (p < .01) fewer moderately and tightly adherent bacteria on outer and luminal surfaces, and fewer adherent bacteria when outer surfaces alone were examined (p < .01). Scanning electron microscopy showed bacterial biofilm and adherence on the control catheters but not on the antiseptic catheters. There were no abnormal histopathologic changes associated with the test catheter, and serum concentrations of the antibacterial agents were shown to be within nontoxic ranges. ### conclusion The antiseptic-impregnated catheters prevented bacterial adherence and biofilm formation and produced no local or systemic toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/7736748/"}
{"doc_id": "b4f6178a851fbb8ac91841c9d9abd82d", "sentence": "In multivariate analysis , LDP and LAP were significantly associated with stavudine ( d4 T ) use , while LAP was also associated with zidovudine ( ZDV ) treatment .", "spans": [{"span_id": 0, "text": "stavudine", "start": 74, "end": 83, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "zidovudine", "start": 134, "end": 144, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition. This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. ### methods We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. ### results According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis , LDP and LAP were significantly associated with stavudine ( d4 T ) use , while LAP was also associated with zidovudine ( ZDV ) treatment . There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. ### conclusions The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.", "source": "https://pubmed.ncbi.nlm.nih.gov/11737398/"}
{"doc_id": "3312c85c700cfa1e3aa5d494128f7a6f", "sentence": "KARs , new semisynthetic antitumor bis-indole derivatives , were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine , used in chemotherapy .", "spans": [{"span_id": 0, "text": "vinblastine", "start": 139, "end": 150, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "vincristine", "start": 154, "end": 165, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y.  KARs , new semisynthetic antitumor bis-indole derivatives , were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine , used in chemotherapy . Here, we compare the effect of KARs with those of vinblastine and vincristine on cell viability, cell proliferation, and cell cycle in neuroblastoma cell line (SH-SY5Y). At concentrations of the different compounds equivalent in causing 50% of inhibition of cell growth, KARs induced a complete arrest in the G2/M phase, whereas vinblastine and vincristine induced a partial arrest in both G0/G1 and G2/M. Moreover, a combination of KAR-2 and W13 (an anticalmodulin drug) qualitatively caused a similar arrest in both G0/G1 and G2/M than vinblastine. Levels of cyclin A and B1 were higher in KARs-treated cells than in vinblastine- or vincristine-treated cells. Cdc2 activity was much higher in KAR-2 than in vinblastine-treated cells, indicating a stronger mitotic arrest. The effect of KAR2 and vinblastine on microtubules network was analyzed by immunostaining with anti-tubulin antibody. Results indicated that KAR-2-induces the formation of aberrant mitotic spindles, with not apparent effect on interphase microtubules, whereas vinblastine partially destroyed interphase microtubules coexisting with normal and aberrant mitotic spindles.", "source": "https://pubmed.ncbi.nlm.nih.gov/11723230/"}
{"doc_id": "7a364d400198ab1388ee69dc9abe8494", "sentence": "More than one-third ( 36 % ) of AA patients in our study received Danazol as monotherapy , whereas less than a third ( 32 % ) each received standard doses of IST with equine Anti Thymocyte Globulin ( ATG ) and Cyclosporine combination , or Cyclosporine and Danazol combination , respectively .", "spans": [{"span_id": 0, "text": "Danazol", "start": 66, "end": 73, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "Anti Thymocyte Globulin", "start": 174, "end": 197, "token_start": 35, "token_end": 38}, {"span_id": 2, "text": "Cyclosporine", "start": 210, "end": 222, "token_start": 42, "token_end": 43}, {"span_id": 3, "text": "Cyclosporine", "start": 240, "end": 252, "token_start": 46, "token_end": 47}, {"span_id": 4, "text": "Danazol", "start": 257, "end": 264, "token_start": 48, "token_end": 49}], "rels": [{"class": "NEG", "spans": [3, 4], "is_context_needed": true}, {"class": "NEG", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Danazol increases T regulatory cells in patients with aplastic anemia. danazol is an attenuated androgen and is used in the treatment of aplastic anemia (AA) in resource constraint settings. We chose to study the role of CD4+ CD25 ### methods T-regs' percentages of 25 acquired idiopathic AA patients and 25 healthy controls who completed study protocol were analyzed by performing multicolor flowcytometry on peripheral blood samples. ### results More than one-third ( 36 % ) of AA patients in our study received Danazol as monotherapy , whereas less than a third ( 32 % ) each received standard doses of IST with equine Anti Thymocyte Globulin ( ATG ) and Cyclosporine combination , or Cyclosporine and Danazol combination , respectively . Results showed that all AA patients had a significantly lower percentage of T-regs at the time of diagnosis when compared to healthy controls (p\u2009<\u20090.0001), implicating their role in the pathophysiology. On treatment, all 25 patients showed a significant rise in the percentage of T-regs when compared to baseline (p\u2009<\u20090.0001). ### discussion The rise in T-regs' percentage was higher in patients treated with danazol alone when compared to standard IST (ATG with cyclosporine), or cyclosporine with danazol combinations (p\u2009=\u20090.585). ### conclusion We conclude that danazol also leads to increase in T-regs in acquired idiopathic AA.", "source": "https://pubmed.ncbi.nlm.nih.gov/29415633/"}
{"doc_id": "59a99e3c9b66f3a6dea60a3461efacf5", "sentence": "Similarly , antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity , but preimmune IgG had no effect .", "spans": [{"span_id": 0, "text": "colchicine", "start": 73, "end": 83, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "nifedipine", "start": 102, "end": 112, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. colchicine disposition involves both active biliary and renal excretion of parent drug, and at least in mammals a substantial fraction undergoes hepatic demethylation prior to excretion. We investigated the biotransformation of [3H]colchicine in a panel of microsomal preparations obtained from sixteen human liver samples. The production rate of the main metabolites of colchicine's 3-demethylcolchicine (3DMC) and 2-demethylcolchicine (2DMC), was linear in relation to incubation time, cytochrome (P450) content, and substrate concentration. Following the incubation of colchicine (5 nM) with microsomes in the presence of an NADPH-generating system for 60 min, 9.8% and 5.5% of the substrate were metabolized to 3DMC and 2DMC, respectively. The formation rate of colchicine metabolites exhibited a marked variation between the different microsomal preparations. The formation rates of both colchicine metabolites were correlated significantly with nifedipine oxidase activity, a marker of CYP3A4 activity (r = 0.96, P < 0.001), but not with the metabolic markers of CYP2A6, CYP2C19, CYP2C9, CYP2D6, and CYP2E1 activities. Chemical inhibition of CYP3A4 by preincubation with gestodene (40 microM) or troleandomycin (40 microM) reduced the formation of 3DMC and 2DMC by 70 and 80%, respectively, whereas quinidine, diethyldithiocarbamate, and sulfaphenazole had no inhibitory effect. Similarly , antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity , but preimmune IgG had no effect . In conclusion, colchicine was metabolized to 3DMC and 2DMC by human liver microsomes. The production of colchicine metabolites was mediated by CYP3A4, and its rate varied greatly between microsomal preparations obtained from different liver samples. The coadministration of colchicine with known inhibitors or substrates of CYP3A4 may inhibit colchicine metabolism, resulting in concentration-related toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/8960070/"}
{"doc_id": "9a9bc4ed3056eacaad4c006b6b3934eb", "sentence": "Furthermore , our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 58, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "carboplatin", "start": 73, "end": 84, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): a phase II study conducted by the Hellenic Cooperative Oncology Group. To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). ### background paclitaxel is an active agent in ABC. Furthermore , our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC . ### Patients And Methods From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. ### results A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1.5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07-24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07-23+) months and median survival 20.4 (range 0.07-24.5+) months. ### conclusions The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.", "source": "https://pubmed.ncbi.nlm.nih.gov/9818080/"}
{"doc_id": "af9f9d821048ef780830cf1a5992726e", "sentence": "Cyclosporine ( 25 mg/kg per day , s.c . ) was given for 7 days to rats either alone or in combination with resveratrol ( 10 mg/kg per day , i.p . ) .", "spans": [{"span_id": 0, "text": "Cyclosporine", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "resveratrol", "start": 107, "end": 118, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system. cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine ( 25 mg/kg per day , s.c . ) was given for 7 days to rats either alone or in combination with resveratrol ( 10 mg/kg per day , i.p . ) . Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.", "source": "https://pubmed.ncbi.nlm.nih.gov/31613143/"}
{"doc_id": "ab077fde75c5127e2d3d623cc78f7d47", "sentence": "The diagnosis was confirmed by comparative double diagnostic block of the medial branch with bupivacaine and lidocaine .", "spans": [{"span_id": 0, "text": "bupivacaine", "start": 93, "end": 104, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "lidocaine", "start": 109, "end": 118, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of combined treatment with medial branch radiofrequency neurotomy and steroid block in lumbar facet joint arthropathy. To evaluate the long-term efficacy of combined radiofrequency (RF) neurotomy and steroid nerve block in patients with lumbar facet joint arthropathy. ### Materials And Methods Combined RF neurotomy and steroid nerve block was performed in 34 patients with chronic paravertebral low back pain. The diagnosis was confirmed by comparative double diagnostic block of the medial branch with bupivacaine and lidocaine . Under fluoroscopy, RF thermal ablation of the medial branch was performed (at RF needle tip temperature 85\u00b0C for 90 seconds), three times for each target nerve. At the end of the procedure, 20 mg of methylprednisolone acetate (sustained-release preparation) was infiltrated on each ablated nerve. Outcome variable was the degree of improvement in pain using visual analog scale (VAS) and numerical rating scale (NRS). Improvement in the quality of life was assessed using the Roland-Morris (RM) questionnaire. The procedure was repeated in cases of unbearable pain (>5 VAS score). ### results Patients had a mean VAS score of 8.6 before the procedure. Thereafter, VAS score was 0.91 immediately after the procedure and 3.0, 2.8, 3.7, and 3.6 at 1 month, 2 months, 6 months, and 1 year. NRS showed pain relief after the procedure of 85%, 65%, 78%, 62%, and 59.5% at the same time points. RM score was 18 before the procedure, 7.6 at 6 months after the procedure, and 8.5 at 1 year after the procedure. No major complication was noted except local pain in all patients and numbness of the back in six patients after the procedure. ### conclusions Combined RF neurotomy and steroid nerve block produced substantial improvement in terms of long-term pain relief and quality of life.", "source": "https://pubmed.ncbi.nlm.nih.gov/23177113/"}
{"doc_id": "e9e11475fb4dfd19f99abf2096f282df", "sentence": "Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses .", "spans": [{"span_id": 0, "text": "Pemetrexed", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bortezomib", "start": 16, "end": 26, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer. bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors. ### methods Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500-600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7-1.3 mg/m2 on D1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0-1.6 mg/m2 on D1 and 8). ### results We treated 27 patients on four dose levels in arm A and three dose levels in arm B. Tumor types included lung (n = 16), adenoid cystic carcinoma (n = 2), prostate (n = 2), sarcoma (n = 2), breast (n = 1), thymus (n = 1), head and neck (n = 1), and gastrointestinal(n = 2). Dose-limiting toxicities were seen in arm A only; grade 3 asthenia (n = 2), grade 3 transaminitis and dehydration (n = 1). The most common grade 3/4 toxicity was neutropenia. Of 26 evaluable patients, 2 patients had partial response (1 in arm A and 1 in arm B), 13 had stable disease (7 in arm A and 6 in arm B), and 11 had progression (6 in arm A and 5 in arm B). Of the 16 patients with non-small cell lung cancer, 2 (12.5%) had partial response and 9 had stable disease, for a disease control rate of 68.8%. Recommended phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly. ### conclusions Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses . Based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/18090584/"}
{"doc_id": "f1cc7e30edeaee003ffd3a3b25b34687", "sentence": "Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy ( TANIA ): an open-label , randomised phase 3 trial .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bevacizumab", "start": 191, "end": 202, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "TANIA", "start": 223, "end": 228, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy ( TANIA ): an open-label , randomised phase 3 trial . Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. ### methods In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. ### findings Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15\u00b79 months (IQR 9\u00b71-21\u00b77) in the chemotherapy-alone group and 16\u00b71 months (10\u00b76-22\u00b77) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6\u00b73 months [95% CI 5\u00b74-7\u00b72] vs 4\u00b72 months [3\u00b79-4\u00b77], respectively, stratified hazard ratio [HR] 0\u00b775 [95% CI 0\u00b761-0\u00b793], two-sided stratified log-rank p=0\u00b70068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. ### interpretation These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. ### funding F Hoffmann-La Roche.", "source": "https://pubmed.ncbi.nlm.nih.gov/25273342/"}
{"doc_id": "88f525b0e33ed578e19041d6a770e6b1", "sentence": "Goserelin plus tamoxifen after cyclophosphamide , doxorubicin and 5-fluorouracil ( CAF ) chemotherapy resulted in improved disease-free survival compared with CAF alone .", "spans": [{"span_id": 0, "text": "Goserelin", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "tamoxifen", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "cyclophosphamide", "start": 31, "end": 47, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "doxorubicin", "start": 50, "end": 61, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "5-fluorouracil", "start": 66, "end": 80, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": false}], "paragraph": "Goserelin ('Zoladex')--offering patients more choice in early breast cancer. The luteinising hormone-releasing hormone analogue goserelin ('Zoladex') suppresses ovarian oestrogen production in pre- and perimenopausal women. goserelin is a biodegradable, sustained-release 3.6 mg depot that is administered by subcutaneous injection every 28 days. Clinical trials in premenopausal women with hormone-sensitive early breast cancer have demonstrated that goserelin alone, or in combination with tamoxifen, is at least as effective as cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. Goserelin plus tamoxifen after cyclophosphamide , doxorubicin and 5-fluorouracil ( CAF ) chemotherapy resulted in improved disease-free survival compared with CAF alone . These trials have also shown that goserelin is well tolerated and is associated with less acute toxicity than cytotoxic chemotherapy. Early improvements in quality of life over the first 3-6 months of goserelin treatment support the use of this agent as an alternative to chemotherapy in this patient population. Patients should be provided with information on the benefits and risks associated with available treatment options so that they can be involved in the decision-making process.", "source": "https://pubmed.ncbi.nlm.nih.gov/15590321/"}
{"doc_id": "b17be4a07cfbc24af81f8cd537f7184c", "sentence": "An 82-year-old white female developed a 36-hour episode of unresponsiveness/drowsiness after a single dose of triazolam 0.5 mg in combination with cimetidine .", "spans": [{"span_id": 0, "text": "triazolam", "start": 110, "end": 119, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "cimetidine", "start": 147, "end": 157, "token_start": 21, "token_end": 22}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Prolonged hypnotic response to triazolam-cimetidine combination in an elderly patient.  An 82-year-old white female developed a 36-hour episode of unresponsiveness/drowsiness after a single dose of triazolam 0.5 mg in combination with cimetidine . This case illustrates the need for careful dose-titration of drug therapy in the elderly, particularly when a drug with the potential to impair drug metabolism is coadministered. cimetidine, when coadministered with triazolam, may increase the intensity and duration of action of single doses of triazolam.", "source": "https://pubmed.ncbi.nlm.nih.gov/6150838/"}
{"doc_id": "f459330ae9a018833fde1129b805d154", "sentence": "The combination of melatonin at concentrations of 50 \u03bcM with increasing doses of irinotecan ( 7.5 , 15 , 30 , and 60 \u03bcM ) resulted in an increase in the amount of DNA damage in A549 and HT29 cancer cells , but was not effective in inducing DNA damage in healthy human lymphocytes .", "spans": [{"span_id": 0, "text": "melatonin", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "irinotecan", "start": 81, "end": 91, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The modulatory effect of melatonin on genotoxicity of irinotecan in healthy human lymphocytes and cancer cells. Drug-target interactions can be modified by adding modulatory agents to increase treatment efficacy and clinical outcome. Combination chemotherapy has become increasingly important because drugs acting synergistically can achieve therapeutic effects at substantially lower doses and with a limited spectrum of side effects. irinotecan, known as one of the camptothecin analogs, has shown a broad spectrum of antitumor activity against various malignancies. In this study, we evaluated the effect of melatonin on the genotoxic activity of irinotecan in healthy human lymphocytes and a lung cancer cell line (A549) and a colorectal adenocarcinoma cell line (HT29) in vitro. irinotecan, as a single agent, was shown to induce DNA damage in all types of analyzed cells. The combination of melatonin at concentrations of 50 \u03bcM with increasing doses of irinotecan ( 7.5 , 15 , 30 , and 60 \u03bcM ) resulted in an increase in the amount of DNA damage in A549 and HT29 cancer cells , but was not effective in inducing DNA damage in healthy human lymphocytes . Analysis of the efficacy of DNA repair, performed after 60 and 120 minutes of postincubation, showed the gradual decrease of DNA percentage in comet tails during repair postincubation in all experimental samples. Our results indicate that melatonin can modulate the genotoxic activity of irinotecan and DNA repair efficacy in human cancer cells in vitro. These findings may be supportive for the optimization of therapeutic efficacy in irinotecan treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/23126525/"}
{"doc_id": "698946285dc6e66a6520c401db987cc8", "sentence": "Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 87, "end": 103, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "filgrastim", "start": 108, "end": 118, "token_start": 13, "token_end": 14}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial. ### methods Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m2) followed by eight cycles of CMF (cyclophosphamide [600 mg/m2], methotrexate [50 mg/m2], and 5-fluorouracil [600 mg/m2]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m2), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m2) supported by filgrastim (300 microg/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m2) and thiotepa (800 mg/m2). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle . Log-rank tests were used to compare survival rates. All statistical analyses were two-sided. ### results At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (high-dose arm = 62%, 95% CI = 56% to 68%; conventional-dose arm = 64%, 95% CI = 57% to 70%) (P =.38). ### conclusion Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/15265969/"}
{"doc_id": "ebb16d45f12020fe397cb2924711fa22", "sentence": "Although cisplatin is generally the favoured platinum agent , gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 9, "end": 18, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "gemcitabine", "start": 62, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "carboplatin", "start": 89, "end": 100, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Gemcitabine and carboplatin in combination for the treatment of advanced, metastatic, non-small cell lung cancer. The universally accepted first-line treatment for advanced (stage IIIB effusion/IV) non-small-cell lung cancer in patients with a good performance status is a platinum drug in combination with one of gemcitabine, paclitaxel, vinorelbine or docetaxel. Although cisplatin is generally the favoured platinum agent , gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile . Here, the pharmacology, preclinical and clinical data to support the use of this regimen for the treatment of advanced non-small-cell lung cancer is evaluated.", "source": "https://pubmed.ncbi.nlm.nih.gov/18035969/"}
{"doc_id": "0fa064ea7b31d4b077d6fbf11d1a921e", "sentence": "In group B , epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2 , given in the same manner as in group A.", "spans": [{"span_id": 0, "text": "epirubicin", "start": 13, "end": 23, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "paclitaxel", "start": 51, "end": 61, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2-blockers. In group B , epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2 , given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of this combination-line treatment of metastatic breast cancer is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/9374090/"}
{"doc_id": "87f36673a4e1cfaadef99fcdc642a0ed", "sentence": "We assessed the safety and activity of ceritinib plus nivolumab in these patients .", "spans": [{"span_id": 0, "text": "ceritinib", "start": 39, "end": 48, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "nivolumab", "start": 54, "end": 63, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study. Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients . ### methods In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. ### results In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff \u22651% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. ### conclusion ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.", "source": "https://pubmed.ncbi.nlm.nih.gov/31634667/"}
{"doc_id": "789db177edc5cd5c6dfc1760f8ad5d0e", "sentence": "Incubation with somatostatin , 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells .", "spans": [{"span_id": 0, "text": "somatostatin", "start": 16, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "decitabine", "start": 37, "end": 47, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "trichostatin", "start": 52, "end": 64, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "somatostatin", "start": 78, "end": 90, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Incubation with somatostatin , 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells . somatostatin (SMS), binds to its specific receptors (SSTRs) and transduces growth inhibitory, anti-secretory and apoptotic signals. Several human cancers express SSTRs, including prostate cancer, and therefore SMS is of interest for anti-cancer therapy. DNA methylation and histone modifications are involved in normal cell development, gene imprinting and human carcinogenesis. Reversing DNA methylation is an attractive therapeutic possibility, since epigenetic modifications change gene expression without changing the gene function. DNA methylation inhibitors such as 5-aza-2'-deoxycytidine (5'-aza, decitabine) have been used to treat several types of haematological malignancies. Histone deacetylase inhibitors such as trichostatin (TSA), are a new class of 'targeted anti-cancer agents'. TSA and decitabine can induce growth arrest, apoptosis or terminal differentiation in a variety of solid and haematological cancers in advanced disease patients. In the present study, the LNCaP cell line (prostate cancer) was incubated with SMS or Somadex (an SMS polymer conjugate) for three days, 1 nM per day, and the untreated cells were the negative control. For DNA demethylation, cells were grown in the presence of 2.5 microM 5-aza for 120 h, and re-fed with 5-aza-containing fresh medium at day 3. The total incubation time with 5-aza was 120 h. TSA at 1.0 microM was added into the cultured cells for 24 h. The combined treatment of 5-aza and TSA was performed by incubating the cells with 5-aza for 120 h followed by a 24-h exposure to TSA. Using cDNA obtained from these cell lines, the difference in the expression level of SSTR mRNA transcripts before and after 5-aza and TSA treatments was analyzed by RT-PCR. An increased induction of mRNA expression of the five SSTR subtypes was observed in the LNCaP cells when incubated with SMS/Somadex (dose-dependent). The inhibition of DNA methylation and histone acetylation resulted in the up-regulation of SSTR5 mRNA expression. The results demonstrate a positive feedback loop between SMS and its receptors. This regulation pathway may enhance the anti-tumor activity of somatostatin. To benefit from this effect in a clinical setting, the dose, dose frequency and pan affinity of the SMS derivative are important factors. The epigenetic manipulation with DNA methylation or histone deacetylase inhibitors, combined with SMS, may offer a novel alternative for the treatment of advanced prostate cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/18575731/"}
{"doc_id": "4e5dc5ce44c564c270b3f1ccdd19984e", "sentence": "This study was conducted to determine whether famotidine , a H2 antagonist , is effective in the treatment of acute urticaria and compare its effect with that of the H1 antagonist diphenhydramine .", "spans": [{"span_id": 0, "text": "famotidine", "start": 46, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "diphenhydramine", "start": 180, "end": 195, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Famotidine in the treatment of acute urticaria. Recent studies suggest that histamine H2-receptor antagonists may be useful in the treatment of urticaria. This study was conducted to determine whether famotidine , a H2 antagonist , is effective in the treatment of acute urticaria and compare its effect with that of the H1 antagonist diphenhydramine . In this prospective, double-blind, controlled trial, 25 patients with urticaria of less than 72 h duration were randomized to receive a single dose of either famotidine 20 mg i.m. or diphenhydramine 50 mg i.m. Prior to treatment and 30 min after treatment, patients rated pruritus and sedation using visual analogue scales, while physicians evaluated intensity of urticaria and percentage of body surface area involved by urticaria. famotidine was found to reduce pruritus associated with acute urticaria, intensity of urticaria, and body surface area affected by urticaria without causing sedation. famotidine was comparable to diphenhydramine in efficacy; however, there was a (nonsignificant) trend for diphenhydramine to be more effective than famotidine in the treatment of pruritus, and for famotidine to be more effective in the reduction of surface area of involvement. It is concluded that famotidine merits further investigation as a potential medication for treatment of urticaria.", "source": "https://pubmed.ncbi.nlm.nih.gov/10844490/"}
{"doc_id": "405908b1332efb919c7ee2252f499cb0", "sentence": "On the other hand , a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites seems of minor importance since clonazepam ( with a high affinity for these sites ) and chlordiazepoxide ( with a low affinity ) were equipotent in the enhancement of the combined treatment efficacy .", "spans": [{"span_id": 0, "text": "clonazepam", "start": 150, "end": 160, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "chlordiazepoxide", "start": 206, "end": 222, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Effect of combined treatment of diphenylhydantoin with clonazepam and chlordiazepoxide on the threshold for maximal electroconvulsions in mice. The anticonvulsant effect of either clonazepam (0.2-6.4 mg/kg) or chlordiazepoxide (2.5-40 mg/kg) alone or in combination with diphenylhydantoin (4-16 mg/kg) was studied against electroconvulsions in mice. All drugs were injected intraperitoneally, diphenylhydantoin - 75 min and the benzodiazepines - 60 min before the test. Adding either clonazepam or chlordiazepoxide (in doses moderately increasing the convulsive threshold) was more effective than doubling the dose of diphenylhydantoin. Both the interaction between benzodiazepines and diphenylhydantoin at the level of the receptor for picrotoxin-barbiturates and benzodiazepine-induced potentiation of specific diphenylhydantoin binding are likely to contribute to the observed phenomenon. On the other hand , a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites seems of minor importance since clonazepam ( with a high affinity for these sites ) and chlordiazepoxide ( with a low affinity ) were equipotent in the enhancement of the combined treatment efficacy .", "source": "https://pubmed.ncbi.nlm.nih.gov/6855341/"}
{"doc_id": "697581868aee121b2c723980f6bb7cc0", "sentence": "A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive , Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer ( NEO-ORB ) .", "spans": [{"span_id": 0, "text": "Letrozole", "start": 43, "end": 52, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Alpelisib", "start": 58, "end": 67, "token_start": 9, "token_end": 10}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive , Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer ( NEO-ORB ) . Addition of alpelisib to fulvestrant significantly extended progression-free survival in ### results In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade \u22653 adverse events (\u22655% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the ### conclusions In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR", "source": "https://pubmed.ncbi.nlm.nih.gov/30723140/"}
{"doc_id": "b29c15bd2e8ad5f2e59d59be0b49ee8f", "sentence": "Treatment with bromocriptine and pyridoxine showed no improvement .", "spans": [{"span_id": 0, "text": "bromocriptine", "start": 15, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "pyridoxine", "start": 33, "end": 43, "token_start": 4, "token_end": 5}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Aromatic amino Acid decarboxylase deficiency not responding to pyridoxine and bromocriptine therapy: case report and review of response to treatment. Aromatic L-amino acid decarboxylase (AADC) deficiency (MIM #608643) is an autosomal recessive inborn error of monoamines. It is caused by a mutation in the DDC gene that leads to a deficiency in the AADC enzyme. The clinical features of this condition include a combination of dopamine, noradrenaline, and serotonin deficiencies, and a patient may present with hypotonia, oculogyric crises, sweating, hypersalivation, autonomic dysfunction, and progressive encephalopathy with severe developmental delay. We report the case of an 8-month-old boy who presented with the abovementioned symptoms and who was diagnosed with AADC deficiency based on clinical, biochemical, and molecular investigations. Treatment with bromocriptine and pyridoxine showed no improvement . These data support the findings observed among previously reported cohorts that showed poor response of this disease to current regimens. Alternative therapies are needed to ameliorate the clinical complications associated with this disorder.", "source": "https://pubmed.ncbi.nlm.nih.gov/24453523/"}
{"doc_id": "15808b8203edebf1c7bd379a66f5135e", "sentence": "Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli K-12 .", "spans": [{"span_id": 0, "text": "trimethoprim", "start": 25, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "sulfamethoxazole", "start": 68, "end": 84, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli K-12 . The combined effects of trimethoprim and sulfamethoxazole on the viability of Escherichia coli K-12 and resistant strains possessing resistance plasmids were examined in minimal medium. When methionine, glycine, and adenine were present, sulfamethoxazole could enhance trimethoprim activity against E. coli K-12 so that the combination was bactericidal. However, this enhancement occurred over a narrow range of trimethoprim concentrations (0.04 to 0.2 mg liter-1) and only when the sulfamethoxazole concentration was more than 10 times that of trimethoprim. Under certain conditions, sulfamethoxazole enhanced trimethoprim bactericidal activity against E. coli K-12 carrying plasmid R1 at concentrations of sulfamethoxazole far below those required to inhibit the organism, but there was no such enhancement with the same host containing the SSu plasmid. Similar differences were found with strains possessing trimethoprim resistance plasmids R483 and R751. sulfamethoxazole can promote a bactericidal response with trimethoprim in E. coli K-12 and some of its resistant derivatives, but only under a narrow range of concentrations.", "source": "https://pubmed.ncbi.nlm.nih.gov/7041815/"}
{"doc_id": "842e788301534fc8e3bcc27876dd50ba", "sentence": "New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil , and real and perceived intolerance to standard drugs such as mefloquine .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 118, "end": 129, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "proguanil", "start": 134, "end": 143, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "mefloquine", "start": 207, "end": 217, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Current status and replies to frequently posed questions on atovaquone plus proguanil (Malarone) for the prevention of malaria. Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection. Almost all cases and fatalities are preventable with the use of measures to reduce mosquito bites and appropriate chemoprophylaxis for those at high risk of infection. There are currently a limited number of licensed drugs available to prevent malaria in travellers. New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil , and real and perceived intolerance to standard drugs such as mefloquine . A newly licensed antimalarial (atovaquone plus proguanil; Malarone) compares favourably with other drug options, although some prescribers may be unfamiliar with the specific advantages and disadvantages of this antimalarial. This article reviews recent clinical experience and randomised controlled trial data in order to address frequently asked questions about this new combination drug.", "source": "https://pubmed.ncbi.nlm.nih.gov/12785875/"}
{"doc_id": "9569e93e22559dc03699092c070d4b6f", "sentence": "They were subsequently exposed to graded doses of cisplatin ( CP ) , etoposide ( VP-16 ) , Adriamycin ( ADR ) , cytarabine ( ara-C ) , cyclophosphamide ( CY ) , or camptothecin ( CAM ) .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 50, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 69, "end": 78, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "cytarabine", "start": 112, "end": 122, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "cyclophosphamide", "start": 135, "end": 151, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Bcl-2 expression correlates with apoptosis induction but not tumor growth delay in transplantable murine lymphomas treated with different chemotherapy drugs. Previously, we have reported that the bcl-2-expressing murine lymphoma cell line LY-ar is resistant to chemotherapy-induced apoptosis when compared to the non-bcl-2-expressing LY-as cell line. The intent of the present study was to determine whether this relationship extends to lymphomas produced from these cell lines in syngeneic mice, after treatment with the same chemotherapy agents. ### methods LY-ar and LY-as tumors were grown in the hind legs of syngeneic mice. They were subsequently exposed to graded doses of cisplatin ( CP ) , etoposide ( VP-16 ) , Adriamycin ( ADR ) , cytarabine ( ara-C ) , cyclophosphamide ( CY ) , or camptothecin ( CAM ) . Apoptotic bodies were scored in histological sections of tumors that had been stained with hematoxylin and eosin. Tumor growth delay was determined on tumors that were treated when they were 8 mm in diameter. Thereafter, tumor diameter was measured daily with a vernier caliper until they had grown to a maximum of 16 mm in diameter. ### results When transplanted into host animals, tumors derived from these two cell lines and treated in vivo with CP, VP-16, ADR, ara-C, CY, and CAM displayed apoptotic propensities similar to those seen in the same cell lines when treated in vitro. Generally, for all the drugs tested, apoptotic indices in LY-as tumors were significantly higher than in LY-ar tumors. However, tumor growth delay measurements could not be predicted with any accuracy from the apoptotic indices. For some drugs LY-ar tumors were more sensitive than LY-as tumors (CP, Vp-16, ADR, ara-C), yet LY-ar tumors were more resistant to CY. ### conclusions Despite considerable interest in using apoptotic indices as predictors of treatment outcome, the data presented here suggest that these relationships are very complex. This may be especially true for chemotherapy agents for which effects in vivo are complicated by pharmacokinetics, host effects, and tumor cell heterogeneity.", "source": "https://pubmed.ncbi.nlm.nih.gov/10501909/"}
{"doc_id": "14dde51b22af3068e58463d286d5e956", "sentence": "In a phase II trial , patients with primary gastric cancer and clinical involvement of para-aortic nodes ( PAN ) were treated by neo-adjuvant chemotherapy with capecitabine and oxaliplatin combination , and responders were then submitted to gastrectomy with D2 lymphadenectomy .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 160, "end": 172, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "oxaliplatin", "start": 177, "end": 188, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Gastric cancer with para-aortic lymph node metastases: do not miss a chance of cure! This letter to editor is a comment to the paper by Wang et al. entitled: \"A phase II trial of Xeloda and oxaliplatin (XELOX) neo-adjuvant chemotherapy followed by surgery for advanced gastric cancer patients with para-aortic lymph node metastasis\". In a phase II trial , patients with primary gastric cancer and clinical involvement of para-aortic nodes ( PAN ) were treated by neo-adjuvant chemotherapy with capecitabine and oxaliplatin combination , and responders were then submitted to gastrectomy with D2 lymphadenectomy . The diagnostic and therapeutic approach adopted in this protocol is discussed, with special reference to the potential limits of computed tomography scan for the clinical diagnosis of PAN metastases (false positive results), and the opportunity to perform a D2 plus para-aortic lymphadenectomy, to further increase the chance of cure in patients with suspected PAN metastases.", "source": "https://pubmed.ncbi.nlm.nih.gov/24889718/"}
{"doc_id": "e7b48bfc94dd35343e16291d3e96a8d4", "sentence": "More myelotoxicity is observed with palbociclib and ribociclib , but more gastrointestinal toxicity is observed with abemaciclib .", "spans": [{"span_id": 0, "text": "palbociclib", "start": 36, "end": 47, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "ribociclib", "start": 52, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "abemaciclib", "start": 117, "end": 128, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib , but more gastrointestinal toxicity is observed with abemaciclib . Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/32145796/"}
{"doc_id": "e18b168a2e78aab4f991c16a7be994bd", "sentence": "Intraoperative epidural bupivacaine , intraoperative intravenous fentanyl use , time to first analgesia request , postoperative visual analogue scale pain scores , tramadol requirements and side-effects were recorded for 72 hours .", "spans": [{"span_id": 0, "text": "bupivacaine", "start": 24, "end": 35, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "tramadol", "start": 164, "end": 172, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Subarachnoid morphine, bupivacaine and fentanyl as part of combined spinal-epidural analgesia for low anterior resection. A prospective, randomised, double-blind clinical trial. This study was designed to compare the efficacy of subarachnoid morphine alone or in combination with bupivacaine and fentanyl for combined spinal-epidural analgesia in colorectal surgery. This is a prospective, randomised, double-blind clinical trial. Sixty patients undergoing low anterior resection were assigned to one of three groups: subarachnoid morphine, bupivacaine and fentanyl, subarachnoid morphine and bupivacaine or subarachnoid morphine only. Epidural catheter placement and subarachnoid injection were done via a combined spinal-epidural Epistar needle at L2-3. The epidural catheter was used for scheduled intraoperative bupivacaine and intermittent postoperative bupivacaine and morphine administration. Intraoperative epidural bupivacaine , intraoperative intravenous fentanyl use , time to first analgesia request , postoperative visual analogue scale pain scores , tramadol requirements and side-effects were recorded for 72 hours . Postoperative analgesia was comparable in all groups. Intraoperative fentanyl and bupivacaine consumption was lowest in the morphine, bupivacaine and fentanyl group. Time to first analgesia request was longer in the morphine, bupivacaine and fentanyl compared to the morphine group (P = 0.009). tramadol use was lower in the morphine and bupivacaine group compared to morphine, bupivacaine and fentanyl (P = 0.017) on postoperative day two. There were no significant adverse effects. All patients ambulated the morning after surgery. The addition of bupivacaine and fentanyl to subarachnoid morphine did not confer any advantage on postoperative visual analogue scale scores and tramadol use, but lowered the need for additional intraoperative intravenous fentanyl and epidural bupivacaine and prolonged the time to first analgesia request.", "source": "https://pubmed.ncbi.nlm.nih.gov/19681410/"}
{"doc_id": "ad8aed5dc7fa01eb977f4265526c6c57", "sentence": "Three eyes had both bevacizumab and ranibizumab ( 1.58 % ) .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 20, "end": 31, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "ranibizumab", "start": 36, "end": 47, "token_start": 6, "token_end": 7}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Intravitreal Anti Vascular Endothelial Growth Factor Agents in The Management of Retinal Diseases: An Audit. The study aimed to describe our initial experience with the use of anti vascular endothelial growth factors (anti-VEGFs) in the treatment of retinal diseases. ### methods The case records of all patients who had received at least 3 doses of intravitreal anti- VEGF injections between January 2012 to December 2016 were reviewed. Information culled from the data was age, sex, indications for treatment, type of injection, presenting visual acuity, post injection visual acuity, systemic and ocular co morbidities. Results were analyzed using Statistical Package for Social Sciences (SPSS) 20.0 for Windows statistical software. ### results A total of 190 injections were given during the study period, to 58 eyes of 50 patients. Twenty-eight females (56.00%) and twenty-two males (44.00%) were seen with a mean age of 59.6\u00b1 11.66. bevacizumab was the most frequently administered anti- VEGF, 142 (74.74%) while only 48(25.26%) injections of ranibizumab were given. Three eyes had both bevacizumab and ranibizumab ( 1.58 % ) . Retinal vein occlusion 61(32.11%) was the commonest indication for the injections followed by diabetic macular edema 43(22.63%) and proliferative diabetic retinopathy 42(22.11%). Others were neovascular age related macular degeneration, neovascular glaucoma, vitreous hemorrhage, myopic choroidal neovascularization and cystoid macular edema. There was an association between age and disease, (p = 0.001). There was an improvement in visual acuity after intervention in cases with retinal vein occlusion and diabetic macular edema, and this was statistically significant. Hypertension was the commonest systemic disorder in this series 81(42.36%) and the supero-temporal quadrant 131(68.95%) was the most preferred position to administer the injection. Floaters was the commonest complication seen. ### conclusion Anti VEGFs have become an invaluable tool in the management of a number of retinal diseases in our center. However, the cost implications are a hindrance to an increased uptake of this form of treatment. Cheaper alternative preparations should be made available to encourage the uptake. Government in developing countries should be encouraged to bear the health burden of the old aged pensioner (OAP).", "source": "https://pubmed.ncbi.nlm.nih.gov/29299078/"}
{"doc_id": "47739c6d1960e7f551fe386519ab6548", "sentence": "Newer treatment regimens , including etoposide , prednisone , vincristine , cyclophosphamide , doxorubicin , rituximab ( EPOCH-R ) , show promise for these patients .", "spans": [{"span_id": 0, "text": "etoposide", "start": 37, "end": 46, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "prednisone", "start": 49, "end": 59, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "vincristine", "start": 62, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "cyclophosphamide", "start": 76, "end": 92, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "doxorubicin", "start": 95, "end": 106, "token_start": 13, "token_end": 14}, {"span_id": 5, "text": "rituximab", "start": 109, "end": 118, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": false}], "paragraph": "Successful Use of EPOCH-R in 2 Young Adult Patients With Burkitt Lymphoma and Acute Kidney Injury: A Case Report. Pediatric Burkitt lymphoma has historically been treated with intensive methotrexate-based chemotherapy, which improves patient survival while causing severe toxicities. Young patients typically have better outcomes with intensive therapies, while adults and immunocompromised patients have higher toxicities and worse outcomes. Newer treatment regimens , including etoposide , prednisone , vincristine , cyclophosphamide , doxorubicin , rituximab ( EPOCH-R ) , show promise for these patients . However, few studies exist to demonstrate efficacy and improved toxicity profile with EPOCH-R. We present 2 cases: a 25-year-old male with Down syndrome and an 18-year-old male with Burkitt lymphoma and significant renal injury who were successfully treated with EPOCH-R with minimal toxicities.", "source": "https://pubmed.ncbi.nlm.nih.gov/30095692/"}
{"doc_id": "084dededdf9fc5e0f52c1576c4723fc4", "sentence": "In two groups of rats , propranolol or atropine were given before the venom administration .", "spans": [{"span_id": 0, "text": "propranolol", "start": 24, "end": 35, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "atropine", "start": 39, "end": 47, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Effect of scorpion Leiurus quinquestriatus (H&E) venom on rat's heart rate and blood pressure. The effects of scorpion Leiurus quinquestriatus (H&E) venom collected from the South Sinai region, Egypt, on heart rate (HR) and mean arterial pressure (MAP) were studied after intramuscular administration of 3 different doses (100, 200 and 400 micrograms/kg) to anesthetized rats. The effects of adrenergic and cholinergic blocking agents on the venom-induced HR and MAP changes were also evaluated. In two groups of rats , propranolol or atropine were given before the venom administration . In the third group the venom was given before the injection of propranolol and atropine in combination. HR was measured by using a cardiotachometer coupler connected to an ECG coupler. MAP was calculated from the recorded arterial blood pressure (ABP) after catheterization of the left common carotid artery. Venom doses of 100 and 200 micrograms/kg produced tachycardia with a dose-response relationship, whereas 400 micrograms/kg evoked sinus tachycardia followed by bradycardia then tachycardia. MAP was elevated after the administration of each dose and reached its maximum value after 60 min with a dose-response relationship. Sinus, atrial and ventricular arrhythmias were observed from the recorded ECG during the time studied. This study revealed that the venom has pressor and depressor effects which are mediated through the autonomic nervous system. propranolol reduced the stimulatory effects of the highest dose of the venom while atropine was effective in eliminating the depressor effect of the venom on HR. The arrhythmias induced by the venom were blocked by the injection of the two blockers and are assumed to be due to the release of catecholamines and acetylcholine.", "source": "https://pubmed.ncbi.nlm.nih.gov/1609434/"}
{"doc_id": "6c1237dfdedfde4c544691167964c0b4", "sentence": "Doxycycline and azithromycin were highly effective in restoring fertility .", "spans": [{"span_id": 0, "text": "Doxycycline", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "azithromycin", "start": 16, "end": 28, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Characteristics of murine model of genital infection with Chlamydia trachomatis and effects of therapy with tetracyclines, amoxicillin-clavulanic acid, or azithromycin. Following intravaginal inoculation of progesterone-treated outbred mice with Chlamydia trachomatis MoPn, 4 to 6 log10 inclusion-forming units were recovered in vaginal swabs for 21 days but all animals were culture negative after 28 days. Serum antibody titers were elevated and remained high for at least 70 days. Between 28 and 70 days, upper tract infection (inflammation and distension of the uterine horns, occlusion of oviducts with inflammatory exudate, pyosalpinx, and hydrosalpinx) was seen in > 80% of the animals. Mice were dosed orally, commencing at 7 days after infection, with minocycline, doxycycline, or amoxicillin-clavulanate. Further groups received azithromycin either as a single high dose or as lower once-daily doses. In addition, minocycline and amoxicillin-clavulanate were administered at 24 h after infection, and this early treatment prevented elevation of antibody titers whereas delayed therapy did not. Vaginal swabs from mice in all treatment regimens were culture negative except for 25% of mice receiving either early amoxicillin-clavulanate or low-dose azithromycin, which yielded low numbers (20 to 70 inclusion-forming units) of chlamydiae. Numbers of fertile mice in the early treatment regimens and their litter sizes were similar to those of noninfected controls, although 25% of amoxicillin-clavulanate-treated mice had unilateral hydrosalpinges. In comparison, 88% of untreated mice developed hydrosalpinges and only 25% conceived. Delayed dosing did not affect the outcome of amoxicillin-clavulanate therapy but did diminish the protective efficacy of minocycline such that 50% of treated mice had either unilateral hydrosalpinges or ovarian abscesses. Doxycycline and azithromycin were highly effective in restoring fertility . This model makes possible the study of both short- and long-term outcomes of chlamydial infection.", "source": "https://pubmed.ncbi.nlm.nih.gov/7811001/"}
{"doc_id": "c6eacb69cd79ef372a339fb7c864b630", "sentence": "The pupillary dilation caused by amantadine is not abolished by pretreatment with reserpine , or by combined pretreatment with reserpine and alpha-methyl-p-tyrosine , although the mydriasis is reduced by approximately 25 % .", "spans": [{"span_id": 0, "text": "amantadine", "start": 33, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "reserpine", "start": 82, "end": 91, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "reserpine", "start": 127, "end": 136, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "alpha-methyl-p-tyrosine", "start": 141, "end": 164, "token_start": 21, "token_end": 22}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}, {"class": "NEG", "spans": [0, 2, 3], "is_context_needed": true}], "paragraph": "Effect of amantadine on pupillary diameter in mice. amantadine, injected into mice, produces dose-dependent mydriasis. The pupillary dilation caused by amantadine is not abolished by pretreatment with reserpine , or by combined pretreatment with reserpine and alpha-methyl-p-tyrosine , although the mydriasis is reduced by approximately 25 % . Thus, release of catecholamines from nerve terminals can account for only 25% of amantadine-produced mydriasis. haloperidol and phentolamine can partially block the effect of amantadine, but, when given after reserpine, neither of the antagonists increases the blockade produced by reserpine alone. We conclude that the catecholaminergic system contributes only partially to the pupillary effect of amantadine, and that other mechanisms appear to be involved.", "source": "https://pubmed.ncbi.nlm.nih.gov/7068338/"}
{"doc_id": "a22b07f3cb48da03270484e2473ec013", "sentence": "Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment .", "spans": [{"span_id": 0, "text": "curcumin", "start": 23, "end": 31, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "etoposide", "start": 48, "end": 57, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species. curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment . curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/26893544/"}
{"doc_id": "2d36dba4e272f444c0a25809f4006d63", "sentence": "Combination Chemotherapy with Mitomycin C , Vinorelbine , and Cisplatin ( MVrP ) in Patients with Advanced Non-Small Cell Lung Cancer .", "spans": [{"span_id": 0, "text": "Mitomycin", "start": 30, "end": 39, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "Vinorelbine", "start": 44, "end": 55, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "Cisplatin", "start": 62, "end": 71, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Combination Chemotherapy with Mitomycin C , Vinorelbine , and Cisplatin ( MVrP ) in Patients with Advanced Non-Small Cell Lung Cancer . A phase II study was conducted in patients with advanced non-small cell lung cancer (NSCLC) in order to evaluate the efficacy and toxicity of the combination chemotherapy regimen of mitomycin C, vinorelbine, and cisplatin (MVrP). ### Materials And Methods Between June 1996 and December 2000, fifty-nine patients with unresectable stage IIIB to IV, pathologically documented NSCLC were enrolled in this study. One cycle consisted of mitomycin C 10 mg/m2 i.v. day 1, vinorelbine 30 mg/m2 i.v. days 1 & 15, and cisplatin 80 mg/m2 i.v day 1 and the next cycle consisted of vinorelbine 30 mg/m2 i.v. days 29 & 43, and cisplatin 80 mg/m2 i.v day 29. Each cycle was alternated and treatments were repeated every 8 weeks. ### results We were able to evaluate fifty-three of 59 patients. Objective responses were seen in 22 (41.5%) patients (CR 0%, PR 41.5%). The median duration of response was 13.7 weeks and the median time to progression was 17.7 weeks. The median overall survival was 45.6 weeks. There was a significantly longer survival seen in responders (p=0.041). The toxicities of this regimen were acceptable without treatment related toxic death. ### conclusion This study suggests that a combination regimen of mitomycin C, vinorelbine, and cisplatin is relatively effective and well tolerated for the treatment of advanced NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/26680811/"}
{"doc_id": "ad6d1792a20b887be35ca92cb81ed90a", "sentence": "Bitches were also treated with amoxicillin ( 15 mg/kg body wt/48 h ) and/or gentamicin ( 4 mg/kg body wt/day ) administered as intramuscular ( i.m . ) injections .", "spans": [{"span_id": 0, "text": "amoxicillin", "start": 31, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "gentamicin", "start": 76, "end": 86, "token_start": 14, "token_end": 15}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Intravaginal prostaglandin F2 alpha for the treatment of metritis and pyometra in the bitch. The purpose of this study was to determine whether intravaginal prostaglandin F2 alpha (PGF2 alpha) would be effective for the treatment of metritis or pyometra in the bitch. Seventeen bitches with metritis or pyometra were treated with PGF2 alpha. Prostaglandin F2 alpha (150 micrograms/kg body weight) was administered once or twice daily by infusing 0.3 ml per 10 kg body wt into the vaginal lumen. Bitches were also treated with amoxicillin ( 15 mg/kg body wt/48 h ) and/or gentamicin ( 4 mg/kg body wt/day ) administered as intramuscular ( i.m . ) injections . Fifteen bitches were treated successfully with intravaginally administered PGF2 alpha for 3 to 12 days and with intramuscularly administered antibiotics for 4 to 12 days. Success of treatment was judged by cessation of vaginal discharge, the absence of fluid in the uterus as determined by ultrasonography, and the overall health status of the animal. As two bitches with pyometra showed clinical deterioration in spite of medical treatment, ovariohysterectomy was performed after the first and the second treatment, respectively. No side effects (salivation, vomiting, diarrhoea, hyperpnoea, ataxia, urination, anxiety, pupillary dilatation followed by contraction) were observed after PGF2 alpha treatment. The disease did not recur during the subsequent oestrous cycles within 12 months after the initial treatment. The results demonstrate that intravaginal administration of PGF2 alpha was effective in 13 dogs (86.6%) with metritis or pyometra, and caused no side effects. Although the study was based on a relatively small number of cases, it is concluded that prostaglandin F2 alpha can be a useful means of treating bitches with metritis or pyometra. However, in severe cases of pyometra ovariohysterectomy is needed.", "source": "https://pubmed.ncbi.nlm.nih.gov/10213934/"}
{"doc_id": "807f8268ae2d780c813d7fb26f9fdd0c", "sentence": "So far , chloroquine , lopinavir , hydroxychloroquine , azithromycin , favipiravir , ribavirin , darunavir , remdesivir , and umifenovir have been tested in COVID-19 clinical trials .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 9, "end": 20, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "lopinavir", "start": 23, "end": 32, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "hydroxychloroquine", "start": 35, "end": 53, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "azithromycin", "start": 56, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 4, "text": "favipiravir", "start": 71, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 5, "text": "ribavirin", "start": 85, "end": 94, "token_start": 13, "token_end": 14}, {"span_id": 6, "text": "darunavir", "start": 97, "end": 106, "token_start": 15, "token_end": 16}, {"span_id": 7, "text": "remdesivir", "start": 109, "end": 119, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Tissue distributions of antiviral drugs affect their capabilities of reducing viral loads in COVID-19 treatment. Repurposing of approved antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising strategy to treat Coronavirus disease 2019 (COVID-19) patients. Previously we reported our hypothesis that the antiviral drugs with high lung distributions might benefit COVID-19 patients by reducing viral loads. So far , chloroquine , lopinavir , hydroxychloroquine , azithromycin , favipiravir , ribavirin , darunavir , remdesivir , and umifenovir have been tested in COVID-19 clinical trials . Here we validated our hypothesis by comparing the pharmacokinetics profiles of these drugs and their capabilities of reducing viral load in clinical trials. According to bulk RNA and single cell RNA sequencing analysis, we found that high expression of both angiotensin converting enzyme 2 (ACE2) and transmembrane Serine Protease 2 (TMPRSS2) makes the lung and intestine vulnerable to SARS-CoV-2. Hydroxychloroquine, chloroquine, and favipiravir, which were highly distributed to the lung, were reported to reduce viral loads in respiratory tract of COVID-19 patients. Conversely, drugs with poor lung distributions, including lopinavir/ritonavir, umifenovir and remdesivir, were insufficient to inhibit viral replication. lopinavir/ritonavir might inhibit SARS-CoV-2 in the GI tract according to their distribution profiles. We concluded here that the antiviral drugs should be distributed straight to the lung tissue for reducing viral loads in respiratory tract of COVID-19 patients. Additionally, to better evaluate antiviral effects of drugs that target the intestine, the stool samples should also be collected for viral RNA test in the future.", "source": "https://pubmed.ncbi.nlm.nih.gov/33031797/"}
{"doc_id": "a98224a670df50e4b56be6492f4addf1", "sentence": "Of the currently known pure antiandrogens , bicalutamide offers some advantages over flutamide as it possesses a much longer half-life , allowing a once daily regimen , and has advantages over nilutamide in terms of fewer adverse effects .", "spans": [{"span_id": 0, "text": "bicalutamide", "start": 44, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "flutamide", "start": 85, "end": 94, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "nilutamide", "start": 193, "end": 203, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer. Prostatic cancer is the second most common cause of cancer death in males. Treatment by radical prostatectomy and radiotherapy is useful in the early stages of the disease. Whenever metastases occur, patients are usually treated by surgical (orchidectomy) or medical [gonadotropin releasing hormone (GnRH) analogue] castration. This form of treatment is, however, associated with unwanted adverse effects, such as flushing, loss of libido and potency and all patients ultimately escape therapy after a delay of 1 to 2 years. For this reason antiandrogens have been developed as another means of endocrine ablation therapy. Antiandrogens fall in 2 groups of which the first group, the steroidal antiandrogens such as cyproterone acetate (CPA), have a direct blocking effect at the cellular level but also inhibit testosterone production by their additional gestagenic properties blocking gonadotropin secretion. Except in preventing the flare-up associated with the start of GnRH analogue therapy and in reducing flushing, no evidence exist of any superiority for CPA over classical therapy in terms of adverse effects and survival. The second group, the nonsteroidal or 'pure' antiandrogens, only block androgens at the cellular level without any central effects. In contrast with other forms of castration, patients on pure antiandrogens as monotherapy preserve their sexual function and potency, at the expense of a slightly inferior androgen blockade and gynecomastia. These latter effects are explained by a compensatory rise in androgens as a result of the blockade at the central level, which weakens the androgen blockade, and by peripheral aromatisation of the increased androgens to oestrogens. In addition, some evidence exist that pure antiandrogens improve survival if combined with other forms of castration as they also inhibit the adrenal androgens, the so-called maximal androgen blockade (MAB). If patients escape control under MAB, a trial of stopping the antiandrogen must always be considered, as some tumours have 'learned' to be activated by these drugs. At the moment it is not yet clear if antiandrogens are of any benefit in downstaging the extent of disease before prostatectomy and/or radiotherapy. Of the currently known pure antiandrogens , bicalutamide offers some advantages over flutamide as it possesses a much longer half-life , allowing a once daily regimen , and has advantages over nilutamide in terms of fewer adverse effects .", "source": "https://pubmed.ncbi.nlm.nih.gov/9592622/"}
{"doc_id": "56f2acbe3d2bef73cccca2cb430faed2", "sentence": "Fifty-seven patients with advanced measurable urothelial tract cancer , 52 of whom had an adequate trial , were treated weekly with 3 to 4 mg . per m.2 vinblastine and 30 to 40 mg . per m.2 methotrexate .", "spans": [{"span_id": 0, "text": "vinblastine", "start": 152, "end": 163, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "methotrexate", "start": 190, "end": 202, "token_start": 37, "token_end": 38}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Vinblastine and methotrexate for advanced bladder cancer.  Fifty-seven patients with advanced measurable urothelial tract cancer , 52 of whom had an adequate trial , were treated weekly with 3 to 4 mg . per m.2 vinblastine and 30 to 40 mg . per m.2 methotrexate . Of 3 patients with unidimensional parameters 2 showed improvement lasting 16 and 27 months, which was documented by serial cystoscopic examinations. An additional 2 patients had measurable disease that could have been encompassed in a preoperative radiotherapy field. Both patients are free of disease at more than 12 and 14 months, respectively. Of the 47 patients with bidimensionally measurable parameters 19 (40 per cent) achieved a complete or partial remission lasting a median of 8 months, with a range of 1 to 24 months. Of 25 patients with intra-abdominal or pelvic disease 7 achieved a complete or partial remission and 5 also had a minor remission. Of note, 18 of 38 patients who had received no prior chemotherapy achieved a remission versus 1 of 9 who had been treated previously (p equals 0.06). Responders frequently obtained another remission with subsequent chemotherapy (4 of 9 versus 0 of 16, p equals 0.03). Responders lived 14 months versus 8 months for nonresponders (p equals 0.02). Four responders had brain metastases compared to none of 28 nonresponders. The combination of vinblastine and methotrexate is a well tolerated, effective outpatient regimen for patients with urothelial tract cancers.", "source": "https://pubmed.ncbi.nlm.nih.gov/3981708/"}
{"doc_id": "0e62b82f017a0682b72160f2502977f0", "sentence": "The results indicate that bombesin and acetylcholine are the main intramural neural regulators of gastrin and somatostatin secretion .", "spans": [{"span_id": 0, "text": "bombesin", "start": 26, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "somatostatin", "start": 110, "end": 122, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Inhibition of neurally mediated gastrin secretion by bombesin antiserum. In vitro studies on the vascularly perfused rat stomach have shown that gastrin secretion is regulated by intramural cholinergic and noncholinergic neurons. We have postulated that bombesin (gastrin-releasing peptide), a known gastrin stimulant present in antral mucosal nerve fibers, is the most likely candidate for noncholinergic transmitter. bombesin antiserum (final dilution, 1:150) but not control serum added to the vascular perfusate inhibited the gastrin response to 1,1-dimethyl-4-phenylpiperazinium by 59 +/- 17% (P less than 0.01) and to electrical field stimulation by 60 +/- 16% (P less than 0.01), and its effect was additive to that of 10(-7) M atropine (75-94%), thus accounting for the greater part of neurally induced gastrin secretion. The effects of atropine and bombesin antiserum on somatostatin secretion were consistent also with blockade of cholinergic and noncholinergic neurons, respectively. The results indicate that bombesin and acetylcholine are the main intramural neural regulators of gastrin and somatostatin secretion . Acetylcholine acts predominantly to decrease the paracrine secretion of somatostatin, thereby eliminating the continuous restraint of somatostatin on gastrin secretion and enabling bombesin to exert its potent stimulatory effect on gastrin secretion.", "source": "https://pubmed.ncbi.nlm.nih.gov/2858981/"}
{"doc_id": "024d9fa53cb36e2f053a42cd0283b6ff", "sentence": "Synergistic effects were seen between zeaxanthin and resveratrol or meclofenamic acid .", "spans": [{"span_id": 0, "text": "resveratrol", "start": 53, "end": 64, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "meclofenamic acid", "start": 68, "end": 85, "token_start": 9, "token_end": 11}, {"span_id": 2, "text": "zeaxanthin", "start": 38, "end": 48, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Resveratrol protects human retinal pigment epithelial cells from acrolein-induced damage. Although the exact pathogenesis of age-related macular degeneration (AMD) is not clear, most studies indicate a role for retinal pigment epithelial (RPE) cell damage and death caused by oxidative stress. The purpose of this study was to examine the potential protective effects of lutein, zeaxanthin, meclofenamic acid, and resveratrol on the acrolein-induced oxidative stress in human RPE cells. ### methods Cultured human RPE R-50 cells were treated with acrolein at different concentrations and treatment times. The protective effects of lutein (100 microM), zeaxanthin (100 microM), meclofenamic acid (30 microM), and resveratrol (10 microM) were investigated by pretreatment with the above agents before toxicant exposure in acute toxicity models and cotreatment with the toxicant in chronic toxicity models. The synergistic effects of acrolein and hydrogen peroxide exposure were also studied. Fluorescent latex beads were used to assess the phagocytic function of the cells. ### results Acrolein inhibited the phagocytic function of human RPE R-50 cells, and the inhibitory effects were time dependent. Pretreatment with lutein, zeaxanthin, meclofenamic acid, or resveratrol alleviated the inhibition of phagocytosis in the acute acrolein and combined acrolein/hydrogen peroxide toxicity models. Synergistic effects were seen between zeaxanthin and resveratrol or meclofenamic acid . Cotreatment with lutein, zeaxanthin, meclofenamic acid, or resveratrol showed a protective effect against the damage caused by 7-day acrolein exposure followed by hydrogen peroxide treatment. ### conclusions Our results indicated an inhibitory effect of compounds found in cigarette smoke on human RPE phagocytosis, and lutein, zeaxanthin, meclofenamic acid, and resveratrol each offered protection against this inhibition. Therefore, red wine polyphenol, resveratrol, might ameliorate acrolein-induced or age-related RPE degeneration, such as AMD.", "source": "https://pubmed.ncbi.nlm.nih.gov/20565308/"}
{"doc_id": "cf1168701bbaab2b930ece01ee27c709", "sentence": "Among the non-faecalis organisms , penicillin resistance was significantly more frequent among isolates from patients given penicillin than from patients not given this antibiotic , and clindamycin resistance was significantly more frequent among isolates from patients given lincomycin and clindamycin than from patients not given these antibiotics .", "spans": [{"span_id": 0, "text": "clindamycin", "start": 186, "end": 197, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "lincomycin", "start": 276, "end": 286, "token_start": 37, "token_end": 38}, {"span_id": 2, "text": "clindamycin", "start": 291, "end": 302, "token_start": 39, "token_end": 40}], "rels": [], "paragraph": "Antibiotic susceptibilities of streptococci from the mouth and blood of patients treated with penicillin or lincomycin and clindamycin. Patients undergoing dental extractions were non-randomly allocated to three groups, one of which received no antibiotic, one benzylpenicillin followed by oral penicillin for 5 days, and the third intramuscular lincomycin followed by oral clindamycin. Dental extraction was performed at the beginning of the course of chemotherapy. Streptococci were isolated from the extracted teeth, from blood cultures collected before and immediately after dental extraction, and from sutures removed from the gums 5-7 days after the operation. The species of these organisms was determined, and their susceptibilities to penicillin, clindamycin, cephaloridine, erythromycin and tetracycline were assessed. The majority of streptococci isolated from teeth belonged to the species Streptococcus sanguis, S. mitior, S. mutans and S. milleri. Occasional isolates of each of these organisms collected before the antibiotic could take effect were resistant to penicillin. Three of these species, but not S. mutans, were the commonest streptococci to be isolated from the blood after dental extraction. Penicillin completely suppressed dental bacteriaemia under the conditions of our investigation, and lincomycin reduced the incidence by about 60 per cent. The commonest streptococci from sutures were also S. sanguis, S. mitior, S. mutans and S. milleri. S. faecalis was also isolated, but only in patients who had received antibiotics. Among the non-faecalis organisms , penicillin resistance was significantly more frequent among isolates from patients given penicillin than from patients not given this antibiotic , and clindamycin resistance was significantly more frequent among isolates from patients given lincomycin and clindamycin than from patients not given these antibiotics .", "source": "https://pubmed.ncbi.nlm.nih.gov/1050385/"}
{"doc_id": "39fc1b8fd6fc73d93cc01a141dfaf692", "sentence": "Fifthteen patients were included : 12 underwent erlotinib treatment and 3 a crizotinib treatment .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 48, "end": 57, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "crizotinib", "start": 76, "end": 86, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "[Patient's beliefs about oral targeted therapies and impact on drug adherence in lung cancer: A pilot prospective study]. Oral targeted therapies are a new option for lung cancer treatment. However, patient's belief about these drugs - which may interact with adherence - is poorly known in this setting. ### method Our study is a pilot prospective unicentric study. Inclusion criteria were: to have been diagnosed with a lung cancer; and to be prescribed with an oral targeted therapy in second line or more. The main objective was to assess patient's specific (SB) and general beliefs (GB) about these drugs according to the Beliefs about Medicines Questionnaire (BMQ). The declared adherence was assessed with the Morisky's test. All included patients underwent a semi-structured interview with a psychologist. ### results Fifthteen patients were included : 12 underwent erlotinib treatment and 3 a crizotinib treatment . The mean score (\u00b1standard deviation) at BMQ was 54/85 (\u00b16) overall; 34/50 (\u00b15) for specific belief and 19/35 (\u00b13) for general belief about drugs. During interview, 47% believed in efficacy of targeted oral therapy; 93% reported concerns about their drug; 80% considered that the information given by the physician about the drug was comprehensive; but 40% still required additional information about it. The mean score at Morisky's test was 3/4 (\u00b12) and 53% reported to have forgotten at least once their antineoplastic drug. No correlation was found between belief and adherence. ### conclusion Belief about t anti-cancer targeted oral therapy is relatively fair but adherence is moderate in this pilot study. Interview shows the need for additional information about the prescribed drug.", "source": "https://pubmed.ncbi.nlm.nih.gov/26210879/"}
{"doc_id": "2b9d190145ddd4a628f05555cb7921d3", "sentence": "The combination of trastuzumab with paclitaxel ( Taxol ) is well approved .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 19, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "paclitaxel", "start": 36, "end": 46, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "Taxol", "start": 49, "end": 54, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Immunotherapy: new options in breast cancer treatment. Immunotherapy is a promising new approach in breast cancer treatment, complementing surgery, chemotherapy, radiation and antihormonal therapy. Primarily, two treatment options are available which are supported by a rapidly growing body of clinical evidence. These are active specific immunotherapy with Theratope and passive immunotherapy targeting the HER-2 receptor with trastuzumab (Herceptin). trastuzumab has a proven efficacy as monotherapy as well as in combination with chemotherapeutic agents in HER-2-overexpressing metastatic breast cancer. trastuzumab is generally well tolerated although cardiotoxicity has been observed, especially when in combination with doxorubicin (Adriamycin), where this can be a serious concern. Therefore, less cardiotoxic combinations with docetaxel (Taxotere), vinorelbine (Navelbine) and epirubicin (Pharmorubicin) or cyclophosphamide (Endoxana) have been tested. The combination of trastuzumab with paclitaxel ( Taxol ) is well approved . The use of trastuzumab in adjuvant and preoperative therapy is currently being examined in controlled trials. After a brief outline of immunotherapy with Theratope and trastuzumab, this article reviews recent and ongoing clinical studies conducted with trastuzumab.", "source": "https://pubmed.ncbi.nlm.nih.gov/12820782/"}
{"doc_id": "94681c8fb169a65440199170cf112a55", "sentence": "Intensive regimen of combined immunosuppressive therapy ( high-dose corticosteroids , oral cyclosporin and intravenous cyclophosphamide ( IVCY , 900 - 1000 mg/m(2 ) in every other week ) ) improved the survival rate of anti-MDA5-positive patients .", "spans": [{"span_id": 0, "text": "cyclosporin", "start": 91, "end": 102, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "cyclophosphamide", "start": 119, "end": 135, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "corticosteroids", "start": 68, "end": 83, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "[Anti-MDA5 (melanoma differentiation-associated gene 5) antibody and dermatomyositis with rapidly progressive interstitial pneumonia]. Anti-MDA5 antibody is one of the dermatomyositis-specific autoantibodies and anti-MDA5-potsitive patients show characteristic clinical features, such as hypomyositis, high prevalence of acute/subacute interstitial pneumonia (A/SIP) with poor prognosis, hyperferritinemia and elevated hepatobiliary enzyme. We found that serum IL-6, IL-18, M-CSF and IL-10 were significantly higher and serum IL-12 and IL-22 were significantly lower in anti-MDA5-positive patients than in anti-MDA5-negative patients before treatment. Taking together these serological findings, we hypothesized that monocyte and macrophage activation may underlie in the pathophysiology of anti-MDA5-positive patients. They rarely survive after they become to need oxygenation, and so need to be treated as soon as possible once the diagnosis has been made. Intensive regimen of combined immunosuppressive therapy ( high-dose corticosteroids , oral cyclosporin and intravenous cyclophosphamide ( IVCY , 900 - 1000 mg/m(2 ) in every other week ) ) improved the survival rate of anti-MDA5-positive patients . Especially, the serum ferritin levels tended to go down about 14 days after IVCY, suggesting that IVCY might be a key drug in the treatment of anti-MDA5-positive A/SIP patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/23629426/"}
{"doc_id": "386773ec27190e0288d3c849b56376e8", "sentence": "Drug sensitivity was associated with hsa-let-7a-5p for Bortezomib , hsa-miR-135a-3p for JNJ-707 and hsa-miR-185 - 3p for Panobinostat .", "spans": [{"span_id": 0, "text": "Bortezomib", "start": 55, "end": 65, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Panobinostat", "start": 121, "end": 133, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. In this way they might influence whether a cell is sensitive or resistant to a certain drug. So far, only a limited number of relatively small scale studies comprising few cell lines and/or drugs have been performed. To obtain a broader view on miRNAs and their association with drug response, we investigated the expression levels of 411 miRNAs in relation to drug sensitivity in 36 breast cancer cell lines. For this purpose IC50 values of a drug screen involving 34 drugs were associated with miRNA expression data of the same breast cancer cell lines. Since molecular subtype of the breast cancer cell lines is considered a confounding factor in drug association studies, multivariate analysis taking subtype into account was performed on significant miRNA-drug associations which retained 13 associations. These associations consisted of 11 different miRNAs and eight different drugs (among which paclitaxel, docetaxel and veliparib). The taxanes, paclitaxel and docetaxel, were the only drugs having miRNAs in common: hsa-miR-187-5p and hsa-miR-106a-3p indicative of drug resistance while paclitaxel sensitivity alone associated with hsa-miR-556-5p. tivantinib was associated with hsa-let-7d-5p and hsa-miR-18a-5p for sensitivity and hsa-miR-637 for resistance. Drug sensitivity was associated with hsa-let-7a-5p for Bortezomib , hsa-miR-135a-3p for JNJ-707 and hsa-miR-185 - 3p for Panobinostat . Drug resistance was associated with hsa-miR-182-5p for veliparib and hsa-miR-629-5p for Tipifarnib. Pathway analysis for significant miRNAs was performed to reveal biological roles, aiding to find a potential mechanistic link for the observed associations with drug response. By doing so hsa-miR-187-5p was linked to the cell cycle G2-M checkpoint in line with this checkpoint being the target of taxanes. In conclusion, our study shows that miRNAs could potentially serve as biomarkers for intrinsic drug resistance and that pathway analyses can provide additional information in this context.", "source": "https://pubmed.ncbi.nlm.nih.gov/31063487/"}
{"doc_id": "4606c1b0568cd281128a16c2bbeef511", "sentence": "No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported .", "spans": [{"span_id": 0, "text": "regorafenib", "start": 85, "end": 96, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "lenvatinib", "start": 175, "end": 185, "token_start": 24, "token_end": 25}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Interstitial pneumonia suspected during regorafenib administration and exacerbated by subsequent therapy with lenvatinib for unresectable hepatocellular carcinoma. Recently, three tyrosine kinase inhibitors (TKIs) have become available for treatment of unresectable hepatocellular carcinoma (HCC). We herein report a case of a 59-year-old man with interstitial pneumonia that was suspected during regorafenib administration and was exacerbated by subsequent lenvatinib treatment for advanced HCC. After sorafenib was discontinued due to progressive HCC, regorafenib treatment was started. Progressive HCC was again noted and reticular shadows were suspected in both lower lung fields at 2\u00a0months after starting regorafenib administration. Subsequent treatment with lenvatinib obtained a partial response for HCC, but the reticular shadows became marked and dyspnea on effort emerged, followed by hypoxemia and an increased Krebs von den Lungen-6 (KL-6) value. Because we suspected acute interstitial pneumonia, due to these TKIs, intravenous pulse steroid therapy was started immediately after discontinuing lenvatinib. Within 1 week after starting steroid therapy, the patient's respiratory condition and hypoxemia gradually began improving. No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported . This case emphasizes that it is necessary to observe the patient's respiratory condition and to perform imaging examinations to monitor for adverse events during TKI treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/31020569/"}
{"doc_id": "859d945a579d4986f9e78e5574061f18", "sentence": "Treatment of articular manifestations of Lyme borreliosis is based on doxycycline , ceftriaxone , or amoxicillin for 28 days .", "spans": [{"span_id": 0, "text": "doxycycline", "start": 70, "end": 81, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "ceftriaxone", "start": 84, "end": 95, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "amoxicillin", "start": 101, "end": 112, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Lyme borreliosis and other tick-borne diseases. Guidelines from the French scientific societies (II). Biological diagnosis, treatment, persistent symptoms after documented or suspected Lyme borreliosis. The serodiagnosis of Lyme borreliosis is based on a two-tier strategy: a screening test using an immunoenzymatic technique (ELISA), followed if positive by a confirmatory test with a western blot technique for its better specificity. Lyme serology has poor sensitivity (30-40%) for erythema migrans and should not be performed. The seroconversion occurs after approximately 6 weeks, with IgG detection (sensitivity and specificity both>90%). Serological follow-up is not recommended as therapeutic success is defined by clinical criteria only. For neuroborreliosis, it is recommended to simultaneously perform ELISA tests in samples of blood and cerebrospinal fluid to test for intrathecal synthesis of Lyme antibodies. Given the continuum between early localized and disseminated borreliosis, and the efficacy of doxycycline for the treatment of neuroborreliosis, doxycycline is preferred as the first-line regimen of erythema migrans (duration, 14 days; alternative: amoxicillin) and neuroborreliosis (duration, 14 days if early, 21 days if late; alternative: ceftriaxone). Treatment of articular manifestations of Lyme borreliosis is based on doxycycline , ceftriaxone , or amoxicillin for 28 days . Patients with persistent symptoms after appropriate treatment of Lyme borreliosis should not be prescribed repeated or prolonged antibacterial treatment. Some patients present with persistent and pleomorphic symptoms after documented or suspected Lyme borreliosis. Another condition is eventually diagnosed in 80% of them.", "source": "https://pubmed.ncbi.nlm.nih.gov/31155367/"}
{"doc_id": "efa4b08c5bbcc2355040e7796d79ceea", "sentence": "Serious adverse events were reported by 24 ( 34 % ) of 71 patients receiving olaparib and abiraterone ( seven of which were related to treatment ) and 13 ( 18 % ) of 71 patients receiving placebo and abiraterone ( one of which was related to treatment ) .", "spans": [{"span_id": 0, "text": "olaparib", "start": 77, "end": 85, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "abiraterone", "start": 90, "end": 101, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "abiraterone", "start": 200, "end": 211, "token_start": 39, "token_end": 40}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. ### methods We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. ### findings Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13\u00b78 months (95% CI 10\u00b78-20\u00b74) with olaparib and abiraterone and 8\u00b72 months (5\u00b75-9\u00b77) with placebo and abiraterone (hazard ratio [HR] 0\u00b765, 95% CI 0\u00b744-0\u00b797, p=0\u00b7034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 ( 34 % ) of 71 patients receiving olaparib and abiraterone ( seven of which were related to treatment ) and 13 ( 18 % ) of 71 patients receiving placebo and abiraterone ( one of which was related to treatment ) . One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. ### interpretation olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer. ### funding AstraZeneca.", "source": "https://pubmed.ncbi.nlm.nih.gov/29880291/"}
{"doc_id": "7c77850fbf02b6b1536f130d367ec91e", "sentence": "In autoperfused hindquarters , the pressor-response curve to noradrenaline was dose-dependently shifted to the left by propranolol and to the right by labetalol or prazosin .", "spans": [{"span_id": 0, "text": "propranolol", "start": 119, "end": 130, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "labetalol", "start": 151, "end": 160, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "prazosin", "start": 164, "end": 172, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Blood pressure lowering action and alpha-adrenolytic effect of adimolol in rats. Adimolol is a new antihypertensive agent with strong nonselective beta- and moderate alpha-adrenolytic properties. In order to elucidate whether the alpha-adrenoceptor blockade by adimolol may contribute to the blood pressure lowering action of the compound, we tested 1) the effect on heart rate and blood pressure in conscious spontaneously hypertensive rats after oral administration and 2) the influence on the pressor effect of intra-arterially injected noradrenaline in autoperfused rat hindquarters after i.v. administration. Adimolol was compared with propranolol, labetalol, prazosin and combinations of propranolol plus low-dose prazosin. In conscious spontaneously hypertensive rats, labetalol, propranolol plus low-dose prazosin and adimolol lowered blood pressure considerably in parallel with heart rate. propranolol alone acutely lowered heart rate, but not blood pressure. Low-dose prazosin alone lowered blood pressure and heart rate only moderately. In autoperfused hindquarters , the pressor-response curve to noradrenaline was dose-dependently shifted to the left by propranolol and to the right by labetalol or prazosin . The leftward shift by propranolol could be antagonized dose-dependently by addition of low doses of prazosin. Adimolol, at doses of 0.1, 10 and 20 mg/kg, did not significantly influence the pressor-response curve to noradrenaline in this model, whereas a slight but significant shift to the left was observed with 1 mg/kg. In summary, the cardiovascular effects of adimolol in rats cannot completely be explained by beta-adrenoceptor blockade. They can be mimicked by the concomitant administration of a beta-adrenoceptor blocking and an alpha-adrenoceptor blocking agent. We conclude that the alpha-adrenolytic activity of adimolol can be demonstrated in vivo and may contribute to the blood pressure lowering action of the compound in rats.", "source": "https://pubmed.ncbi.nlm.nih.gov/2576194/"}
{"doc_id": "15c493f5c41258d28222b26c07daf4de", "sentence": "Expert opinion : Rivastigmine , a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase , is effective for dementia , whereas the use of Donepezil is still in the realm of investigation .", "spans": [{"span_id": 0, "text": "Rivastigmine", "start": 17, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "Donepezil", "start": 160, "end": 169, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "Pharmacotherapies for Parkinson's disease symptoms related to cholinergic degeneration. Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion : Rivastigmine , a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase , is effective for dementia , whereas the use of Donepezil is still in the realm of investigation . Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.", "source": "https://pubmed.ncbi.nlm.nih.gov/27785919/"}
{"doc_id": "d505ef0fff3fd78f3452d6b88fde849a", "sentence": "Chemotherapy with methotrexate , cyclophosphamide , vincristine , doxorubicin , etoposide , and dexamethasone was effective , and the patient has been free from the disease for 1 year since completion of consolidation treatment with autologous peripheral blood stem cell transplantation .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 18, "end": 30, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "cyclophosphamide", "start": 33, "end": 49, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "vincristine", "start": 52, "end": 63, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "doxorubicin", "start": 66, "end": 77, "token_start": 8, "token_end": 9}, {"span_id": 4, "text": "etoposide", "start": 80, "end": 89, "token_start": 10, "token_end": 11}, {"span_id": 5, "text": "dexamethasone", "start": 96, "end": 109, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": false}], "paragraph": "[Burkitt's lymphoma occurring as a primary lymphomatous effusion]. A 39-year-old man was admitted with massive ascites. Specimens of ascitic fluid contained numerous cells with a FAB-L3 appearance, and small noncleaved cell lymphoma morphology. These cells expressed CD10, CD19, CD20, CD38, CD45, HLA-DR, and IgM antigens, and were positive for IgM and c-myc protein in cytoplasmic immunostaining tests. Clonal rearrangements of IgH and c-myc genes were detected by Southern blot analysis. No mass lesions were found by physical examination, and systemic computed photography did not reveal enlargement of lymph nodes, spleen, or liver. Bone marrow aspiration showed no infiltration of malignant cells. Ga scintigraphy indicated hot lesions only in the abdomen. These findings suggested that Burkitt's lymphoma had developed in the peritoneal cavity as a primary lymphomatous effusion. Chemotherapy with methotrexate , cyclophosphamide , vincristine , doxorubicin , etoposide , and dexamethasone was effective , and the patient has been free from the disease for 1 year since completion of consolidation treatment with autologous peripheral blood stem cell transplantation .", "source": "https://pubmed.ncbi.nlm.nih.gov/10846464/"}
{"doc_id": "815dc3835a7afa5fb197dd55ae65116e", "sentence": "We have examined whether the DNA-damaging agents etoposide ( VP-16 ) and doxorubicin can affect IL-8 , VEGF , and HIF-1 expressions in human melanoma cancer cells .", "spans": [{"span_id": 0, "text": "etoposide", "start": 49, "end": 58, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "doxorubicin", "start": 73, "end": 84, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "A(2B) and A(3) adenosine receptors modulate vascular endothelial growth factor and interleukin-8 expression in human melanoma cells treated with etoposide and doxorubicin. Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often have abnormal growth factor and cytokine profiles. Thus, serum levels of interleukin-8 (IL-8) are elevated in patients with malignant melanoma. In addition to IL-8, aggressive melanoma cells secrete, through its transcriptional regulator hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), which promotes angiogenesis and metastasis of human cancerous cells. Whether these responses are related to adenosine, a ubiquitous mediator expressed at high concentrations in cancer and implicated in numerous inflammatory processes, is not known and is the focus of this study. We have examined whether the DNA-damaging agents etoposide ( VP-16 ) and doxorubicin can affect IL-8 , VEGF , and HIF-1 expressions in human melanoma cancer cells . In particular, we have investigated whether these responses are related to the modulation of the adenosine receptor subtypes, namely, A(1), A(2A), A(2B), and A(3). We have demonstrated that A(2B) receptor blockade can impair IL-8 production, whereas blocking A(3) receptors, it is possible to further decrease VEGF secretion in melanoma cells treated with VP-16 and doxorubicin. This understanding may present the possibility of using adenosine antagonists to reduce chemotherapy-induced inflammatory cytokine production and to improve the ability of chemotherapeutic drugs to block angiogenesis. Consequently, we conclude that adenosine receptor modulation may be useful for refining the use of chemotherapeutic drugs to treat human cancer more effectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/19794965/"}
{"doc_id": "fff0835233d3ddbb7dcf88fe31cc57ee", "sentence": "The effect of combined therapy with tamsulosin hydrochloride and meloxicam in patients with benign prostatic hyperplasia symptoms and impact on nocturia and sleep quality .", "spans": [{"span_id": 0, "text": "tamsulosin", "start": 36, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "meloxicam", "start": 65, "end": 74, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The effect of combined therapy with tamsulosin hydrochloride and meloxicam in patients with benign prostatic hyperplasia symptoms and impact on nocturia and sleep quality . We aimed to compare the effect and feasibility of a combined therapy with tamsulosin hydrochloride plus meloxicam, and tamsulosin hydrochloride alone in patients with benign prostate hyperplasia symptoms and impact on nocturia and sleep quality. ### Materials And Methods Four hundred male patients were included in this study between 2008 and 2011. Patients were randomly divided into two groups: one received tamsulosin hydrochloride 0.4 mg (Group 1, 200 patients) and the other tamsulosin hydrochloride 0.4 mg plus meloxicam 15 mg (Group 2, 200 patients) prospectively. Patients were evaluated for benign prostate hyperplasia (BPH) symptoms according to the American Urological Association clinical guidelines and sleep quality according to Pittsburgh Sleep Quality Index (PSQI). Patients were reevaluated after three months of treatment. The International Prostatic Symptom Score (IPSS), IPSS-Quality of Life (IPSS-QoL), maximal urinary flow rates (Qmax), average urinary flow rates (AFR), post void residual urine volumes (PVR), nocturia and Pittsburgh Sleep Quality Score (PSQS) were recorded at baseline and after three months. ### results Mean age was 63.3 \u00b1 6.6 and 61.4 \u00b1 7.5 years in groups 1 and 2, respectively (p = 0.245). There were no statistically significant differences between both groups. Also, baseline prostate specific antigen (PSA), prostate volume, creatinine, International Prostatic Symptom Score (IPSS), IPSS-Quality of Life (IPSS-QoL), maximal urinary flow rates (Qmax), average urinary flow rates (AFR), post void residual urine volumes (PVR), nocturia and Pittsburgh Sleep Quality Score (PSQS) were similar in both groups. In addition, the total IPSS, IPSS-QoL, PVR, nocturia, and PSQS were significantly lower in Group 2 compared with Group 1 after treatment (p < 0.05). Qmax and AFR were higher significantly in Group 2 compared with Group 1 after treatment (p < 0.05). ### conclusions Cyclooxygenase (COX)-2 inhibitors in combination with an alpha blocker may decrease benign prostatic hyperplasia symptoms and increase sleep quality without serious side effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/24267123/"}
{"doc_id": "92b0668dfd2cd4b06c20baf98572f867", "sentence": "We investigated two human ( RD2 and TE 671 ) cell lines by cultivating them with doxorubicin , cisplatinum , and etoposide .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 81, "end": 92, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "etoposide", "start": 113, "end": 122, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "cisplatinum", "start": 95, "end": 106, "token_start": 18, "token_end": 19}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Induction of drug resistance in human rhabdomyosarcoma cell lines is associated with increased maturation: possible explanation for differentiation in recurrences? In rhabdomyosarcoma (RMS) of childhood and adolescence very little is known about interactions of cytotoxic drugs and tumor cells. In recurrent RMS the tumor cells are often more mature than in the primary tumor. The biological properties of these cells are still a subject of controversy. We investigated two human ( RD2 and TE 671 ) cell lines by cultivating them with doxorubicin , cisplatinum , and etoposide . Degree of differentiation and proliferation rate were estimated morphologically and by means of immunohistochemistry and a monolayer proliferation assay. Both morphological and immunohistochemical maturation was measurable in most resistant cell lines. An increase in myosin expression was most marked in the etoposide- and doxorubicin-resistant RD cell lines. The proliferation rate was decreased in almost all resistant cell lines. Nevertheless, the resistant cell lines tolerated high-dose levels of cytotoxic drugs at a higher proliferation rate than parental cell lines cultivated under similar conditions. The maturation seen in some recurrent tumors of RMS can be simulated in vitro by cultivating cell lines with cytotoxic drugs at sublethal doses. Interestingly, the resistance-associated induced maturation was not accompanied by p170 expression. After comparing these in vitro results with the maturation seen in RMS specimens after chemotherapy, we conclude that chemotherapy-induced differentiation in vivo might be a morphological sign of chemoresistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/12007020/"}
{"doc_id": "fdbfe393e896f570074585fcec3e2409", "sentence": "Retrospective study on antihyperlipidemic efficacy and safety of simvastatin , ezetimibe and their combination in Korean adults .", "spans": [{"span_id": 0, "text": "simvastatin", "start": 65, "end": 76, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "ezetimibe", "start": 79, "end": 88, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Retrospective study on antihyperlipidemic efficacy and safety of simvastatin , ezetimibe and their combination in Korean adults . Antihyperlipidemic agents such as 3-hydroxymethyglutaryl-coenzyme A reductase inhibitors and cholesterol transporter inhibitors are used in coronary heart disease. However, controversy remains over the pharmacologic effects and safety of these drugs, especially when used in combination therapies. This retrospective study evaluated the therapeutic effect and safety of simvastatin 20 mg and ezetimibe 10 mg combination therapy compared to simvastatin 20 mg or ezetimibe 10 mg monotherapy in Korean patients according to gender, age, baseline low-density lipoprotein cholesterol, and cardiovascular risk factors. We observed significant differences among patient subgroups. simvastatin and ezetimibe monotherapies and combination therapy reduced low-density lipoprotein cholesterol levels by 27.6%, 10.1%, and 36.8% (p < 0.001) and total cholesterol levels by 17.5%, 9.2%, and 25.3% (p < 0.001), respectively. Both monotherapy and combination therapy groups had similar incidences of all types of adverse events. However, one case of rhabdomyolysis was observed in the combination therapy group. These results suggest that, compared to monotherapy, combination therapy has an additive effect that is not influenced by risk factors. Despite the low incidence of adverse events, caution is required when using these drugs, especially in the context of musculoskeletal side effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/21910055/"}
{"doc_id": "622f8e3f26b52587b2eda3e55333e6f1", "sentence": "The primary melanoma was surgically resected , and combination hepatic arterial infusion ( HAI ) therapy using dacarbazine , nimustine , vincristine ( DAV ) , and cisplatin was applied to the metastatic focus .", "spans": [{"span_id": 0, "text": "dacarbazine", "start": 111, "end": 122, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "nimustine", "start": 125, "end": 134, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "vincristine", "start": 137, "end": 148, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "cisplatin", "start": 163, "end": 172, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Combination hepatic arterial infusion therapy is effective for ocular melanoma metastasis to the liver. Regional treatments including chemotherapy have been applied to patients with malignant melanoma metastasis to the liver in clinical trials, but with limited efficacy. To improve efficacy, combination therapy may be beneficial. We had a case of multiple liver metastasis from right ocular malignant melanoma. The primary melanoma was surgically resected , and combination hepatic arterial infusion ( HAI ) therapy using dacarbazine , nimustine , vincristine ( DAV ) , and cisplatin was applied to the metastatic focus . After HAI, marked regression of the liver metastatic focus was observed. Unfortunately, the patient passed away due to involvement of thrombotic thrombocytopenic purpura 9 months after the initial consultation, however, aggravation of the liver metastatic focus was not observed. Combination HAI therapy may have a potent therapeutic effect on malignant melanoma metastasis to the liver, and our regimen using DAV and CDDP may be beneficial to the improvement of prognosis without serious side effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/16273253/"}
{"doc_id": "d30d8e197ed62a5846fa39352fea2768", "sentence": "These results were similar to those of previously reported salvage therapies for relapsed AML including intensive chemotherapy consisting of intermediate-dose Ara-C and sequential mitoxantrone with or without etoposide ( MC/MEC ) , which we previously adopted .", "spans": [{"span_id": 0, "text": "Ara-C", "start": 159, "end": 164, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "mitoxantrone", "start": 180, "end": 192, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "etoposide", "start": 209, "end": 218, "token_start": 27, "token_end": 28}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Comparison of low-dose cytosine arabinoside and aclarubicin in combination with granulocyte colony-stimulating factor to intermediate-dose cytosine arabinoside and mitoxantrone with or without etoposide in the treatment of relapsed acute myeloid leukemia]. We used a new chemotherapy regimen for the treatment of 18 consecutive patients with relapsed AML. The regimen consisted of low-dose cytosine arabinoside (Ara-C), low-dose aclarubicin and concurrent use of G-CSF (CAG regimen). Fifteen out of 18 patients (83%) achieved complete remission (CR). Median CR duration and median survival were 6 months and 15 months, respectively. These results were similar to those of previously reported salvage therapies for relapsed AML including intensive chemotherapy consisting of intermediate-dose Ara-C and sequential mitoxantrone with or without etoposide ( MC/MEC ) , which we previously adopted . Myelosuppression and non-hematological toxicities were apparently lower and less frequent compared to MC/MEC. The CAG regimen seems promising for the treatment of relapsed AML with its low toxicity contributing to a high quality of life for the patient.", "source": "https://pubmed.ncbi.nlm.nih.gov/7540220/"}
{"doc_id": "ebad3a925e573f30f197694c7209639f", "sentence": "Sensitivity of the test samples to the anti-cancer drugs cisplatin ( CDDP ) , doxorubicin ( DXR ) and etoposide ( VP-16 ) was examined using the MTT\u00bf3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl [2H]-tetrazolium bromide \u00bf assay .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 57, "end": 66, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "CDDP", "start": 69, "end": 73, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "doxorubicin", "start": 78, "end": 89, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "DXR", "start": 92, "end": 95, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "etoposide", "start": 102, "end": 111, "token_start": 19, "token_end": 20}, {"span_id": 5, "text": "VP-16", "start": 114, "end": 119, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Expression of multidrug-resistance-associated protein (MRP) and chemosensitivity in human gastric cancer. Evidence has accumulated that, in addition to the MDR1 gene-coded P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP) also mediates the multidrug resistance (MDR) of various human tumors. In the case of gastric cancer, there is little or no involvement of P-glycoprotein, and the mechanisms of MDR remain to be understood. To search for a possible relationship between expression of MRP and sensitivity to anti-cancer agents in gastric cancer, 4 gastric cancer cell lines, 43 human gastric carcinomas and 17 adjacent normal gastric tissue samples were analyzed. Expression of MRP mRNA was evaluated using reverse transcription PCR (RT-PCR) and Southern hybridization. Sensitivity of the test samples to the anti-cancer drugs cisplatin ( CDDP ) , doxorubicin ( DXR ) and etoposide ( VP-16 ) was examined using the MTT\u00bf3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl [2H]-tetrazolium bromide \u00bf assay . Immunohistochemical staining with the use of the MRP antibody (MRPr1) was done to confirm the findings regarding the expression of mRNA levels. The MRP expression evaluated with RT-PCR and Southern hybridization as well as with immunohistochemical staining revealed that 23 of 43 gastric-cancer tissues (53.5%), 15 of 17 normal gastric tissues (88%) and 3 of 4 gastric-cancer cell lines (75%) were positive. The MTT assay showed that DXR was significantly more sensitive (p < 0.01) in gastric carcinoma tissues lacking MRP expression than in those with positive expression. The same tendency was seen with the other agents used. Of the cell lines, one which showed no MRP expression also had a higher sensitivity to CDDP, DXR and VP-16 than the other positive cases. These results show that MRP expression is involved in MDR of human gastric cancer and is inversely related to the chemosensitivity of tumor cells against some anticancer drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/8903480/"}
{"doc_id": "87e13e6988ace8256ef6c96df9bd8310", "sentence": "In this phase I study , we combined cyclophosphamide , alvocidib and rituximab ( CAR ) in a schema designed to mitigate tumor lysis syndrome ( TLS ) seen previously with alvocidib .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 36, "end": 52, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "alvocidib", "start": 55, "end": 64, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "rituximab", "start": 69, "end": 78, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia. Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study , we combined cyclophosphamide , alvocidib and rituximab ( CAR ) in a schema designed to mitigate tumor lysis syndrome ( TLS ) seen previously with alvocidib . Nine nucleoside analog-na\u00efve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/23867058/"}
{"doc_id": "e08870403d68a688ed8b3eb1241f2f6d", "sentence": "Newer-generation recombinant tissue-type plasminogen activators , such as desmoteplase and tenecteplase , will also help extend the time window .", "spans": [{"span_id": 0, "text": "desmoteplase", "start": 74, "end": 86, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "tenecteplase", "start": 91, "end": 103, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "[Current and future aspects of intravenous thrombolysis for acute stroke]. Intravenous thrombolysis using alteplase was approved for clinical use for acute ischemic stroke treatment in Japan in 2005, on the basis of the results of a domestic clinical trial, Japan alteplase Clinical Trial. This therapeutic strategy has become the standard strategy during the following 8 years. However, this therapy still has room for improvement. One of the important drawbacks of intravenous thrombolysis is the limited therapeutic time window. On the basis of the results of the European Cooperative Acute Stroke Study III and the pooled analysis, the current time window is within 4.5 h of stroke onset. The window may be extended to 6 h or longer, probably by appropriate determination of the eligibility of a patient for receiving therapy by using penumbral imaging techniques, such as diffusion-weighted imaging (DWI)/perfusion-weighted imaging mismatch and DWI/magnetic resonance imaging mismatch. Newer-generation recombinant tissue-type plasminogen activators , such as desmoteplase and tenecteplase , will also help extend the time window . Patients with wake-up and unclear-onset strokes are generally ineligible for thrombolysis; therefore, the optimal therapeutic strategy for such patients should be established. Another important drawback is acute stroke therapy paralleling or following intravenous thrombolysis. Mechanical recanalization by endovascular therapy, antithrombotic therapy, neuroprotective therapy (e.g., using intravenous free radical scavenger), and sonothrombolysis are promising candidates for combined use with intravenous thrombolysis.", "source": "https://pubmed.ncbi.nlm.nih.gov/23832978/"}
{"doc_id": "672452da6ce653fb21320042736dbde0", "sentence": "Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide ( 200 mg/m(2 ) per day ) , doxorubicin ( 12.5 mg/m(2 ) per day ) , and etoposide ( 60 mg/m(2 ) per day ) ( CDE ) by continuous intravenous infusion for 4 days ( 96 hours ) every 3 weeks for a maximum of 8 cycles .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 98, "end": 114, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "doxorubicin", "start": 142, "end": 153, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "etoposide", "start": 186, "end": 195, "token_start": 28, "token_end": 29}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase 2 trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with poor-prognosis, intermediate-grade non-Hodgkin lymphoma: an Eastern Cooperative Oncology Group trial (E3493). Preclinical and clinical evidence suggest a potential advantage for infusional therapy in lymphoma. Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide ( 200 mg/m(2 ) per day ) , doxorubicin ( 12.5 mg/m(2 ) per day ) , and etoposide ( 60 mg/m(2 ) per day ) ( CDE ) by continuous intravenous infusion for 4 days ( 96 hours ) every 3 weeks for a maximum of 8 cycles . By the age-adjusted International Prognostic Index (IPI), 42% were at high risk and 58% were at high-intermediate risk. Complete response (CR) occurred in 30 (48%) patients (95% confidence interval [CI], 35%, 64%), and partial response occurred in 16 (26%) patients, yielding an overall response rate of 74% (95% CI, 62%, 84%). Failure-free survival (FFS) rates at 1 and 2 years were 55% (95% CI, 43%, 67%) and 50% (95% CI, 38%, 62%), respectively. When comparing the outcome for 62 patients receiving infusional CDE with historical data derived from 927 IPI-matched lymphoma patients using a Cox proportional hazards model, there was a nonsignificant trend favoring CDE in FFS (P =.12) and overall survival (P =.09). Severe or life-threatening toxicity included neutropenia (68%), anemia (57%), thrombocytopenia (44%), and infection (24%). Two patients (3%) died of treatment-related infectious complications. The primary end point of improving 1-year FFS from 55% to 70% was not achieved with infusional CDE given as initial therapy in patients with poor-risk intermediate-grade lymphoma. It is unlikely that infusional therapy as used in this study produces a 25% or greater relative improvement in FFS compared with standard therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/12176882/"}
{"doc_id": "4f68a01aceb6dbfae710114c2757110d", "sentence": "Preinjection of blocking doses of unlabeled epibatidine , (-)-nicotine , lobeline and cytisine significantly inhibited [18F]FPH binding in thalamus and superior colliculus , but not in cerebellum , whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR ( e.g. , mecamylamine , scopolamine , N-methylspiperone and ketanserin ) had no effect on [18F]FPH accumulation in any of the brain regions examined .", "spans": [{"span_id": 0, "text": "cytisine", "start": 86, "end": 94, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "mecamylamine", "start": 306, "end": 318, "token_start": 45, "token_end": 46}, {"span_id": 2, "text": "scopolamine", "start": 321, "end": 332, "token_start": 47, "token_end": 48}, {"span_id": 3, "text": "ketanserin", "start": 357, "end": 367, "token_start": 51, "token_end": 52}], "rels": [], "paragraph": "Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors. Visualization of central nicotinic acetylcholine receptors (nAChRs) with modern PET or SPECT imaging techniques has been hampered by the lack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics appropriate for the half-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent 18F-labeled analog of epibatidine, (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), in the mouse brain with the view towards application of this tracer for PET imaging of nAChR in human brain. ### methods Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the brain and other organs. Saturation and pharmacology of [18F]FPH binding was demonstrated in vivo by preinjecting unlabeled FPH or other drugs with known pharmacological action before [18F]FPH was injected. The effect of the drugs on [18F]FPH accumulation was evaluated. ### results [18F]FPH was rapidly incorporated into the mouse brain; peak activity (2.4% of the injected dose) was measured at 5 min after intravenous administration, followed by washout to 1.1% injected dose (ID) at 60 min. Highest concentrations of 18F occurred at 15 min in areas known to contain high densities of nAChR \u00bfe.g., thalamus [9.7% of injected dose per gram tissue (ID/g\u00bf] and superior colliculus (8.3% ID/g)]. Accumulation of the 18F tracer in hippocampus, striatum, hypothalamus and cortical areas was intermediate (5.0, 5.6, 4.2 and 5.6% ID/g, respectively) and low in the cerebellum (2.8% ID/g). The distribution of [18F]FPH in the mouse brain matched that of other in vivo nAChR probes such as 3H-labeled epibatidine or norchloroepibatidine, [3H](-)-nicotine and [3H]cytisine and that of nAChR densities determined in postmortem autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine , (-)-nicotine , lobeline and cytisine significantly inhibited [18F]FPH binding in thalamus and superior colliculus , but not in cerebellum , whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR ( e.g. , mecamylamine , scopolamine , N-methylspiperone and ketanserin ) had no effect on [18F]FPH accumulation in any of the brain regions examined . ### conclusion Fluorine-18-FPH labels nAChR in vivo in the mouse brain. Because of its high uptake into the brain and high ratios of specific-to-nonspecific binding, this radioligand appears to be ideally suited for PET imaging of nAChR in the mammalian brain.", "source": "https://pubmed.ncbi.nlm.nih.gov/9255161/"}
{"doc_id": "fc51943869ba80c534c3a9735da9494e", "sentence": "The combination carboplatin 35 mg/m2 , etoposide 50 mg/m2 , and ifosfamide 1,200 mg/m2 was administered intravenously daily for 3 consecutive days .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 16, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "etoposide", "start": 39, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "ifosfamide", "start": 64, "end": 74, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Carboplatin, etoposide, and ifosfamide as second-line treatment for ovarian cancer. A total of 25 patients with epithelial ovarian cancer were treated with second-line carboplatin, etoposide, and ifosfamide (ICE) following failure of first-line cisplatin-based combination chemotherapy. The combination carboplatin 35 mg/m2 , etoposide 50 mg/m2 , and ifosfamide 1,200 mg/m2 was administered intravenously daily for 3 consecutive days . Response was seen in 13 patients (52%) with 7 complete responses (28%) and 6 partial responses (24%). Median duration of response was 9+ months (range: 4-17+ months). Response rate to second-line ICE relates directly to prior response to first-line cisplatin-based chemotherapy: 12 patients (67%) responded to second-line ICE who responded to first-line cisplatin-based chemotherapy, while only 1 patient (14%) responded who progressed on first-line cisplatin-based chemotherapy. Median survival was 18+ months (range: 2-31+ months). There were six episodes (4%) of grade 4 neutropenia, seven episodes (4%) of grade 4 thrombocytopenia and no grade 3 or 4 nonhematologic toxicity. ICE has moderate activity with minimal toxicity as second-line treatment of advanced epithelial ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/8048396/"}
{"doc_id": "12a4c168d9a7ea026a7670baf0c300e0", "sentence": "Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells .", "spans": [{"span_id": 0, "text": "Aspirin", "start": 0, "end": 7, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "tamoxifen", "start": 62, "end": 71, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells . tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/28415819/"}
{"doc_id": "35f8267ec936fcf39e0b686b22908b3a", "sentence": "Eighty-three patients were in the control group who have performed a surgical intervention with pre-operative 120-hour antibiotic prophylaxis by Claforan ( cefotaxime ) combining with Metrogel ( metronidazole ) .", "spans": [{"span_id": 0, "text": "cefotaxime", "start": 156, "end": 166, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "metronidazole", "start": 195, "end": 208, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Antibacterial Prophylaxis in Emergency Surgery of Abdominal Infection. The results of antibiotic prophylaxis in 148 patients with destructive acute surgical sicknesses of abdominal cavity being urgently operated in the Republican hospital of Baku city from 2011 to 2016 were analyzed. Sixty-five patients were in the basic group which had got as preoperative antibiotic prophylaxis 120-hour course of amoxiclav (amoxicillin in combination with clavulanic acid). Eighty-three patients were in the control group who have performed a surgical intervention with pre-operative 120-hour antibiotic prophylaxis by Claforan ( cefotaxime ) combining with Metrogel ( metronidazole ) . it was showed that applying antibiotic prophylaxis using amoxiclav positively lowered the frequency of as postoperative purulent-septic complications as recurring operations to 8.1%.", "source": "https://pubmed.ncbi.nlm.nih.gov/30828552/"}
{"doc_id": "a1696a8b7ddd5677c27fdea2510cac89", "sentence": "The regimen was CD DP 40 mg/m2 day 1 and 6 , 5-FU 600 mg/m2 day 2 and 4 , leucovorin 20 mg/m2 day 2 and 4 , etoposide 60 mg/m2 day 3 and 5 , and doxorubicin 20 mg/m2 day 7 , with repetition every 28 days .", "spans": [{"span_id": 0, "text": "CD DP", "start": 16, "end": 21, "token_start": 3, "token_end": 5}, {"span_id": 1, "text": "leucovorin", "start": 74, "end": 84, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "etoposide", "start": 108, "end": 117, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "doxorubicin", "start": 145, "end": 156, "token_start": 37, "token_end": 38}, {"span_id": 4, "text": "5-FU", "start": 45, "end": 49, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "[Etoposide, doxorubicin, cisplatin and 5-FU (EAP-F) therapy of advanced gastric cancer--its antitumor effect and evaluation of quality of life]. Fourteen patients with advanced gastric cancer were treated with EAP-F therapy. The regimen was CD DP 40 mg/m2 day 1 and 6 , 5-FU 600 mg/m2 day 2 and 4 , leucovorin 20 mg/m2 day 2 and 4 , etoposide 60 mg/m2 day 3 and 5 , and doxorubicin 20 mg/m2 day 7 , with repetition every 28 days . Thirteen patients were evaluable; one patient was CR, four were PR, five were NC and three were PD. The response rate was 38.5% and median survival was 7 months. Hematologic toxicities were moderate to severe but tolerable, gastrointestinal toxicities were mild and renal toxicity was absent. Quality of life (QOL) of the patients was evaluated by means of symptom-free ratio (duration of symptom-free to survival time) and outpatient ratio (duration at home in relation to survival time). Patients with lymph node metastasis showed a higher symptom-free ratio and outpatient ratio than those with liver metastasis or peritoneal dissemination. All high-QOL patients were chemotherapy responders. In conclusion, EAP-F therapy is effective for advanced gastric cancer and its side effects are tolerable. CR or PR is necessary to achieve a high QOL.", "source": "https://pubmed.ncbi.nlm.nih.gov/8379671/"}
{"doc_id": "8baac7e5456a6ad064382efcdc6c224a", "sentence": "A German Hodgkin 's lymphoma ( HL ) study group designed the BEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisolone ) regimen .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 71, "end": 80, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "etoposide", "start": 83, "end": 92, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "doxorubicin", "start": 95, "end": 106, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "cyclophosphamide", "start": 109, "end": 125, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "vincristine", "start": 128, "end": 139, "token_start": 22, "token_end": 23}, {"span_id": 5, "text": "procarbazine", "start": 142, "end": 154, "token_start": 24, "token_end": 25}, {"span_id": 6, "text": "prednisolone", "start": 157, "end": 169, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": true}], "paragraph": "Multicentre phase II study of the baseline BEACOPP regimen for patients with advanced-stage Hodgkin's lymphoma.  A German Hodgkin 's lymphoma ( HL ) study group designed the BEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisolone ) regimen . In the BEACOPP regimen, treatment intervals were shortened and the dose-intensity was increased compared with those in the ABVD regimen (doxorubicin, bleomycin, vinblastine and darcarbacine), resulting in a long-term disease-free survival rate of approximately 75-80%. In the present study, we evaluated the safety and efficacy of the BEACOPP regimen. Between April 2001 and February 2004, 20 patients with HL of stage IIB or higher who had received no previous treatment were enrolled. The patients were aged 17-69 years (median 22 years). The histologic types were mixed cellularity in four cases and nodular sclerosis in 16 cases. The stages were stage IIB in four cases, stage III in 12 cases, and stage IV in four cases. Nineteen (95%) of the 20 patients achieved complete remission. The 3-year survival rate was 100% and the 3-year progression-free survival rate was 89.7%. Adverse drug reactions were grade 4 neutropenia in 12 patients, grade 3-4 thrombocytopenia in seven patients, and grade 3 or higher non-hematologic toxicities in two patients (stomatitis in one patient and ALT/AST elevation in one patient). The BEACOPP regimen for advanced-stage HL showed an excellent complete remission rate and high efficacy even in stage III/IV patients. However, a long-term risk of the BEACOPP regimen is the development of secondary leukemia or myelodysplastic syndrome. Therefore, long-term follow-up of these patients, including monitoring for toxicities, is necessary.", "source": "https://pubmed.ncbi.nlm.nih.gov/17065005/"}
{"doc_id": "3ce3c390490d351b517a25102e52bd40", "sentence": "High-risk node-negative or low-risk node-positive breast cancer patients received AC given : ( arm I ) concurrently ( AC ) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously ( IV ) every 3 weeks for six cycles ; or ( arm II ) in sequence ( A C ) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 123, "end": 134, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "cyclophosphamide", "start": 148, "end": 164, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "doxorubicin", "start": 260, "end": 271, "token_start": 49, "token_end": 50}, {"span_id": 3, "text": "cyclophosphamide", "start": 341, "end": 357, "token_start": 65, "token_end": 66}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). ### Patients And Methods High-risk node-negative or low-risk node-positive breast cancer patients received AC given : ( arm I ) concurrently ( AC ) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously ( IV ) every 3 weeks for six cycles ; or ( arm II ) in sequence ( A C ) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles . Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. ### results Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar. ### conclusion The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.", "source": "https://pubmed.ncbi.nlm.nih.gov/17308269/"}
{"doc_id": "7c6e57e9403313b30190f927bebc1b20", "sentence": "The CAV/PE-W consisted of 4 alternating cycles of cyclophosphamide : 500 mg/m2 , doxorubicin : 30 mg/m2 , and vincristine : 1 mg/m2 ( day 1 ) and cisplatin : 50 mg/m2 ( day 8) and etoposide : 75 mg/m2 ( days 8 and 9 ) .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 50, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "doxorubicin", "start": 81, "end": 92, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "vincristine", "start": 110, "end": 121, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "cisplatin", "start": 146, "end": 155, "token_start": 28, "token_end": 29}, {"span_id": 4, "text": "etoposide", "start": 180, "end": 189, "token_start": 36, "token_end": 37}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Dose-intensive weekly alternating chemotherapy for patients with small cell lung cancer: randomized trial, can it improve survival of patients with good prognostic factors? We conducted a randomized trial of dose-intensive weekly alternating chemotherapy (CAV/PE-W) and standard alternating chemotherapy (CAV/PE) in small cell lung cancer (SCLC) patients with good prognostic factors. A total of 76 patients with SCLC was randomized. The CAV/PE-W consisted of 4 alternating cycles of cyclophosphamide : 500 mg/m2 , doxorubicin : 30 mg/m2 , and vincristine : 1 mg/m2 ( day 1 ) and cisplatin : 50 mg/m2 ( day 8) and etoposide : 75 mg/m2 ( days 8 and 9 ) . The CAV/PE consisted of 2 alternating cycles of cyclophosphamide: 800 mg/m2, doxorubicin: 50 mg/m2, and vincristine: 1.4 mg/m2 (day 1), cisplatin: 100 mg/m2 (day 22) and etoposide: 100 mg/m2 (days 22, 23 and 24). Eligibility criteria were no prior therapy, no active concomitant malignancy, ECOG PS of 0 or 1, age < or =75, adequate hematologic functions and no brain metastasis. The complete response (CR) rate for CAV/PE-W (14/38, 36.8%) was significantly higher than that for CAV/PE (6/38, 15.8%, chi2; p=0. 032). However, the response rate in patients on CAV/PE-W (36/38, 94. 7%) was not significantly higher than the rate for CAV/PE (31/38, 81. 6%, chi2; p=0.076). Progression-free survival for patients on CAV/PE-W was significantly longer than that of patients on CAV/PE (41.4 weeks vs. 21.3 weeks, log-rank; p=0.0007, generalized Wilcoxon; p=0.0034) as was overall median survival (67.0 weeks vs. 51.2 weeks, log-rank; p=0.028). Actual dose-intensity of CAV/PE-W was 1.74 times that of CAV/PE. Hematological toxicities were equally frequent and G-CSF contributes to treatment efficacy by allowing administration of dose-intensive chemotherapy. The CAV/PE-W achieved a higher CR rate and longer survival, than the CAV/PE.", "source": "https://pubmed.ncbi.nlm.nih.gov/10671676/"}
{"doc_id": "804db6df1fe6220163926d911218acbe", "sentence": "Cyclophosphamide , methotrexate , 5-fluorouracil , and folinic acid ( CMFF ) as first line chemotherapy for treatment of advanced breast cancer .", "spans": [{"span_id": 0, "text": "Cyclophosphamide", "start": 0, "end": 16, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "methotrexate", "start": 19, "end": 31, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "5-fluorouracil", "start": 34, "end": 48, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "folinic acid", "start": 55, "end": 67, "token_start": 7, "token_end": 9}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Cyclophosphamide , methotrexate , 5-fluorouracil , and folinic acid ( CMFF ) as first line chemotherapy for treatment of advanced breast cancer . In order to evaluate the maximum tolerable dose of a combination chemotherapy consisting of cyclophosphamide, methotrexate, 5-fluorouracil, and folinate (CMFF), 30 female patients with histopathologically confirmed, previously untreated advanced breast cancer were entered into this pilot study. Chemotherapy consisted of fixed doses for methotrexate (40 mg/m2 i.v. on day 1), 5-fluorouracil (500 mg/m2 i.v. on day 2 to 4) and folinic acid (2 x 200 mg/m2 i.v., 0 + 2 h on day 2 to 4). The dose of cyclophosphamide was escalated stepwise, starting with 200 mg/m2 i.v. on day 2 to 4, to 240 mg/m2, 290 mg/m2, 360 mg/m2 and 400 mg/m2, respectively, for each subsequent five patients. Treatment was repeated every four weeks. A total of 92 treatment cycles was given. Myelosuppression was the dose-limiting toxicity: leukopenia WHO grade III or IV was observed after a total of 28 cycles and anemia of equal intensity after 1 cycle. No thrombocytopenia WHO grade III or IV was recorded. Myelotoxicity increased with higher doses of cyclophosphamide. Among non-hematologic toxicities, alopecia was reported in two-thirds of the patients. Nausea and vomiting was noted in 25% of treatment cycles, but in one cycle only WHO grade III was recorded. No other toxicities exceeding WHO grade II occurred.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/7556280/"}
{"doc_id": "56fc8b6a971baec8e8e6232a1d49c4db", "sentence": "High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia .", "spans": [{"span_id": 0, "text": "rosuvastatin", "start": 14, "end": 26, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "rosuvastatin", "start": 56, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "fenofibrate", "start": 74, "end": 85, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": false}], "paragraph": "High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia . The aim of the study was to compare the efficacy of high-dose rosuvastatin, low-dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega-3 fatty acids with regard to the lipid profile in patients with mixed hyperlipidemia. The primary endpoint was changes in non-high density lipoprotein-cholesterol (non-HDL-C) levels. Study participants were randomly allocated to receive rosuvastatin 40 mg (n = 30, R group), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 30, RF group) or rosuvastatin 10 mg plus n-3 fatty acids 2 g (n = 30, RN group). Non-HDL-C levels were reduced in all groups: in R group by 54%, in RF group by 42% and in RN group by 42%. Significant reductions in total cholesterol (TC), low density lipoprotein (LDL)-C and triglyceride levels were observed in all groups. The reductions in total and LDL-C were greatest in the R group while a more pronounced reduction of triglycerides in the RF group compared with that in the R and the RN group was observed. HDL-C levels were significantly increased only in the RF group. In conclusion, high doses of rosuvastatin and small doses of rosuvastatin plus either fenofibrate or n-3 fatty acids exhibit favorable effects on both LDL-C and non-HDL-C levels. However, rosuvastatin monotherapy more potently reduces these parameters. The combination of rosuvastatin plus fenofibrate leads to a greater decrease in triglyceride levels and a greater increase in HDL-C levels compared with the other two treatments. While awaiting the results of ongoing trials high doses of rosuvastatin may represent the treatment of choice in individuals with mixed dyslipidemia.", "source": "https://pubmed.ncbi.nlm.nih.gov/21327725/"}
{"doc_id": "17cb9a6a848c31e4bcf08252e3b4f2a4", "sentence": "Patients were divided randomly into 3 groups ( Group A : 0.5 % bupivacaine 5 mL , n = 12 ; Group B : 0.5 % bupivacaine 4.5 mL + 20 mg of triamcinolone 0.5 mL , n = 10 ; and Group C : 0.5 % bupivacaine 4 mL + 40 mg of triamcinolone 1 mL , n = 10 ) .", "spans": [{"span_id": 0, "text": "bupivacaine", "start": 63, "end": 74, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "bupivacaine", "start": 107, "end": 118, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "triamcinolone", "start": 137, "end": 150, "token_start": 33, "token_end": 34}, {"span_id": 3, "text": "bupivacaine", "start": 189, "end": 200, "token_start": 47, "token_end": 48}, {"span_id": 4, "text": "triamcinolone", "start": 217, "end": 230, "token_start": 54, "token_end": 55}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}, {"class": "POS", "spans": [3, 4], "is_context_needed": true}], "paragraph": "Effects of stellate ganglion block on breast cancer-related lymphedema: comparison of various injectates. To determine the effects of SGB in BCRL patients and the efficacy of corticosteroids in SGB. ### Study Design A double-blinded, randomized, controlled trial. ### setting A single academic hospital, outpatient setting. ### methods In total, 32 patients with BCRL were recruited. Patients were divided randomly into 3 groups ( Group A : 0.5 % bupivacaine 5 mL , n = 12 ; Group B : 0.5 % bupivacaine 4.5 mL + 20 mg of triamcinolone 0.5 mL , n = 10 ; and Group C : 0.5 % bupivacaine 4 mL + 40 mg of triamcinolone 1 mL , n = 10 ) . All patients received 3 consecutive SGBs, every 2 weeks. The primary outcomes were changes in forearm and upper arm circumference. Circumference was measured at baseline, 2 weeks (before the second injection), 4 weeks (before the third injection), and 8 weeks (one month follow-up after 3 consecutive SGBs). Moreover, subjective data were collected using EORTC C-30 at baseline and 8 weeks. ### results After 3 consecutive SGBs, forearm and upper arm circumferences were decreased significantly from baseline in all groups (P < 0.05/3). The upper arm circumference of group C was reduced significantly more than that of group A (P < 0.05/3). The subjective data by EORTC-C30 at baseline and one month after 3 consecutive SGBs revealed no statistically significant difference. ### limitations Relatively few patients were enrolled. We did not compare SGB with any other BCRL treatment, such as complex decongestive therapy. ### conclusions This study suggests that SGB may be an effective treatment for BCRL. Furthermore, it appears that corticosteroids could have an additive effect in SGB.", "source": "https://pubmed.ncbi.nlm.nih.gov/25675063/"}
{"doc_id": "997c056fe37bad3e5f2f38a1ca36251f", "sentence": "Irinotecan and etoposide were combined using the ( d x 5)2 i.v . schedule for both drugs , in which irinotecan was given 2 h before or 2 h after the administration of etoposide .", "spans": [{"span_id": 0, "text": "Irinotecan", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "etoposide", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "irinotecan", "start": 100, "end": 110, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "etoposide", "start": 167, "end": 176, "token_start": 33, "token_end": 34}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}, {"class": "NEG", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Evaluation of irinotecan in combination with 5-fluorouracil or etoposide in xenograft models of colon adenocarcinoma and rhabdomyosarcoma. irinotecan [7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothec in] administered i.v. in two courses, each course consisting of administration every day for 5 days [(dx5)2] on days 1-5 and 8-12, has demonstrated significant activity against advanced human tumor xenografts derived from colon adenocarcinomas and several childhood cancers. To build on this therapy, we have evaluated the combination of irinotecan given on this schedule with 5-fluorouracil given on days 1, 7, and 14 with or without leucovorin [(dx5)3 i.v.] against colon tumors, or combined with etoposide administered (dx5)2 i.v. either 2 h before or 2 h after irinotecan for treatment of colon tumors and rhabdomyosarcomas. A combination of 5-fluorouracil at 75% and irinotecan at 50% of their respective maximum tolerated doses when administered as single agents on this schedule gave acceptable toxicity. Against colon adenocarcinoma xenografts, 5-fluorouracil did not enhance the response rate compared with that obtained with the optimum dose of irinotecan given as a single agent. Against GC3/TK- xenografts, which lack thymidine kinase and cannot salvage thymidine to circumvent the inhibition of thymidylate synthase, the addition of leucovorin to the combination increased the complete response rate from 10 to >90%, whereas the response rates for the optimal doses of irinotecan or 5-fluorouracil, as single agents, were 30 and <10%, respectively. etoposide d x 5 i.v. for two or three courses or (d x 5)3 p.o. did not cause objective regression of any colon tumors. In contrast, three of five rhabdomyosarcoma lines demonstrated a high frequency of partial regressions or complete regressions when treated (d x 5)1 i.v. Repetitive courses [e.g., (d x 5)2 or (d x 5)3] i.v. or p.o. or by 4-h infusion d x3 i.v. were either equally effective or less effective. Irinotecan and etoposide were combined using the ( d x 5)2 i.v . schedule for both drugs , in which irinotecan was given 2 h before or 2 h after the administration of etoposide . Each drug could be combined at only 38% of its respective maximum tolerated dose when administered as a single agent, indicating greater than additive toxicity. Toxicity was similar irrespective of the sequence of administration and was manifested by loss of weight (73% of the initial weight, nadir day 7), myelosuppression, and prolonged thrombocytopenia. The responses of colon carcinomas to the combination given in either sequence were similar to that achieved with irinotecan given alone at the same dose as used in the combination. Similarly, when etoposide was given before irinotecan, the responses of rhabdomyosarcomas were similar to those for irinotecan. However, in experiments in which etoposide was administered 2 h after each dose of irinotecan, there was significant antagonism of the antitumor activity of irinotecan.", "source": "https://pubmed.ncbi.nlm.nih.gov/9816097/"}
{"doc_id": "621f146564276541685c53b25bb29395", "sentence": "Combination of sofosbuvir , pegylated-interferon and ribavirin for treatment of hepatitis C virus genotype 1 infection : a systematic review and meta-analysis .", "spans": [{"span_id": 0, "text": "sofosbuvir", "start": 15, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "pegylated-interferon", "start": 28, "end": 48, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "ribavirin", "start": 53, "end": 62, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Combination of sofosbuvir , pegylated-interferon and ribavirin for treatment of hepatitis C virus genotype 1 infection : a systematic review and meta-analysis . Hepatitis C virus (HCV) infection is an important cause of chronic liver disease which has been affected 3% of world's population. Some studies have shown that adding sofosbuvir (SOF), an HCV polymerase inhibitor to the conventional therapy of Pegylated-interferon (PegIFN) plus ribavirin (RBV) can increase the rate of sustained virologic response (SVR) among HCV-infected patients. This study was conducted to determine the effect of combination therapy with PegIFN and RBV plus SOF for chronic hepatitis C genotype 1 infection using systematic review with meta-analysis. ### methods In this study, electronic databases including PubMed, Scopus, Science Direct, and Web of Science were comprehensively searched using appropriate strategies containing all related keywords of \"hepatitis C\", \"PegIFN\", \"RBV\" and \"SOF\". Studies assessed the efficacy of combination therapy with PegIFN and RBV plus SOF for chronic hepatitis C genotype 1 infection were included in the meta-analysis. ### results After screening of 757 records, we included five articles with total sample size of 411 to the meta-analysis. Based on the fixed-effect model (\u03c7 ### conclusions Combination therapy with PegIFN and RBV plus SOF results in high treatment response in patients with HCV genotype 1 infection.", "source": "https://pubmed.ncbi.nlm.nih.gov/28427463/"}
{"doc_id": "0918877efd6947ff1d51584709e4a6d1", "sentence": "Immunosuppressive protocol : preoperative : Cyclosporin + Azathioprine .", "spans": [{"span_id": 0, "text": "Cyclosporin", "start": 44, "end": 55, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "Azathioprine", "start": 58, "end": 70, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[Predictive variables of early mortality after orthotopic heart transplant in adults]. The purpose of the study was to analyze some variables of donors, recipients and surgical procedures in order to discover factors that could predict mortality during the early stage (< 30 days) of orthotopic heart transplants. ### Material And Method 125 consecutive orthotopic heart transplants in adults were analyzed. The average age was 51 +/- 11 (range: 12-67), 109 (87%) were men, 16 were women (13%). Two groups were compared: 15 patients who died within 30 days after heart transplant and 110 who survived during that period. Immunosuppressive protocol : preoperative : Cyclosporin + Azathioprine . Intraoperative: methylprednisolone Postoperative: methylprednisolone (first 24 h), antilymphocyte monoclonal antibodies (7-10 days after heart transplant) + cyclosporin + azathioprine + Corticoids. The following parameters of the recipient were analyzed: sex, age, weight, size, thoracic perimeter, pretransplant cardiopathy, previous thoracic operations, functional stage or need for catecholamines during the days prior to the transplant, pulmonary artery pressure and resistance, history of systemic arterial hypertension, elevation of creatinine, blood type, urgent transplant indication, receptor/donor weight relationship. The following parameters of donors and operation were analyzed: sex, age, weight, thoracic perimeter, period in intensive care unit, dose of dopamine and dobutamine, blood type, origin of the organ, cause of death, ischaemia time, cardiopulmonary by-pass time and cardioplegia type. ### results The rate of early mortality was 12%. The univariate analysis showed differences in: prior cardiovascular surgery, receptor blood type, need for urgent transplantation, pulmonary artery resistance > 2.5 Wood Units, cardiopulmonary by-pass time, weight relationship between receptor and donor. The death cause of the donor proved significant. On multivariate analysis, the following parameters independently predicted early mortality: history of operation with extracorporeal circulation, high pulmonary artery resistance, urgent transplant, receptor/donor weight relation and time of extracorporeal circulation. ### conclusions We believe that the results of our experience can help to stratify the risk in the orthotopic heart transplant recipient and even to contraindicate the procedure in some cases showing an accumulation of poor prognostic factors in borderline recipients.", "source": "https://pubmed.ncbi.nlm.nih.gov/9380932/"}
{"doc_id": "a30e9207f775411973062008ed2b4768", "sentence": "Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 41, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "interferon alfa", "start": 65, "end": 80, "token_start": 9, "token_end": 11}], "rels": [], "paragraph": "Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma . A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-alpha) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. ### Patients And Methods Seven hundred fifty treatment-na\u00efve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-alpha 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. ### results Median overall survival was greater in the sunitinib group than in the IFN-alpha group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-alpha group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). ### conclusion sunitinib demonstrates longer overall survival compared with IFN-alpha plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/19487381/"}
{"doc_id": "59354e45aad85a9d345a328c1ae46f7d", "sentence": "All patients received chemotherapy regimens that included doxorubicin ( 6 ) or etoposide ( 1 ) , and six were treated with infradiaphragmatic irradiation .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 58, "end": 69, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "etoposide", "start": 79, "end": 88, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group. This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. ### Patients And Methods The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. ### results Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin ( 6 ) or etoposide ( 1 ) , and six were treated with infradiaphragmatic irradiation . The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. ### conclusions The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/11216701/"}
{"doc_id": "b503fc2fdf98c99285b21e109f520a8b", "sentence": "Of 1490 articles identified , we included 3 papers and 1 abstract with patients on aspirin and/or NSAIDs , 1 paper on warfarin , 2 abstracts on clopidogrel , and 2 papers on clopidogrel plus aspirin and/or NSAIDs .", "spans": [{"span_id": 0, "text": "aspirin", "start": 83, "end": 90, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "warfarin", "start": 118, "end": 126, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "clopidogrel", "start": 144, "end": 155, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "clopidogrel", "start": 174, "end": 185, "token_start": 33, "token_end": 34}, {"span_id": 4, "text": "aspirin", "start": 191, "end": 198, "token_start": 35, "token_end": 36}], "rels": [], "paragraph": "Systematic review with meta-analysis: the risk of gastrointestinal haemorrhage post-polypectomy in patients receiving anti-platelet, anti-coagulant and/or thienopyridine medications. For patients undergoing colonoscopy with polypectomy, current guidelines recommend temporary cessation of blood-thinning medications. The data regarding periprocedural management of these medications are sparse. ### aim To perform a systematic review and meta-analysis to determine the risk of post-polypectomy bleeding (PPB) in patients taking anti-platelet, anti-coagulant and/or thienopyridine medications. ### methods We searched Pubmed, Scopus, Web of Science, Biosis and Proceedings First from 1970 to 2015. PPB was defined as overt haemorrhage or drop in haemoglobin of at least 2\u00a0g/dL. ### results Of 1490 articles identified , we included 3 papers and 1 abstract with patients on aspirin and/or NSAIDs , 1 paper on warfarin , 2 abstracts on clopidogrel , and 2 papers on clopidogrel plus aspirin and/or NSAIDs . While the rate of immediate PPB on aspirin and/or NSAIDs was not increased (OR\u00a0=\u00a01.1, 95% CI 0.7-1.9, P\u00a0=\u00a00.7), the risk of delayed PPB was increased (OR\u00a0=\u00a01.7, 95% CI 1.0-2.4, P\u00a0=\u00a00.0009, I(2) \u00a0=\u00a060%) but rendered non-significant with elimination of a small study. There was an elevated risk of delayed PPB on clopidogrel (OR\u00a0=\u00a09.7, 95% CI 3.1-30.8, P\u00a0=\u00a00.0, I(2) \u00a0=\u00a00). There was an increased risk of delayed PPB in patients on clopidogrel + aspirin and/or NSAIDs (OR\u00a0=\u00a03.4, 95% CI 1.3-8.8, P\u00a0=\u00a00.01, I(2) \u00a0=\u00a00). Based on a single study on warfarin, the PPB rate was elevated. There were no data regarding PPB and usage of the newer anti-coagulant agents. ### conclusions Usage of aspirin or NSAIDs does not increase risk of post-polypectomy bleeding. clopidogrel and warfarin should be discontinued in the periprocedural period to prevent the occurrence of post-polypectomy bleeding.", "source": "https://pubmed.ncbi.nlm.nih.gov/26290157/"}
{"doc_id": "0ee5facfd933895edac8cca7e2f1c707", "sentence": "Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 76, "end": 87, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "etoposide", "start": 91, "end": 100, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide . In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/9862568/"}
{"doc_id": "8432d329c360d59237a984529cc02420", "sentence": "We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4 .", "spans": [{"span_id": 0, "text": "efavirenz", "start": 17, "end": 26, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "etravirine", "start": 31, "end": 41, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "A computational study of CYP3A4 mediated drug interaction profiles for anti-HIV drugs. Molecular docking is a reliable method with which to identify the binding conformations of substrates, inducers and inhibitors of cytochrome P450 (CYP) enzymes. We used the docking method to explore possible binding modes of an entry inhibitor (maraviroc) and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz and etravirine) to cytochrome P450 3A4 (CYP3A4). In addition, docking results were compared with the binding conformations of HIV protease drugs to infer the binding site residues and potential drug-drug interaction profiles for combination therapy in the treatment of AIDS. We observed that efavirenz and etravirine induce metabolism of co-administered drugs by binding to a unique position in the active site of CYP3A4 . Dosage adjustment is required for delavirdine and maraviroc when combined with HIV protease drugs. The present results are in good agreement with experimental data from drug interaction profiles. The information provided in this paper will be helpful in furthering our understanding the functions of CYP3A4, and could aid in the design of new drugs that would be metabolized easily without having any drug-drug interaction profile.", "source": "https://pubmed.ncbi.nlm.nih.gov/21080015/"}
{"doc_id": "7ba792e04aba157338edb97b548221a7", "sentence": "First , we searched for the most synergistic combination of KPT-8602 with dexamethasone , vincristine , or doxorubicin", "spans": [{"span_id": 0, "text": "KPT-8602", "start": 60, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dexamethasone", "start": 74, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "vincristine", "start": 90, "end": 101, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "doxorubicin", "start": 107, "end": 118, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 3], "is_context_needed": true}], "paragraph": "The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia. KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL. ### Experimental Design First , we searched for the most synergistic combination of KPT-8602 with dexamethasone , vincristine , or doxorubicin ### results KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as ### conclusions Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/32826328/"}
{"doc_id": "e5be67692bd5bdc02b9cf9d8fc2fe673", "sentence": "In Thailand , artesunate and artemether are the mainly used antimalarials for treatment of severe or multidrug resistant falciparum malaria .", "spans": [{"span_id": 0, "text": "artesunate", "start": 14, "end": 24, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "artemether", "start": 29, "end": 39, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "The rational use of qinghaosu and its derivatives: what is the future of new compounds?  In Thailand , artesunate and artemether are the mainly used antimalarials for treatment of severe or multidrug resistant falciparum malaria . However, their availability (supply) and the registration requirements are the major limitations for their large-scale use. At Bangkok Hospital for Tropical Diseases, Thailand, we have studied the new artemisinin derivatives, dihydroartemisinin and arteether, and artesunate suppositories. We found that the three preparations are well tolerated, safe, and efficacious.", "source": "https://pubmed.ncbi.nlm.nih.gov/10212910/"}
{"doc_id": "33ce13cf1b55df095019be91cf6bb3db", "sentence": "Epidural analgesia during labor--0.5 % lidocaine with fentanyl vs. 0.08 % ropivacaine with fentanyl .", "spans": [{"span_id": 0, "text": "lidocaine", "start": 39, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "fentanyl", "start": 54, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "ropivacaine", "start": 74, "end": 85, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "fentanyl", "start": 91, "end": 99, "token_start": 13, "token_end": 14}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Epidural analgesia during labor--0.5 % lidocaine with fentanyl vs. 0.08 % ropivacaine with fentanyl . Although lidocaine is a cheap and globally available local anesthetic, yet it is not a popular drug for labor analgesia. This is claimed to its higher intensity of motor block, possibility of transient neurological symptoms (TNS) and its placental transfer with probable drawbacks on fetal well-being. However, these effects could be concentration dependent and, the evidence linking them to lidocaine is still lacking. This study was designed to evaluate the efficacy and safety of 0.5% epidural lidocaine plus fentanyl during labor. ### methods One hundred and twenty healthy full term nulliparous women in early labor with a single fetus presented by the vertex were enrolled in this randomized, double-blind clinical trial. Parturient were assigned to receive epidural analgesia either with lidocaine 0.5% plus fentanyl 2 microg(-1 mL) (LF), or ropivacaine 0.08% plus fentanyl 2 microg(-1 ml) (RF) when their cervix was dilated to 4 centimeters. Analgesia was provided with 20 ml bolus of the study solution and maintained at 10 ml(-1) h. Upper level of sensory loss to cold, Visual Analogue Pain Score (VAPS), motor block (modified Bromage score), the duration of the first and second stages of labor, numbers of instrumental vaginal and cesarean deliveries, the neonatal apgar score, patient satisfaction and side effects, were recorded. ### results There were no significant differences in sensory level, pain scores, duration of the first and second stages of labor, numbers of instrumental and cesarean deliveries, the neonatal apgar scores, patient satisfaction or side effect between groups. Although motor block was significantly high in lidocaine group compared to ropivacaine group (p < 0.05), all parturient were moving satisfactorily in bed. ### conclusions Dilute epidural lidocaine (0.5%) with fentanyl effectively and safely initiates epidural analgesia clinically indistinguishable from 0.08% epidural ropivacaine with fentanyl. Although it induces significant motor block compared to ropivacaine, it still preserves maternal ability to move satisfactorily in bed. Whether further reduction in lidocaine concentration could trim down the motor block, remains to be investigated.", "source": "https://pubmed.ncbi.nlm.nih.gov/20394248/"}
{"doc_id": "64a3b76e2b54f5ee4881a58c79d310d1", "sentence": "Inhibition of Boyden Chamber migration of MNL 's in a MNL-lymphocyte mixture was achieved after 1/2 hr incubation by 10(-3 ) and 10(-4 ) mol/L. concentrations of chloroquine ( maximum inhibition 63 % + /- 2.8 ) , dexamethasone ( 58 % + /- 8.6 ) , 6-mercaptopurine ( 62 % + /- 4.2 ) , methotrexate ( 66 % + /- 6.4 ) , and vinblastine ( 100 % ) .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 162, "end": 173, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "dexamethasone", "start": 213, "end": 226, "token_start": 38, "token_end": 39}, {"span_id": 2, "text": "methotrexate", "start": 284, "end": 296, "token_start": 56, "token_end": 57}, {"span_id": 3, "text": "vinblastine", "start": 321, "end": 332, "token_start": 66, "token_end": 67}], "rels": [], "paragraph": "The effect of immunosuppressive and anti-inflammatory drugs on monocyte function in vitro. MNL cellular chemotaxis, bacterial killing and phagocytosis, and Oil Red O phagocytosis were studied in vitro in the presence of eight anti-inflammatory or immunosuppressive drugs. Inhibition of Boyden Chamber migration of MNL 's in a MNL-lymphocyte mixture was achieved after 1/2 hr incubation by 10(-3 ) and 10(-4 ) mol/L. concentrations of chloroquine ( maximum inhibition 63 % + /- 2.8 ) , dexamethasone ( 58 % + /- 8.6 ) , 6-mercaptopurine ( 62 % + /- 4.2 ) , methotrexate ( 66 % + /- 6.4 ) , and vinblastine ( 100 % ) . Bacterial killing was not significantly affected by any of the drugs studied. Bacterial phagocytosis was improved by vinblastine at 10(-3) and 10(-4)M and by 6-mercaptopurine at 10(-5)M, but there was apparent interference with the assay at high drug concentrations. Modification of the Oil Red O technique showed inhibitions of MNL phagocytosis by vinblastine at 10(-3)M (69% +/- 2.8 inhibition), chloroquine at 10(-3)M (49% +/- 8.5), and mercaptopurine at 10(-3)M (32.5% +/- 0.7). cyclophosphamide, although reported to require hepatic conversion in vivo, may be partially activated in a lymphocyte-MNL mixture in vitro, producing a decrease in cell viability but no statistically significant impairment of MNL function. These results support direct inhibition of MNL cellular function as one of the mechanisms of the anti-inflammatory action of chloroquine, dexamethasone, methotrexate, 6-mercaptopurine, and vinblastine.", "source": "https://pubmed.ncbi.nlm.nih.gov/894108/"}
{"doc_id": "5c48e47b075eca5367f30d260ec18b82", "sentence": "The proactive intense care strategy was applied , which includes : ( i ) an education and training course on the topic of SLE-PAH for ED physicians ; ( ii ) a SLE-PAH patient triage protocol with prompt specialist consultation and admission ; and ( iii ) intensive care with prompt initiation of combination PAH-targeted therapy , that is , at least two drugs from the three categories as represented by iloprost , bosentan and sildenafil .", "spans": [{"span_id": 0, "text": "iloprost", "start": 404, "end": 412, "token_start": 71, "token_end": 72}, {"span_id": 1, "text": "bosentan", "start": 415, "end": 423, "token_start": 73, "token_end": 74}, {"span_id": 2, "text": "sildenafil", "start": 428, "end": 438, "token_start": 75, "token_end": 76}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Severe pulmonary arterial hypertension secondary to lupus in the emergency department: proactive intense care associated with a better short-term survival. Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE) and could be an acute critical condition presenting to the emergency department (ED). Our previous retrospective study revealed that the ED-related mortality of such patients was over 50%. The aim of the current prospective study is to initiate a proactive intense care strategy on severe SLE-PAH patients in the emergency setting and evaluate its impact on the short-term survival. ### methods The proactive intense care strategy was applied , which includes : ( i ) an education and training course on the topic of SLE-PAH for ED physicians ; ( ii ) a SLE-PAH patient triage protocol with prompt specialist consultation and admission ; and ( iii ) intensive care with prompt initiation of combination PAH-targeted therapy , that is , at least two drugs from the three categories as represented by iloprost , bosentan and sildenafil . Consecutive SLE-PAH patients with WHO functional class III or IV who attended the ED were enrolled following the aforementioned protocol. A historical group of SLE-PAH patients in the ED (n\u00a0=\u00a011) was set up as a comparison, and 3-month short-term survival was calculated. ### results During October 2010 to December 2012, a total of 11 consecutive severe SLE-PAH patients were included in the present study. Compared with the historical group, an improved short-term survival can be appreciated over time (historical group vs. proactive group, 27.3% vs. 72.7%, P\u00a0=\u00a00.033). The application of PAH-targeted combination therapy apparently contributed to the better outcome (P\u00a0=\u00a00.0099). ### conclusions Proactive care and combination PAH-targeted treatment can improve short-term survival of severe SLE-PAH in the emergency setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/24946184/"}
{"doc_id": "e0ce038cda2c1b7018b761f0c218ef45", "sentence": "Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa ( 53 - 57 % in either 2:1 or 4:1 ratios ) and A. baumannii ( 38 - 46 % in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam ) isolates .", "spans": [{"span_id": 0, "text": "sulbactam", "start": 7, "end": 16, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "piperacillin", "start": 20, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "sulbactam", "start": 245, "end": 254, "token_start": 44, "token_end": 45}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data. We investigated the in vitro activity of various piperacillin and sulbactam combinations against Gram-negative bacterial isolates from Intensive Care Units (ICUs) in Taiwan. Antimicrobial susceptibility testing of 1030 bacterial isolates recovered from ICUs of nine major teaching hospitals was performed using the agar dilution method. sulbactam was added to piperacillin either at a fixed sulbactam concentration of 4 mg/L and 8 mg/L or at a piperacillin:sulbactam ratio of 2:1 and 4:1. piperacillin/sulbactam at a ratio of 2:1 or a fixed 8 mg/L concentration of sulbactam had better activities against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Serratia marcescens than other piperacillin/sulbactam formulations. For Pseudomonas aeruginosa, piperacillin/sulbactam (2:1 or 4:1 ratios) had MIC(90) values (minimum inhibitory concentration for 90% of the organisms) of 64 mg/L (>90% susceptibility) compared with 64 mg/L for cefoperazone/sulbactam (68% susceptibility) and 128 mg/L for piperacillin/tazobactam (82% susceptibility). For Acinetobacter baumannii, both piperacillin/sulbactam (either 2:1 ratio or a fixed 8 mg/L sulbactam) and cefoperazone/sulbactam were the most potent agents. Adding sulbactam to piperacillin resulted in increased susceptibility rates among piperacillin-resistant P. aeruginosa ( 53 - 57 % in either 2:1 or 4:1 ratios ) and A. baumannii ( 38 - 46 % in either 2:1 ratio or a fixed 8 mg/L concentration of sulbactam ) isolates . Results of susceptibility tests with piperacillin/sulbactam are dependent on the method used. piperacillin/sulbactam combinations possessed better in vitro activities than piperacillin alone or piperacillin/tazobactam against P. aeruginosa and A. baumannii.", "source": "https://pubmed.ncbi.nlm.nih.gov/16815690/"}
{"doc_id": "6e67d5265ebd6238ff666027cd88d6a6", "sentence": "Senescence can be efficiently induced in cultured cells by DNA-damaging drugs , including doxorubicin ( DOX ) , cisplatin and etoposide .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 90, "end": 101, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "cisplatin", "start": 112, "end": 121, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "etoposide", "start": 126, "end": 135, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Occurrence of senescence-escaping cells in doxorubicin-induced senescence is enhanced by PD0332991, a cyclin-dependent kinase 4/6 inhibitor, in colon cancer HCT116 cells. Cancer treatment induces cellular senescence, and it is considered to be one of the factors that determines treatment outcome. Senescence can be efficiently induced in cultured cells by DNA-damaging drugs , including doxorubicin ( DOX ) , cisplatin and etoposide . Cells in senescence cease proliferation; however, it has been demonstrated that colonies that are formed from cells escaping senescence appear in drug-induced senescence; however, the conditions influencing the emergence of such senescence-escaping cells (SECs) remain unclear. The present study aimed to investigate the relevance of the cell cycle phase and colony formation in the DOX-induced senescence of human colon cancer HCT116 cells. After release from serum starvation in the presence of DOX, cells synchronously progressed through the cell cycle and were arrested in the G", "source": "https://pubmed.ncbi.nlm.nih.gov/30655877/"}
{"doc_id": "4536a87da2d436767647005f00c2039b", "sentence": "Preoperative treatment was 5 fractions radiation therapy ( 25 Gy to involved mesorectum , 20 Gy to elective nodes ) , followed by 4 cycles of FOLFOX [ 5-fluorouracil , oxaliplatin , leucovorin ] .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 168, "end": 179, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "leucovorin", "start": 182, "end": 192, "token_start": 32, "token_end": 33}, {"span_id": 2, "text": "5-fluorouracil", "start": 151, "end": 165, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Five fractions of radiation therapy followed by 4 cycles of FOLFOX chemotherapy as preoperative treatment for rectal cancer. Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy. ### Methods And Materials Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy ( 25 Gy to involved mesorectum , 20 Gy to elective nodes ) , followed by 4 cycles of FOLFOX [ 5-fluorouracil , oxaliplatin , leucovorin ] . Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls. ### results 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%). ### conclusion This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/24606849/"}
{"doc_id": "57bb15b3534944dc4b84b3425ec59ca6", "sentence": "The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus .", "spans": [{"span_id": 0, "text": "dapagliflozin", "start": 26, "end": 39, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "sulfonylurea", "start": 47, "end": 59, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "metformin", "start": 76, "end": 85, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus . To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. ### methods Clinical inputs sourced from a head-to-head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. ### results The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of \u00a31246 (95% CI: \u00a3613; \u00a31637). This resulted in an ICER point estimate of \u00a32671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of \u00a320,000 per QALY. ### conclusions dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/25817050/"}
{"doc_id": "9498c5215c5fc49f8655cbf2b2ec2198", "sentence": "The mean reduction of night time points was statistically lower than that of day time points for latanoprost ( P = 0.031 ) , timolol ( P = 0.032 ) , and brimonidine ( P = 0.050 ) , but not for dorzolamide ( P = 0.60 ) , bimatoprost ( P = 0.057 ) , travoprost ( P = 0.064 ) .", "spans": [{"span_id": 0, "text": "latanoprost", "start": 97, "end": 108, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "timolol", "start": 125, "end": 132, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "brimonidine", "start": 153, "end": 164, "token_start": 32, "token_end": 33}, {"span_id": 3, "text": "dorzolamide", "start": 193, "end": 204, "token_start": 42, "token_end": 43}, {"span_id": 4, "text": "bimatoprost", "start": 220, "end": 231, "token_start": 49, "token_end": 50}, {"span_id": 5, "text": "travoprost", "start": 248, "end": 258, "token_start": 56, "token_end": 57}], "rels": [], "paragraph": "Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines. To evaluate efficacy and safety data of currently available ocular hypotensive medicines derived from 24-hour studies, of similar design, in patients with primary open-angle glaucoma (POAG), exfoliative glaucoma, or ocular hypertension (OH). ### design Meta-analysis of published articles evaluating patients with POAG, exfoliative glaucoma, or OH. ### methods We included articles that were randomized, prospective, single- or double-masked, comparative studies of ocular hypotensive therapies over 24 hours. Each article selected contained an untreated baseline, >or=4-week treatment period, >/=20 patients per treatment arm, and >or=6 time points not spaced >5 hours apart and used Goldmann applanation or Tonopen tonometry (supine measurements) to measure intraocular pressure (IOP). ### Main Outcome Measure Twenty-four-hour IOP efficacy. ### results This analysis included 864 separate 24-hour treatment curves from 386 patients in 28 treatment arms from 11 studies. A statistical difference in the mean diurnal pressure decrease existed between monotherapy treatments for POAG/OH patients, with bimatoprost (29%) and travoprost (27%) showing the greatest 24-hour reduction (P = 0.026). timolol 0.5% was less effective than latanoprost (24% vs. 19% reduction) but decreased the pressure at each night time point (P = 0.0003). dorzolamide showed a 19% 24-hour pressure reduction and brimonidine 0.2% a 14% one. In exfoliative glaucoma patients, latanoprost and travoprost showed higher baseline and treatment pressures, although the pressure reductions (29% and 31%, respectively) were greater generally than observed with POAG/OH. An evening-dosed latanoprost/timolol fixed combination reduced the pressure 33%, and the dorzolamide/timolol fixed combination (DTFC), 26%. However, the power to detect a difference for this specific comparison was probably low, due to the limited number of patients (n = 20) in the DTFC group. A statistical difference between evening-dosed (24%) and morning-dosed (18%) latanoprost (P<0.0001) was noted, but not between evening (27%) and morning (26%) travoprost (P = 0.074). The mean reduction of night time points was statistically lower than day time points for latanoprost (P = 0.031), timolol (P = 0.032), and brimonidine (P = 0.050), but not for dorzolamide. dorzolamide (P = 0.60), travoprost (P = 0.064), and bimatoprost (P = 0.057) did not demonstrate nighttime pressures lower than daytime ones. The mean reduction of night time points was statistically lower than that of day time points for latanoprost ( P = 0.031 ) , timolol ( P = 0.032 ) , and brimonidine ( P = 0.050 ) , but not for dorzolamide ( P = 0.60 ) , bimatoprost ( P = 0.057 ) , travoprost ( P = 0.064 ) . ### conclusions Similar relative efficacies generally exist in various classes of ocular hypotensive agents during night and day hours.", "source": "https://pubmed.ncbi.nlm.nih.gov/18082886/"}
{"doc_id": "2f57f437e23ddbbccfa7c89638e083d0", "sentence": "Moreover , the beneficial effects of dronedarone , amiodarone analogues , against Trypanosoma cruzi and Leishmania mexicana have recently been demonstrated and such treatment regimens resulted in lower side effects .", "spans": [{"span_id": 0, "text": "dronedarone", "start": 37, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "amiodarone", "start": 51, "end": 61, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Emerging role of amiodarone and dronedarone, as antiarrhythmic drugs, in treatment of leishmaniasis. Leishmaniasis is a group of human and animal diseases causing 20,000-40,000 annual deaths and its etiological agents belong to the Leishmania genus. The most current treatment against leishmaniasis is chemotherapy. Pentavalent antimonials such as glucantime and pentostam have been administrated as the first-line drugs in treatment of various forms of leishmaniasis. The second-line drugs such as amphotericin B, liposomal amphotericin B, miltefosine, pentamidine, azole drugs and paromomycin are used in resistant cases to pentavalent antimonials. Because of drawbacks of the first-line and second-line drugs including adverse side effects on different organs, increasing resistance, high cost, need to hospitalization and long-term treatment, it is necessary to find an alternative drug for leishmaniasis treatment. Several investigations have reported the effectiveness of amiodarone, the most commonly used antiarrhythmic drug, against fungi, Trypanosomes and Leishmania spp. in vitro, in vivo and clinical conditions. Moreover , the beneficial effects of dronedarone , amiodarone analogues , against Trypanosoma cruzi and Leishmania mexicana have recently been demonstrated and such treatment regimens resulted in lower side effects . The anti- leishmanial and anti- trypanosomal effectiveness of amiodarone and dronedarone has been attributed to destabilization of intracellular Ca", "source": "https://pubmed.ncbi.nlm.nih.gov/29689189/"}
{"doc_id": "b391e83b6f4e8652576666a65eb55339", "sentence": "This study aimed to investigate the efficacy and safety of iguratimod ( T-614 ) in combination with methotrexate ( MTX ) for active rheumatoid arthritis ( RA ) patients .", "spans": [{"span_id": 0, "text": "iguratimod", "start": 59, "end": 69, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "methotrexate", "start": 100, "end": 112, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy and safety evaluation of a combination of iguratimod and methotrexate therapy for active rheumatoid arthritis patients: a randomized controlled trial.  This study aimed to investigate the efficacy and safety of iguratimod ( T-614 ) in combination with methotrexate ( MTX ) for active rheumatoid arthritis ( RA ) patients . Sixty active RA patients were enrolled according to the 2010 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification criteria, and were randomized into MTX\u2009+\u2009T-614 group and MTX group. T-614 was orally administered at a dosage of 50 mg/day (25 mg twice daily) for 24 weeks. MTX was orally administered to RA patients at a stable weekly dosage of 10 mg/week for the first 4 weeks and subsequent 12.5 mg/week for the later 20 weeks. Clinical features at baseline and efficacy endpoints of the ACR 20 % response (ACR20), ACR50, ACR70, and adverse events at 24 weeks were evaluated, respectively. After 24 weeks of treatment, clinical features at baseline, including counts for tender joints and swelling joints, visual analog scale for pain, patient's and physician's global assessment, erythrocyte sedimentation rate, C-reactive protein, disease activity score 28, health assessment questionnaire, simplified disease activity index, and ACR50 in the MTX\u2009+\u2009T-614 group, showed statistically significant differences comparing with the MTX group (P\u2009<\u20090.05). There was no significant increase in adverse events in the MTX\u2009+\u2009T-614 group comparing with the MTX group (P\u2009>\u20090.05). The combination of MTX and T-614 therapy appeared to have a good efficacy and safety for active RA and was superior to MTX-alone therapy after 24 weeks of treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/26139202/"}
{"doc_id": "d5a2bde71955f6f2fbed75223c47d79f", "sentence": "Cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide , vincristine , doxorubicin , high-dose methotrexate/ifosfamide , etoposide , high-dose cytarabine ( CODOX-M/IVAC ) , or dose-adjusted etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( DA-EPOCH ) are possible options .", "spans": [{"span_id": 0, "text": "Cyclophosphamide", "start": 0, "end": 16, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 19, "end": 30, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "vincristine", "start": 33, "end": 44, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "prednisone", "start": 51, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 4, "text": "cyclophosphamide", "start": 154, "end": 170, "token_start": 24, "token_end": 25}, {"span_id": 5, "text": "vincristine", "start": 173, "end": 184, "token_start": 26, "token_end": 27}, {"span_id": 6, "text": "doxorubicin", "start": 187, "end": 198, "token_start": 28, "token_end": 29}, {"span_id": 7, "text": "etoposide", "start": 237, "end": 246, "token_start": 33, "token_end": 34}, {"span_id": 8, "text": "cytarabine", "start": 259, "end": 269, "token_start": 36, "token_end": 37}, {"span_id": 9, "text": "etoposide", "start": 306, "end": 315, "token_start": 43, "token_end": 44}, {"span_id": 10, "text": "prednisone", "start": 318, "end": 328, "token_start": 45, "token_end": 46}, {"span_id": 11, "text": "vincristine", "start": 331, "end": 342, "token_start": 47, "token_end": 48}, {"span_id": 12, "text": "cyclophosphamide", "start": 345, "end": 361, "token_start": 49, "token_end": 50}, {"span_id": 13, "text": "doxorubicin", "start": 368, "end": 379, "token_start": 52, "token_end": 53}, {"span_id": 14, "text": "methotrexate/ifosfamide", "start": 211, "end": 234, "token_start": 31, "token_end": 32}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [4, 5, 6, 7, 8, 14], "is_context_needed": true}, {"class": "COMB", "spans": [9, 10, 11, 12, 13], "is_context_needed": true}], "paragraph": "Plasmablastic Lymphoma: A Review of Current Knowledge and Future Directions. Plasmablastic lymphoma (PBL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL), which frequently arises in the oral cavity of human immunodeficiency virus (HIV) infected patients. PBL shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts/plasmablasts, or with plasmacytic features and an immunophenotype of plasma cells. PBL remains a diagnostic challenge due to its peculiar morphology and an immunohistochemical profile similar to plasma cell myeloma (PCM). PBL is also a therapeutic challenge with a clinical course characterized by a high rate of relapse and death. There is no standard chemotherapy protocol for treatment of PBL. Cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) or CHOP-like regimens have been the backbone while more intensive regimens such as cyclophosphamide , vincristine , doxorubicin , high-dose methotrexate/ifosfamide , etoposide , high-dose cytarabine ( CODOX-M/IVAC ) , or dose-adjusted etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( DA-EPOCH ) are possible options . Recently, a few studies have reported the potential value of the proteasome inhibitor bortezomib and thalidomide in PBL patients. The introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs) and CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials. The aim of this paper is to review the recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and outcome in patients with PBL.", "source": "https://pubmed.ncbi.nlm.nih.gov/26357515/"}
{"doc_id": "2cd79396bfa06a9c42c9eb3059f89db1", "sentence": "Irinotecan tended to result in more gastrointestinal tract reactions than oxaliplatin did , but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen .", "spans": [{"span_id": 0, "text": "Irinotecan", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "oxaliplatin", "start": 74, "end": 85, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "oxaliplatin", "start": 157, "end": 168, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "irinotecan", "start": 182, "end": 192, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Irinotecan or oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer: a meta-analysis. To compare clinical efficacy and toxicity of irinotecan combined with 5-fluorouracil and leucovorin with those of oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer. ### methods Literature search was performed by keywords \"irinotecan\", \"oxaliplatin\" and \"colorectal cancer\" on all randomized controlled trails reported on irinotecan versus oxaliplatin combined with 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer in MEDLINE, OVID, Springer, Cochrane Controlled Trials Register (CCTR) and CBMdisc (Chinese Biology and Medicine disc) before January 2010. Two authors drew the details of trial design, characteristics of patients, outcomes, and toxicity from the studies included. Data analysis was performed by RevMan 4.2. ### results According to the screening criteria, 7 clinical studies with 2095 participants of advanced colorectal cancer were included in this meta analysis. The baseline characteristics of irinotecan group were similar to those of oxaliplatin group. The response rate of oxaliplatin group was higher than that of irinotecan group (relative risk (RR) = 0.82, 95% confidence interval (95%CI) (0.70, 0.96), P = 0.01), and the median overall survival of oxaliplatin group was longer by 2.04 months than that of irinotecan group (95%CI (-3.54, -0.54), P = 0.008). In the comparison of grade 3 - 4 toxicity between the two groups, the incidences of nausea, emesis, diarrhoea and alopecia in irinotecan group were higher than those in oxaliplatin group (RR = 1.94, 95%CI (1.22, 3.09), P = 0.005; 1.71, 95%CI (1.34, 2.18), P < 0.001; 14.56, 95%CI (4.11, 51.66), P < 0.0001), respectively. However, the incidence of neurotoxicity, neutropenia and thrombocytopenia in irinotecan group were lower than those in oxaliplatin group (RR = 0.06, 95%CI (0.03, 0.14), P < 0.00001; 0.70, 95%CI (0.55, 0.91), P = 0.006; 0.18, 95%CI (0.05, 0.61), P = 0.006), respectively. ### conclusions Both irinotecan and oxaliplatin combined with 5-fluorouracil and leucovorin were effective in the first-line therapy of advanced colorectal cancer. However, the combined regimen of oxaliplatin plus 5-fluorouracil and leucovorin is more excellent. Irinotecan tended to result in more gastrointestinal tract reactions than oxaliplatin did , but the myelosuppression and neurotoxicity were more frequent in oxaliplatin regimen than irinotecan regimen .", "source": "https://pubmed.ncbi.nlm.nih.gov/21163137/"}
{"doc_id": "964216668a8e62cda52cb0268e6ede6b", "sentence": "[ Intraoperative anaphylactic shock induced by methylergometrine and oxytocin ] .", "spans": [{"span_id": 0, "text": "methylergometrine", "start": 47, "end": 64, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "oxytocin", "start": 69, "end": 77, "token_start": 8, "token_end": 9}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Intraoperative anaphylactic shock induced by methylergometrine and oxytocin ] . We report a case of intraoperative anaphylactic shock in a 32-year-old multigravida woman undergoing elective cesarean section for partial placenta previa. Anesthesia was performed using combined spinal and epidural technique. After the baby was born, methylergometrine was administered i.v. simultaneously with oxytocin, the latter injected directly into the uterine muscle by an obstetrician. Several minutes later, she presented with dyspnea and became agitated. Because of the potential risk of pulmonary embolism, the patient was immediately intubated and mechanical ventilation was started. Her systolic blood pressure decreased to 50 mmHg and SpO2 to 87% under 100% oxygen administration. After catecholamine infusion, however, her respiratory condition soon improved. Postoperatively, her conjunctiva and vulva were not edematous. From the clinical course, it was considered that the patient was very likely to have suffered an anaphylactic reaction to oxytocin or methylergometrine. Forty days later, serological examinations as well as skin tests for those two drugs were carried out. While the serological tests were negative, the skin tests indicated the patient was allergic to both drugs. It is concluded that the endogenous peptide oxytocin can induce anaphylactic shock in multiparous women.", "source": "https://pubmed.ncbi.nlm.nih.gov/16634548/"}
{"doc_id": "dcfbf5ae688ecd29ac90163f21d6fbff", "sentence": "Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 91, "end": 102, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "etoposide", "start": 127, "end": 136, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo. Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide . Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/24083030/"}
{"doc_id": "6d1ec19f332c2fdafef2d6f1ecdf91c9", "sentence": "The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel , gemcitabine , pemetrexed , and erlotinib and for patients with target-specific oncogenes afatinib , osimertinib , crizotinib , alectinib , and ceritinib .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 94, "end": 103, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "gemcitabine", "start": 106, "end": 117, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "pemetrexed", "start": 120, "end": 130, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "erlotinib", "start": 137, "end": 146, "token_start": 19, "token_end": 20}, {"span_id": 4, "text": "afatinib", "start": 195, "end": 203, "token_start": 26, "token_end": 27}, {"span_id": 5, "text": "osimertinib", "start": 206, "end": 217, "token_start": 28, "token_end": 29}, {"span_id": 6, "text": "crizotinib", "start": 220, "end": 230, "token_start": 30, "token_end": 31}, {"span_id": 7, "text": "alectinib", "start": 233, "end": 242, "token_start": 32, "token_end": 33}, {"span_id": 8, "text": "ceritinib", "start": 249, "end": 258, "token_start": 35, "token_end": 36}], "rels": [], "paragraph": "Second-Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological, and Molecular Aspects of Nintedanib. Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel , gemcitabine , pemetrexed , and erlotinib and for patients with target-specific oncogenes afatinib , osimertinib , crizotinib , alectinib , and ceritinib . In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC). nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor). Several preclinical and clinical studies have proven the usefulness of nintedanib as an anticancer agent for NSCLC. The most important study was the phase III LUME-Lung 1 trial, which investigated the combination of nintedanib with docetaxel for second-line treatment in advanced NSCLC patients. The significant improvement in overall survival and the manageable safety profile led to the approval of this new treatment in Europe. This review focuses on the preclinical and clinical studies with nintedanib in NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/28293555/"}
{"doc_id": "de4688dd3f066547588c91f65dfc3edc", "sentence": "an increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews .", "spans": [{"span_id": 0, "text": "formoterol", "start": 56, "end": 66, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "salmeterol", "start": 79, "end": 89, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.  an increase in serious adverse events with both regular formoterol and regular salmeterol in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews . This increase was significant in trials that did not randomise participants to an inhaled corticosteroid, but less certain in the smaller numbers of participants in trials that included an inhaled corticosteroid in the randomised treatment regimen. ### objectives we set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment ### Search Strategy trials were identified using the Cochrane Airways Group Specialised Register of trials. Manufacturers' web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol were also checked. The date of the most recent search was July 2009. ### Selection Criteria controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid), and were of at least 12 weeks duration. ### Data Collection And Analysis two authors independently selected trials for inclusion in the review and extracted outcome data. Unpublished data on mortality and serious adverse events were sought from the sponsors and authors. ### Main Results eight studies met the eligibility criteria of the review recruiting 6,163 adults and adolescents. There were seven studies (involving 5,935 adults and adolescents) comparing formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 50 mcg and budesonide 400 mcg twice daily versus salmeterol 50 mcg and fluticasone 250 mcg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma. There was no significant difference between treatment groups for non-fatal serious adverse events, either all-cause (Peto OR 1.14; 95% CI 0.82 to 1.59, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively. There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions. No studies were found in children. ### Authors Conclusions the seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, but no serious adverse events occurred in this study. No studies were found in children. Overall there is insufficient evidence to decide whether regular formoterol and budesonide or beclomethasone have equivalent or different safety profiles from salmeterol and fluticasone.", "source": "https://pubmed.ncbi.nlm.nih.gov/21181075/"}
{"doc_id": "ad63705caf5963c9313fbcab36b8fd43", "sentence": "[ An elderly patient with myelodysplastic syndrome successfully treated with combination of granulocyte-colony stimulating factor and continuous-drip infusion of low-dose cytarabine and etoposide ] .", "spans": [{"span_id": 0, "text": "cytarabine", "start": 171, "end": 181, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "etoposide", "start": 186, "end": 195, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[ An elderly patient with myelodysplastic syndrome successfully treated with combination of granulocyte-colony stimulating factor and continuous-drip infusion of low-dose cytarabine and etoposide ] . A 73-year-old man was given a diagnosis of myelodysplastic syndrome in October 1997. He was treated with red blood cell transfusion and granulocyte-colony stimulating factor (G-CSF). In February 1998, he was admitted due to progression of pancytopenia. Bone marrow aspiration revealed refractory anemia with excess of blasts in transformation. The patient was treated with continuous-drip infusion of low-dose cytarabine and etoposide with G-CSF (AVG therapy). Complete remission (CR) was obtained after 2 courses of AVG therapy. Non-hematologic adverse effects were mild enough to be tolerated. CR has been maintained for 16 months with 1 course of consolidation therapy and 3 courses of intensification therapy using the AVG regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/10774251/"}
{"doc_id": "47a4d9d3f5318ec4636de288bc670d2e", "sentence": "Among the GNB , a higher prevalence of resistance was observed against cefoxitin ( 93.1 % ) followed by ampicillin ( 79.4 % ) , chloramphenicol ( 72.6 % ) , ceftizoxime ( 65.7 % ) , aztreonam ( 64.9 % ) , cefotaxime ( 53.6 % ) , imipenem ( 38.3 % ) , ceftazidime ( 33.5 % ) , gentamicin ( 32.6 % ) , tetracycline ( 22.2 % ) , and ciprofloxacin ( 19.8 % ) .", "spans": [{"span_id": 0, "text": "cefoxitin", "start": 71, "end": 80, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "ampicillin", "start": 104, "end": 114, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "chloramphenicol", "start": 128, "end": 143, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "ceftizoxime", "start": 157, "end": 168, "token_start": 31, "token_end": 32}, {"span_id": 4, "text": "aztreonam", "start": 182, "end": 191, "token_start": 37, "token_end": 38}, {"span_id": 5, "text": "cefotaxime", "start": 205, "end": 215, "token_start": 43, "token_end": 44}, {"span_id": 6, "text": "imipenem", "start": 229, "end": 237, "token_start": 49, "token_end": 50}, {"span_id": 7, "text": "ceftazidime", "start": 251, "end": 262, "token_start": 55, "token_end": 56}, {"span_id": 8, "text": "gentamicin", "start": 276, "end": 286, "token_start": 61, "token_end": 62}, {"span_id": 9, "text": "tetracycline", "start": 300, "end": 312, "token_start": 67, "token_end": 68}, {"span_id": 10, "text": "ciprofloxacin", "start": 330, "end": 343, "token_start": 74, "token_end": 75}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10], "is_context_needed": true}], "paragraph": "Prevalence of multiple antibiotic-resistant Gram-negative bacteria on bagged, ready-to-eat baby spinach. In this study, multiple antibiotic-resistant (MAR) Gram-negative bacteria (GNB) were isolated from triple-washed, bagged, ready-to-eat (RTE) baby spinach. Biochemical identification of randomly selected bacterial colonies showed the predominance of cytochrome oxidase-positive Pseudomonas species. Among the GNB , a higher prevalence of resistance was observed against cefoxitin ( 93.1 % ) followed by ampicillin ( 79.4 % ) , chloramphenicol ( 72.6 % ) , ceftizoxime ( 65.7 % ) , aztreonam ( 64.9 % ) , cefotaxime ( 53.6 % ) , imipenem ( 38.3 % ) , ceftazidime ( 33.5 % ) , gentamicin ( 32.6 % ) , tetracycline ( 22.2 % ) , and ciprofloxacin ( 19.8 % ) . Multiple antibiotic resistance (MAR) linked to two or more antibiotics was found in 95.3% of isolates, and resistance was transferable in the strains tested. These findings confirm the presence of MAR bacteria on RTE baby spinach and suggest that human consumption of this produce would amplify the MAR gene pool via conjugal transfer of MAR genes to commensal gut microflora and bacterial pathogens.", "source": "https://pubmed.ncbi.nlm.nih.gov/22838727/"}
{"doc_id": "4bde78413693b71b460a3ea9799bd664", "sentence": "The results suggested that irinotecan , 5-FU and leucovorin combination chemotherapy in a biweekly schedule is a practical and tolerable treatment option in patients with advanced colorectal cancer .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 27, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "5-FU", "start": 40, "end": 44, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "leucovorin", "start": 49, "end": 59, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Phase II study of irinotecan, 5-fluorouracil, and leucovorin in relapsed or metastatic colorectal cancer as first-line therapy. The purpose of this study was to assess the efficacy and toxicity of biweekly irinotecan plus 5-fluorouracil (FU) and leucovorin (LV) in patients with relapsed or metastatic colorectal cancer. ### Materials And Methods Between March 2002 and May 2004, 24 patients with histologically confirmed relapsed or metastatic colorectal cancer were enrolled in this study. One chemotherapy cycle consisted of irinotecan 180 mg/m(2) on days 1 and 15; 5-FU 400 mg/m(2) bolus IV with 600 mg/m(2) by a 22 hour intravenous infusion on days 1, 2, 15 and 16; and leucovorin 20 mg/m(2) on days 1, 2, 15 and 16, every 4 weeks. ### results The median age of the 24 was 57.5 years (range, 38 approximately 69). Their metastatic sites included: the liver (62.5%), lung (20.8%), peritoneum (16.7%), lymph node (12.5%), ovary (8.3%) and pelvis/vagina (8.3%). Twenty-two patients were evaluable for a response. Six and 7 patients achieved partial responses and stable diseases, respectively. The overall response rate was 27.3% (95% Confidence interval; 10.3 approximately 44.5%). The median follow-up duration for surviving patients was 14.7 months (range, 1.7 approximately 26.5). Median overall survival (OS) and 1-year OS rates were 19 months and 86.3%, respectively. Median response duration and median progression free survival were 7.47 and 5.57 months, respectively. A total of 83 cycles (median 4 cycles) were administered. The main non-hematologic toxicities were nausea/vomiting (44.5%/18.1%) and diarrhea (8.4%). The most common hematologic toxicity was NCI grade I/II anemia (31.3%) and grade I/II neutropenia was 10.8%. There was no life-threatening toxicity. ### conclusion The results suggested that irinotecan , 5-FU and leucovorin combination chemotherapy in a biweekly schedule is a practical and tolerable treatment option in patients with advanced colorectal cancer .", "source": "https://pubmed.ncbi.nlm.nih.gov/20368840/"}
{"doc_id": "e57d2540d079fe3c4c317a7ef55f2581", "sentence": "Fifty-three consecutive patients with active duodenal ulcer ( DU ) were randomly included in a double-blind , double-dummy study to test the healing and relapsing rate of two treatment regimens : famotidine 40 mg nocte for 4 - 8 weeks , followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth ( CBS ) ( 240 mg bid ) for 4 - 8 weeks , followed by placebo maintenance treatment .", "spans": [{"span_id": 0, "text": "famotidine", "start": 196, "end": 206, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "bismuth", "start": 310, "end": 317, "token_start": 55, "token_end": 56}], "rels": [], "paragraph": "Colloid bismuth versus famotidine in the treatment and prevention of duodenal ulcer relapse: results of a double-blind, double dummy randomized study.  Fifty-three consecutive patients with active duodenal ulcer ( DU ) were randomly included in a double-blind , double-dummy study to test the healing and relapsing rate of two treatment regimens : famotidine 40 mg nocte for 4 - 8 weeks , followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth ( CBS ) ( 240 mg bid ) for 4 - 8 weeks , followed by placebo maintenance treatment . The results of the short term period confirmed the efficacy of CBS in healing DU (24/25 in CBS group and 19/23 in famotidine group). However, the relapse rate in the CBS-treated group was higher (77.8% at 12 months) than in the famotidine group (35.7%) (p = 0.041). Only 7 patients (41.2%) were cleared from Helicobacter pylori (HP) after CBS treatment. In conclusion, the high relapse rate observed in CBS treated patients may be related to the high percentage of patients with HP infection in the tested group and support the hypothesis that lack of efficacy of CBS in preventing DU recurrence is related to its poor eradication of HP.", "source": "https://pubmed.ncbi.nlm.nih.gov/7557824/"}
{"doc_id": "1a73cbf60711bfb9042ed9003466b731", "sentence": "Cytotoxic monotherapy was the most frequently prescribed regimen ( N = 60 , 46 % ) in 2L , followed by combination therapies ( N = 45 , 35 % ) , pembrolizumab monotherapy ( N = 19 , 15 % ) , and bevacizumab monotherapy ( N = 6 , 5 % ) .", "spans": [{"span_id": 0, "text": "pembrolizumab", "start": 145, "end": 158, "token_start": 32, "token_end": 33}, {"span_id": 1, "text": "bevacizumab", "start": 195, "end": 206, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Patient characteristics, treatment patterns, and clinical outcomes among patients with previously treated recurrent or metastatic cervical cancer: A community oncology-based analysis. There is no standard systemic treatment for recurrent or metastatic cervical cancer (r/mCC) after failure of first-line (1L) therapy. This study characterizes the patient experience, treatment patterns, and clinical outcomes of patients who initiated second-line (2L) therapy for r/mCC in a US community oncology setting. ### methods This is an observational study of cervical cancer patients who failed 1L systemic treatment for r/mCC and initiated 2L systemic therapy between 2014 and 2019 within the US Oncology Network (USON). USON's electronic health records were used to identify eligible patients and abstract data. Overall survival (OS), time to treatment discontinuation (TTD), and time to first subsequent treatment (TFST) were estimated using Kaplan-Meier methods. ### results A total of 130 patients were identified (mean age 53\u00a0years). Over 60% of patients had Eastern Cooperative Oncology Group score of 0-1. Cytotoxic monotherapy was the most frequently prescribed regimen ( N = 60 , 46 % ) in 2L , followed by combination therapies ( N = 45 , 35 % ) , pembrolizumab monotherapy ( N = 19 , 15 % ) , and bevacizumab monotherapy ( N = 6 , 5 % ) . Median OS was 9.1\u00a0months (95% CI: 7.2-12.2) after initiation of 2L therapy. Median TTD was 2.8\u00a0months (95% CI: 2.5-3.3), and median TFST was 4.9\u00a0months (95% CI: 4.2-5.7). No significant difference in outcomes was found when stratified by 2L treatments. ### conclusions The observed heterogeneity in 2L r/mCC therapy suggests no clear standard-of-care in this setting. Additionally, short duration of OS observed was consistent across 2L regimens. New, effective treatment options in this setting are needed.", "source": "https://pubmed.ncbi.nlm.nih.gov/33741208/"}
{"doc_id": "a1d1c9a7eb89a7f9e645d79ee15ca140", "sentence": "Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure , portal tributary blood flow and increased hepatocollateral vascular resistance ; terlipressin increased arterial pressure and further decreased cardiac index .", "spans": [{"span_id": 0, "text": "Terlipressin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "octreotide", "start": 53, "end": 63, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "terlipressin", "start": 181, "end": 193, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Haemodynamic responses to a combination of terlipressin and octreotide in portal hypertensive rats. An enhancement of the haemodynamic effects of terlipressin by octreotide (and vice versa) may be useful in the treatment of portal hypertension. The aim of this study was to investigate the short-term effects of terlipressin, octreotide or a combination of these substances on splanchnic and systemic haemodynamics in rats with portal vein stenosis. ### methods Eight rats received an intravenous (i.v.) infusion of isotonic saline (10 microL/min for 15 min). Eight rats received terlipressin first (0.05 mg/kg) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min) 15 min later. Eight other rats first received an i.v. infusion of octreotide and then terlipressin 15 min later. Splanchnic and systemic haemodynamics (radioactive microsphere method) were measured after saline, after terlipressin or octreotide alone, and after the combined treatments. ### results terlipressin and octreotide alone significantly decreased portal pressure, portal tributary blood flow and cardiac index. terlipressin, but not octreotide, significantly increased heptocollateral vascular resistance and arterial pressure. octreotide administration in rats pre-treated with terlipressin did not change portal pressure, caused portal tributary blood flow to increase and decreased hepatocollateral vascular resistance; it also decreased arterial pressure but not cardiac index. Terlipressin administration in rats pre-treated with octreotide further decreased portal pressure , portal tributary blood flow and increased hepatocollateral vascular resistance ; terlipressin increased arterial pressure and further decreased cardiac index . ### conclusions In rats with portal vein stenosis, octreotide decreased short-term splanchnic and systemic vasoconstriction due to terlipressin. In contrast, terlipressin enhanced the splanchnic and systemic vasoconstriction due to octreotide. Thus, the haemodynamic responses to the combination of octreotide and terlipressin depend on the order of administration of these substances.", "source": "https://pubmed.ncbi.nlm.nih.gov/9354212/"}
{"doc_id": "ea378b3a02bedc9af503f0fdabfbc871", "sentence": "Results confirmed the antidepressant action of alprazolam and imipramine .", "spans": [{"span_id": 0, "text": "alprazolam", "start": 47, "end": 57, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "imipramine", "start": 62, "end": 72, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "The effect of sympathetic antagonists on the antidepressant action of alprazolam. alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam-induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a \u03b21-selective adrenoceptor antagonist; propranolol, a non selective \u03b2-adrenoceptor antagonist; and prazocin, an \u03b11-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine . Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates \u03b22 receptors to produce an antidepressant action. imipramine may act by activating \u03b22 receptors by blocking or down-regulating \u03b21 receptors.", "source": "https://pubmed.ncbi.nlm.nih.gov/21499463/"}
{"doc_id": "f692286c20dae2c0dbb64ce180cf9fe8", "sentence": "Cell viability of two human hepatoma cell lines ( Huh7 and Hep-G2 ) was quantitatively investigated under the treatment of two drugs ( doxorubicin and etoposide ) .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 135, "end": 146, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "etoposide", "start": 151, "end": 160, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Towards a high throughput impedimetric screening of chemosensitivity of cancer cells suspended in hydrogel and cultured in a paper substrate. In order to achieve high predictive value of cell chemosensitivity test for clinical efficacy, cancer cells were suggested to be encapsulated and cultured in hydrogel to mimic the natural microenvironment of tumors. However, handling 3D cells/hydrogel culture construct is tedious and cellular response is difficult to be quantitatively analyzed. In the current study, a novel platform for conducting 3D cell culture and analyzing cell viability has been developed towards a high throughput drug screening. Cells encapsulated in the hydrogel were cultured in the microwells of a paper substrate. The substrate was then immersed in the culture medium containing drug for 2 days. At 24 and 48h during the culture course, the paper substrate was placed on the measurement electrodes for conducting the impedance measurement in order to quantify the cell viability in the hydrogel. Cell viability of two human hepatoma cell lines ( Huh7 and Hep-G2 ) was quantitatively investigated under the treatment of two drugs ( doxorubicin and etoposide ) . The results represented by IC", "source": "https://pubmed.ncbi.nlm.nih.gov/28946107/"}
{"doc_id": "ff6667a3254f6d44fc3a3900ef49a8b6", "sentence": "MIF , TRH , and its analog PR-546 , the paraopioid RP , leuenkephalin , dalargin , the ACTH analogue Semax , tafcin , thymosine , interleukin-1 , vasopressin , oxytocin , bradykinin , defencin , and some proline-containing oligopeptides , such as Pro-Gly , Gly-Pro , Trp-Pro , Pro-Gly-Pro , Gly-Pro-Gly-Gly were studied .", "spans": [{"span_id": 0, "text": "vasopressin", "start": 146, "end": 157, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "oxytocin", "start": 160, "end": 168, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "bradykinin", "start": 171, "end": 181, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "[The modulation of hemostatic reactions in vitro and in vivo by representatives of regulatory peptide families]. Data available in the literature and the author's own findings of the effects of regulatory peptide (RP) and their analogues are summarized. MIF , TRH , and its analog PR-546 , the paraopioid RP , leuenkephalin , dalargin , the ACTH analogue Semax , tafcin , thymosine , interleukin-1 , vasopressin , oxytocin , bradykinin , defencin , and some proline-containing oligopeptides , such as Pro-Gly , Gly-Pro , Trp-Pro , Pro-Gly-Pro , Gly-Pro-Gly-Gly were studied . A complex of in vitro and in vivo tests identified three groups of RP: 1) neutral ones as to the hemostatic reactions studied; 2) stimulants of hypercoagulation and fibrin polymerization; 3) inhibitors of blood coagulation, increased fibrinolysis, and fibrin demopolymerization. The fibrinolytic and antithrombotic effects of Semax (in vivo), the procoagulative action of defencin, and the enhanced anticoagulant effects in the combinations of Semax-heparin and tafcin (in vivo) attract particular attention. Semax alone and in combination with heparin is recommended for clinical studies in respective hemostatic abnormalities.", "source": "https://pubmed.ncbi.nlm.nih.gov/8924838/"}
{"doc_id": "7f23e845124671e1faa7b73a1fb4bd9e", "sentence": "In both cohorts , more than 40 % of patients discontinued their index drugs ( 46.4 % pazopanib and 44.1 % sunitinib , P = 0.732 ) .", "spans": [{"span_id": 0, "text": "pazopanib", "start": 85, "end": 94, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "sunitinib", "start": 106, "end": 115, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Persistence and compliance among U.S. patients receiving pazopanib or sunitinib as first-line therapy for advanced renal cell carcinoma: a retrospective claims analysis. For first-line therapy options for advanced renal cell carcinoma (RCC), clinical trials have demonstrated similar efficacy for pazopanib and sunitinib as well as differing side-effect profiles, which may affect patient persistence in self-administration of these oral medications. However, the treatment patterns of each drug in real-world clinical practice, as opposed to the controlled environment of a trial, have not been directly compared. ### objective To compare persistence and compliance (adherence) with pazopanib versus sunitinib in a real-world setting. ### methods This was a retrospective claims analysis using 2 databases: Optum Research Database and Impact National Benchmark Database. Eligible patients included adult patients (aged \u2265 18 years) with \u2265 2 RCC diagnoses and evidence of first-line therapy with \u2265 1 subsequent pharmacy claim for pazopanib or sunitinib between October 2009 and July 2012. The date of the first pazopanib or sunitinib claim was defined as the index date. Additional requirements included continuous enrollment in the health plan for 2 months prior (baseline period) through 6 months after (follow-up period) the index date and no cancers other than those associated with RCC. Propensity score matching was used to minimize selection bias. Persistence with the index drug was compared using days to discontinuation, estimated level of persistence (ELPT) at 180 days, and proportion of days covered (PDC). PDC was defined by dividing the number of days covered with the index drug by the number of follow-up days. Compliance was estimated using medication possession ratio (MPR). For matched cohort pairs with > 1 fill, MPR was defined by dividing the number of days covered with the index drug by the number of days between the first and last index medication fill. ### results We identified 84 matched pairs among 97 patients prescribed pazopanib and 349 prescribed sunitinib. Among the matched population, mean comorbidity index score was 5.8 (95% CI = 1.8-6.0) for pazopanib, and 6.1 (95% CI =1.8-6.0) for sunitinib (P = 0.133). Evidence of any radiation therapy during the baseline period was significantly higher among the sunitinib cohort prior to matching (9% vs. 18%, P = 0.043), and evidence of surgery was higher in the pazopanib cohort after matching (12% vs. 7%, P = 0.046). Cohorts were balanced according to demographic and clinical characteristics with mean (SD) age of 63.0 (9.0) years and 77.4% male. During the 6-month period after drug initiation, there was no significant difference (P > 0.05) by drug cohort in the duration of index drug therapy or the percentage of patients who discontinued their index drugs. The mean (SD) time to discontinuation was 133.4 (62.8) days and 139.9 (55.6) days among the matched pazopanib and sunitinib cohorts, respectively (P = 0.445). In both cohorts , more than 40 % of patients discontinued their index drugs ( 46.4 % pazopanib and 44.1 % sunitinib , P = 0.732 ) . In addition, there was no significant difference by drug cohort in the ELPT at any time examined between 30 and 180 days after initiation of therapy. PDC with the index drug during the fixed 6-month follow-up was also examined. Although the mean PDC was significantly higher among the sunitinib cohort (0.77 vs. 0.68 for pazopanib, P = 0.037), there was no difference by cohort in the percentage of patients with high PDC (defined as \u2265 80%): 52.4% versus 56.0% for pazopanib and sunitinib, respectively (P = 0.622). Mean MPR among matched pairs with at least 2 fills for the index drug was significantly higher among the sunitinib cohort, although there was no difference by cohort in the percentage of patients with high MPR (defined as \u2265 80%): 81.4% versus 93.2% for pazopanib and sunitinib, respectively (P > 0.071). ### conclusions In the first 6 months of treatment, persistence and compliance to pazopanib and sunitinib were similar. Future studies are needed, including those assessing larger cohorts and longer follow-up periods.", "source": "https://pubmed.ncbi.nlm.nih.gov/26011553/"}
{"doc_id": "e0dbd07b99f4b724b1f5fbc279bc2212", "sentence": "The patients were heavily pretreated with anthracycline ( 100 % ) , taxane ( paclitaxel or docetaxel ) ( 100 % ) , capecitabine ( 100 % ) , vinorelbine ( 71 % ) , and mitomycin ( 69 % ) .", "spans": [{"span_id": 0, "text": "pretreated", "start": 26, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "paclitaxel", "start": 77, "end": 87, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "docetaxel", "start": 91, "end": 100, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "capecitabine", "start": 115, "end": 127, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "vinorelbine", "start": 140, "end": 151, "token_start": 29, "token_end": 30}, {"span_id": 5, "text": "mitomycin", "start": 167, "end": 176, "token_start": 36, "token_end": 37}], "rels": [], "paragraph": "Efficacy of S-1 in heavily pretreated patients with metastatic breast cancer: cross-resistance to capecitabine. It is not clear what the optimal treatment of chemotherapy is for patients with heavily treated metastatic breast cancer (MBC). We have retrospectively examined the efficacy and safety of S-1 in patients with MBC who had been previously treated with anthracycline, taxane, and capecitabine. ### methods Patients with MBC who had been administered S-1, an oral modulated compound containing a fluoropyrimidine derivative, between November 2001 and June 2003 at the Cancer Institute Hospital were retrospectively reviewed. S-1 at a standard dose of 50 mg/body was administered twice daily for four weeks, followed by a two-week rest period. This was repeated every six weeks until disease progression or unacceptable toxicity. ### results Thirty-five patients were assessed. The patients were heavily pretreated with anthracycline ( 100 % ) , taxane ( paclitaxel or docetaxel ) ( 100 % ) , capecitabine ( 100 % ) , vinorelbine ( 71 % ) , and mitomycin ( 69 % ) . Median follow-up time of patients was 9.6 months (range, 1.2-26.6). ORR was 3% (95% confidence interval: 0-9%), and CBR was 20% (95% confidence interval: 6-33%). Time to treatment failure was 2.8 months. Overall survival was 21.4 months. Grade 1 or 2 adverse events were observed in 17% and 13%, respectively. Grade 3 events occurred as anorexia (9%), nausea (9%), vomiting (9%), diarrhea (14%), fatigue (3%), and elevation of AST/ALT (3%). No grade 3 was seen as hand-foot syndrome. Neither grade 3 nor 4 was observed in bone marrow suppression. ### conclusions S-1 was fairly well tolerated, but demonstrated very limited activity in capecitabine-pretreated patients who had already been exposed to anthracycline and taxane. It was suggested that S-1 clinically exhibited cross-resistance to capecitabine.", "source": "https://pubmed.ncbi.nlm.nih.gov/18807123/"}
{"doc_id": "35657fbbeccb726f1fb2a4764c0e3450", "sentence": "Therapy includes debridement of necrotic bone and loculated purulence combined with amphotericin B and possibly 5-fluorocytosine or rifampin .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 84, "end": 96, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "rifampin", "start": 132, "end": 140, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Aspergillus osteomyelitis. Report of a case and review of the literature. Aspergillus is a ubiquitous saprophytic fungus seldom pathogenic for normal hosts. Aspergillus osteomyelitis occurs infrequently and is typically limited to patients with predisposing factors, including leukocyte dysfunction, malignancy with neutropenia, steroid or antibiotic therapy, pulmonary aspergillosis, and surgical manipulation. The spine is most frequently affected, and the clinical presentation is nonspecific (50% afebrile). Diagnosis requires demonstration of characteristic, acutely branching, broad, septate hyphae in biopsy material, and culture of Aspergillus. Therapy includes debridement of necrotic bone and loculated purulence combined with amphotericin B and possibly 5-fluorocytosine or rifampin .", "source": "https://pubmed.ncbi.nlm.nih.gov/4064611/"}
{"doc_id": "5846f8aa22262ba57ea026616c35439a", "sentence": "Docetaxel and cisplatin were given at 75 mg/m(2 ) , while capecitabine was initially given at 500 mg/m(2 ) twice a day and subsequently escalated .", "spans": [{"span_id": 0, "text": "Docetaxel", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cisplatin", "start": 14, "end": 23, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "capecitabine", "start": 58, "end": 70, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Induction chemotherapy with docetaxel, cisplatin and capecitabine, followed by combined cetuximab and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck: a phase I-II study. To replace 5-fluorouracil with capecitabine within a trial of induction chemotherapy followed by cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). Also, to replace cisplatin with cetuximab after induction chemotherapy. ### methods Docetaxel and cisplatin were given at 75 mg/m(2 ) , while capecitabine was initially given at 500 mg/m(2 ) twice a day and subsequently escalated . The maximum tolerated dose was used for the phase II study. ### results Seven patients were enrolled. At dose level 1, two dose-limiting toxicities were observed in the first 4 patients (grade 4 neutropenia and grade 3 diarrhea). In both patients, capecitabine was withdrawn and toxicities resolved. Dose escalation was halted and a lower capecitabine dose (750 mg/m(2) daily) was selected. Two complete responses and five partial responses were observed after induction chemotherapy. Four patients were evaluable for response after cetuximab-RT (3 complete response and 1 partial response). ### conclusion Combined chemoradiotherapy is still the gold standard in LA SCCHN and no studies currently support the use of early induction chemotherapy. Our study did not contribute toward addressing this issue since it was discontinued early because of toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/23428719/"}
{"doc_id": "8bd6b10ee379d41f0b0d3c5ed6104e9a", "sentence": "A colorectal cancer cell line ( LOVO cell ) treated by curcumin combined with irinotecan in different ways respectively was used as our comparative model .", "spans": [{"span_id": 0, "text": "curcumin", "start": 55, "end": 63, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "irinotecan", "start": 78, "end": 88, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Proteomic analysis identifies proteins associated with curcumin-enhancing efficacy of irinotecan-induced apoptosis of colorectal cancer LOVO cell. We wish to implement a proteomics-based approach to pick and identify the proteins associated with curcumin enhancing efficacy of irinotecan inducing apoptosis of colorectal cancer LOVO cells, and further explore their synergy mechanism by bioinformatics. ### methods A colorectal cancer cell line ( LOVO cell ) treated by curcumin combined with irinotecan in different ways respectively was used as our comparative model . Protein spots were analyzed through MALDI-TOF/TOF. The location and function of differential protein spots were analyzed through UniProt database. Protein-protein interactions were examined through String software. ### results A total of 54 protein spots differentially expressed with 1.5-fold difference were picked, 11 of which were repeated. They mainly were involved in intracellular calcium pathways, cellular respiratory chain pathway and intracellular redox reaction pathways of LOVO cell. According to the function of various protein points, combining with varying curves of protein points in each treatment groups, we selected five interesting protein spots, 4 of which exists Protein-protein interactions, and they were close to the formation and reduction of disulfides in intracellular endoplasmic reticulum (ER). ### conclusion We selected preliminary but comprehensive data about differential expression protein spots of LOVO cell. Among these, the five interesting differential expression protein spots identified in this study may provide new insight into LOVO cell therapeutic biomarkers. curcumin may suppress GSTM5 expression to enhance the lethal effect of irinotecan on LOVO cells, and maybe their combination via the affection of PDI and PRDX4 to disturb the formation and reduction of disulfides results in inducing apoptosis of LOVO cell.", "source": "https://pubmed.ncbi.nlm.nih.gov/24427321/"}
{"doc_id": "9518550be80156aba0f21621c9edb969", "sentence": "The use of ceftriaxone plus doxycycline as an initial empiric therapy for patients hospitalized with CAP appears safe and effective , and its potential superiority should be evaluated prospectively .", "spans": [{"span_id": 0, "text": "ceftriaxone", "start": 11, "end": 22, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxycycline", "start": 28, "end": 39, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "plus", "start": 23, "end": 27, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Effectiveness of ceftriaxone plus doxycycline in the treatment of patients hospitalized with community-acquired pneumonia. Limited data exist on the effectiveness of ceftriaxone plus doxycycline in the treatment of patients hospitalized with community-acquired pneumonia (CAP). ### methods We performed a retrospective cohort study of all adults hospitalized for pneumonia between January 1999 and July 2001 at an academic medical center. Outcomes were compared for patients with CAP treated with ceftriaxone plus doxycycline versus other appropriate initial empiric antibiotic therapies. Outcomes were adjusted with the use of a propensity score to account for differences in patient characteristics and illness severity between groups. ### results A total of 216 patients were treated with ceftriaxone plus doxycycline and 125 received other appropriate initial empiric antibiotic therapies. After adjustment, use of ceftriaxone plus doxycycline was associated with reduced inpatient mortality (OR = 0.26, 95% CI: 0.08-0.81) and 30-day mortality (OR = 0.37, 95% CI: 0.17-0.81), but not with length of stay or readmission rates. Analysis of a subset of the sample that excluded patients admitted from nursing homes, patients admitted to the ICU, and patients diagnosed with aspiration also showed reduced inpatient mortality with the use of ceftriaxone plus doxycycline. ### conclusions The use of ceftriaxone plus doxycycline as an initial empiric therapy for patients hospitalized with CAP appears safe and effective , and its potential superiority should be evaluated prospectively .", "source": "https://pubmed.ncbi.nlm.nih.gov/17219465/"}
{"doc_id": "3d3ae8bbe9535081977b3941cd0ae869", "sentence": "Metformin ( 50 mg/kg/day ) , genistein ( 20 mg/kg/day ) and combination of genistein and metformin was administered in alloxan-induced diabetic rats .", "spans": [{"span_id": 0, "text": "Metformin", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "genistein", "start": 29, "end": 38, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "genistein", "start": 75, "end": 84, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "metformin", "start": 89, "end": 98, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Genistein enhances the secretion of glucagon-like peptide-1 (GLP-1) via downregulation of inflammatory responses. Glucagon-like peptide-1 (GLP-1) an incretin hormone, is known to regulate the glucose-mediated insulin secretion. However, reduction in the level of GLP-1 is considered to be a major cause for the reduction of GLP-1-dependent insulin secretory response. genistein an isoflavone, is an important polyphenol and has wide range of therapeutic potentials, but its therapeutic effects alone and/or in combination with metformin on GLP-1 secretion have not been investigated yet. Hence, we aimed to investigate the stimulatory action of genistein in combination with metformin on GLP-1 via downregulation of inflammatory mediators, hyperlipidemia and hyperglycemia in alloxan-induced diabetic rats. Diabetes was induced in experimental rats by single administration of alloxan intraperitoneally. Metformin ( 50 mg/kg/day ) , genistein ( 20 mg/kg/day ) and combination of genistein and metformin was administered in alloxan-induced diabetic rats . We found that genistein alone and/or in combination with metformin significantly increased the serum level (P\u2009<\u20090.01) and tissue content (P\u2009<\u20090.05) of GLP-1 in intestine when compared with that of metformin-treated animals. Similarly, genistein alone and/or in combination with metformin also resulted in normoglycemia (P\u2009<\u20090.001), glucose tolerance (P\u2009<\u20090.01), insulin sensitivity (P\u2009<\u20090.0001), hyperlipidemia (P\u2009<\u20090.01), liver and kidney function biomarkers (P\u2009<\u20090.01) as compared to that of metformin-treated experimental animals. Moreover, genistein alone and/or in combination with metformin also downregulated the inflammatory responses by decreasing the levels of interleuin-6, tumor necrosis factor-\u03b1 and C-reactive protein in serum (P\u2009<\u20090.05) and intestine (P\u2009<\u20090.001) more efficiently as compared to that of metformin-treated experimental animals. The downregulation of inflammatory responses in intestine, was positively associated with increased secretion of GLP-1 from intestine. Histopathology of pancreas and intestine also showed that genistein significantly improved the deleterious effects of alloxan on pancreas and intestine. Hence, our work provides new insights on the synergistic effects of genistein and metformin on GLP-1 secretion. This may significantly improve the perception for proposing new GLP-1-based synergistic approaches for the treatment of diabetes mellitus.", "source": "https://pubmed.ncbi.nlm.nih.gov/30784939/"}
{"doc_id": "6aa7633459e4ecb48ae1c169622c608e", "sentence": "CYP3A5 ( intron 3 ) and MDR1 ( exons 12 , 21 , 26 ) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus .", "spans": [{"span_id": 0, "text": "sirolimus", "start": 147, "end": 156, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "tacrolimus", "start": 161, "end": 171, "token_start": 30, "token_end": 31}], "rels": [], "paragraph": "Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. ### methods Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 ( intron 3 ) and MDR1 ( exons 12 , 21 , 26 ) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus . ### results There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. ### conclusions Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.", "source": "https://pubmed.ncbi.nlm.nih.gov/16249748/"}
{"doc_id": "4676399f4bc7e4dfa83e4eaa3a5b3adb", "sentence": "Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen , which combines yttrium-90-labeled ibritumomab tiuxetan ( Zevalin ) with high-dose BEAM ( carmustine , etoposide , cytarabine , melphalan ) chemotherapy .", "spans": [{"span_id": 0, "text": "ibritumomab tiuxetan", "start": 192, "end": 212, "token_start": 26, "token_end": 28}, {"span_id": 1, "text": "carmustine", "start": 247, "end": 257, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "etoposide", "start": 260, "end": 269, "token_start": 37, "token_end": 38}, {"span_id": 3, "text": "cytarabine", "start": 272, "end": 282, "token_start": 39, "token_end": 40}, {"span_id": 4, "text": "melphalan", "start": 285, "end": 294, "token_start": 41, "token_end": 42}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Autologous transplantation for transformed non-Hodgkin lymphoma using an yttrium-90 ibritumomab tiuxetan conditioning regimen. Transformation from indolent non-Hodgkin lymphoma (NHL) to diffuse large B\u00a0cell lymphoma (DLBCL) has historically been associated with a poor prognosis. A small series of autologous stem cell transplantation (ASCT) studies using conventional conditioning regimens has demonstrated durable progression-free survival (PFS) rates ranging from 25% to 47%, but data in the rituximab era are lacking. Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen , which combines yttrium-90-labeled ibritumomab tiuxetan ( Zevalin ) with high-dose BEAM ( carmustine , etoposide , cytarabine , melphalan ) chemotherapy . Sixty-three patients from 4 institutions were treated between 2003 and 2011. Histological confirmation of transformation was required and defined as a diagnosis of DLBCL in patients with either a prior history or concomitant diagnosis of low-grade B\u00a0cell NHL. Median patient age at ASCT was 59.5\u00a0years, median number of prior regimens was 2, and all patients were exposed to rituximab. Disease status at ASCT was as follows: first complete remission (CR) (n\u00a0=\u00a030), first partial remission (n\u00a0=\u00a011), first relapse (n\u00a0=\u00a014), and at least second CR (n\u00a0=\u00a08). The median time from diagnosis of histological transformation to ASCT was 7.5\u00a0months (range, 2.8 to 116). Two-year nonrelapse mortality was 0%. Median follow-up for living patients was 28\u00a0months (range, 5 to 103). Two-year PFS was 68% (95% confidence interval, 58% to 75%), and overall survival was 90% (95% confidence interval, 80% to 95%). In conclusion, the Z-BEAM conditioning regimen for ASCT is well tolerated by patients with transformed lymphoma and demonstrates encouraging clinical outcomes.", "source": "https://pubmed.ncbi.nlm.nih.gov/25079874/"}
{"doc_id": "cca0fb8ed158442e36b07b073bc595a4", "sentence": "Palbociclib is a selective cyclin-dependent kinase ( CDK ) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive ( HR+ ) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer ( ABC/MBC ) .", "spans": [{"span_id": 0, "text": "Palbociclib", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "fulvestrant", "start": 122, "end": 133, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Real-World Palbociclib Use in HR+/HER2- Advanced Breast Cancer in Canada: The IRIS Study.  Palbociclib is a selective cyclin-dependent kinase ( CDK ) 4/6 inhibitor used in combination with aromatase inhibitors or fulvestrant for patients with hormone receptor-positive ( HR+ ) human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer ( ABC/MBC ) . palbociclib was the first CDK 4/6 inhibitor approved for HR+/HER2- ABC/MBC treatment in Canada in combination with letrozole (P+L) as an initial endocrine-based therapy (approved March 2016), or with fulvestrant (P+F) following disease progression after prior endocrine therapy (approved May 2017). The Ibrance Real World Insights (IRIS) study (NCT03159195) collected real-world outcomes data for palbociclib-treated patients in several countries, including Canada. ### methods This retrospective chart review included women with HR+/HER2- ABC/MBC receiving P+L or P+F in Canada. Physicians reviewed medical records for up to 14 patients, abstracting demographic and clinical characteristics, treatment patterns, and clinical outcomes. Progression-free rates (PFRs) and survival rates (SRs) at 6, 12, 18, and 24 months were estimated via Kaplan-Meier analysis. ### results Thirty-three physicians examined medical records for 247 patients (P+L, ### conclusions Dose reduction rates were low and PFR and SR were high in this Canadian real-world assessment of P+L and P+F treatments, suggesting that palbociclib combinations are well tolerated and effective.", "source": "https://pubmed.ncbi.nlm.nih.gov/33498797/"}
{"doc_id": "9750dd0503c6e26b90a93f82a904af2d", "sentence": "Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer : a dose-finding and phase II study .", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 27, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "irinotecan", "start": 58, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "oxaliplatin", "start": 72, "end": 83, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Triplet schedule of weekly 5-fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer : a dose-finding and phase II study . A weekly administration of alternating irinotecan or oxaliplatin associated to 5-fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).", "source": "https://pubmed.ncbi.nlm.nih.gov/20428819/"}
{"doc_id": "949504286ba6bc44ce85c9fa5dd1b301", "sentence": "After larvae were infected with S. aureus , larval survival was enhanced by administering the antistaphylococcal antibiotics daptomycin or vancomycin .", "spans": [{"span_id": 0, "text": "daptomycin", "start": 125, "end": 135, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "vancomycin", "start": 139, "end": 149, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Wax moth larva (Galleria mellonella): an in vivo model for assessing the efficacy of antistaphylococcal agents. To investigate whether the wax moth larva, Galleria mellonella, is a suitable host for assessing the in vivo efficacy of antistaphylococcal agents against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infections. ### methods Wax moth larvae were infected with increasing doses of S. aureus to investigate the effect of inoculum size on larval survival. In addition, infected wax moth larvae were treated with daptomycin, penicillin or vancomycin to examine whether these agents were effective against S. aureus and MRSA infections in vivo. ### results Increasing inoculum doses of live S. aureus cells resulted in greater larval mortality, but heat-killed bacteria and cell-free culture filtrates had no detrimental effects on survival. Larval mortality rate also depended on the post-inoculation incubation temperature. After larvae were infected with S. aureus , larval survival was enhanced by administering the antistaphylococcal antibiotics daptomycin or vancomycin . Larval survival increased with increasing doses of the antibiotics. Moreover, penicillin improved survival of larvae infected with a penicillin-susceptible methicillin-susceptible S. aureus (MSSA) strain, but it was ineffective at similar doses in larvae infected with MRSA (penicillin resistant). daptomycin and vancomycin were also effective when administered to the larvae prior to infection with bacteria. ### conclusions This is the first report to demonstrate that antibiotics are effective in the wax moth larva model for the treatment of infections caused by Gram-positive bacteria. The new wax moth larva model is a useful preliminary model for assessing the in vivo efficacy of candidate antistaphylococcal agents before proceeding to mammalian studies, which may reduce animal experimentation and expense.", "source": "https://pubmed.ncbi.nlm.nih.gov/21622972/"}
{"doc_id": "a000945f4ace572bd2cf8e5cd4ed2383", "sentence": "In terms of progression-free survival ( PFS ) , axitinib was superior compared with placebo ( HR = 0.25 , 95 % CrI : 0.17 - 0.38 ) , sorafenib ( HR = 0.46 , 95 % CrI : 0.32 - 0.68 ) and pazopanib ( HR = 0.47 , 95 % CrI : 0.26 - 0.85 ) .", "spans": [{"span_id": 0, "text": "axitinib", "start": 48, "end": 56, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "sorafenib", "start": 133, "end": 142, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "pazopanib", "start": 186, "end": 195, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis. A systematic review/meta-analysis was conducted to assess the effectiveness and safety of second-line treatments for advanced renal cell carcinoma (RCC), which includes the vascular endothelial growth factor inhibitor axitinib. ### methods Database searches were conducted to identify randomised controlled trials (RCTs). Indirect comparisons using a fixed-effect Bayesian model were used to assess the relative effectiveness of treatments and reported as hazard ratio (HR) and 95% credible intervals (CrI). ### results Although 24 RCTs met eligibility criteria, only three studies were included in the fixed-effect Bayesian meta-analysis, due to differences in patient inclusion criteria/reported outcomes in the wider dataset. Robust meta-analysis was restricted to the subgroup pretreated with cytokines. In terms of progression-free survival ( PFS ) , axitinib was superior compared with placebo ( HR = 0.25 , 95 % CrI : 0.17 - 0.38 ) , sorafenib ( HR = 0.46 , 95 % CrI : 0.32 - 0.68 ) and pazopanib ( HR = 0.47 , 95 % CrI : 0.26 - 0.85 ) . An analysis including all patients, regardless of previous first-line treatment, reported similar results. There was no significant difference in PFS between sorafenib and pazopanib. ### conclusion Results from the present study suggest that axitinib will be an important treatment option to extend PFS in the management of advanced RCC in the second-line setting. Ongoing research will define the optimal treatment algorithm leading to a patient-focused treatment strategy.", "source": "https://pubmed.ncbi.nlm.nih.gov/23256638/"}
{"doc_id": "f8183c84625b670fd1d5ee81a12d76bf", "sentence": "Concomitant and sequential treatment with paclitaxel and gemcitabine had no significant difference in terms of PFS .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 42, "end": 52, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "gemcitabine", "start": 57, "end": 68, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination versus sequential paclitaxel plus gemcitabine as first-line chemotherapy for women with metastatic breast cancer: a prospective randomized phase II study. paclitaxel (T) plus gemcitabine (G) is an active concomitant combination for the treatment of metastatic breast cancer (MBC). However, the efficacy of sequential administration of these two drugs is unclear. This randomized phase II study was conducted to evaluate the efficacy of T and G administered either as a concomitant or as a sequential regimen in patients with MBC. ### methods Patients with MBC (n=66) were randomized to either receive 6 cycles of concomitant T and G or 4 cycles of T followed by 4 cycles of G, as first line chemotherapy. With no progression, the arms would switch to maintenance with paclitaxel. Progression free survival (PFS) was defined as the primary endpoint; secondary endpoints were the overall response rate (ORR), overall survival (OS), and toxicity. In total, 33 patients were randomized to the concomitant or sequential arms. Patient characteristics were well balanced. The median number of chemotherapy cycles was 6 for the concomitant arm and 8 for the sequential arm. ### results No significant difference was observed in terms of PFS, ORR, and OS. Only 13 (39.4%) patients progressed in the sequential arm. Although there was no significant difference between the two arms (p=0.056),the sequential arm had a remarkable trend of longer PFS than the concomitant arm. Toxicities were manageable and similar in both arms.The incidence of neutropenia was significantly higher in the concomitant arm (90.9%) than in the sequential arm (60.6%). Grade 3 or 4 neutropenia was not significantly different between the two arms. ### conclusions Concomitant and sequential treatment with paclitaxel and gemcitabine had no significant difference in terms of PFS .", "source": "https://pubmed.ncbi.nlm.nih.gov/30610781/"}
{"doc_id": "4c3f1b6f9750900aeb10170e8b4cf94f", "sentence": "Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer : A Phase 3 Randomized Clinical Trial .", "spans": [{"span_id": 0, "text": "Margetuximab", "start": 12, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "Trastuzumab", "start": 28, "end": 39, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer : A Phase 3 Randomized Clinical Trial . ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. ### objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. ### Design Setting And Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. ### interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (\u22642, >2), lines of therapy (\u22642, >2), and chemotherapy choice. ### Main Outcomes And Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All \u03b1 was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. ### results A total of 536 patients were randomized to receive margetuximab (n\u2009=\u2009266) or trastuzumab (n\u2009=\u2009270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P\u2009=\u2009.03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P\u2009=\u2009.33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P\u2009<\u2009.001; median, 5.7 vs 4.4 months; September 10, 2019). margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P\u2009=\u2009.06; October 10, 2018), and 25% vs 14% (P\u2009<\u2009.001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. ### Conclusions And Relevance In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. ### Trial Registration ClinicalTrials.gov Identifier: NCT02492711.", "source": "https://pubmed.ncbi.nlm.nih.gov/33480963/"}
{"doc_id": "1b6797e6b26dc93d0b4ece9dcce79972", "sentence": "She was treated with a combination of four cycles of cyclophosphamide , hydroxydaunorubicin , vincristine , and prednisolone ( CHOP ) regimen followed by local radiotherapy ( 36 Gray/20 fractions/4 weeks ) by three-dimensional conformal technique .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 53, "end": 69, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "vincristine", "start": 94, "end": 105, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "prednisolone", "start": 112, "end": 124, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Combined Modality Management of Sinonasal Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma in a Young Adult-Report of a Rare Case. Sinonasal anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) without nodal involvement is extremely rare and the rarity of this tumor often leads to diagnostic dilemma. It has been predominantly reported in pediatric, adolescent and young adult patients, mostly of Asian origin. A 21-year-old female patient presented with history of epistaxis for 1 year. On clinical and radiological examination, there was a 5\u2009cm mass in the right nasal cavity, ethmoid, and frontal sinus. Biopsy at a local center had shown moderately differentiated squamous cell carcinoma. Rebiopsy at our center showed possibility of a hematolymphoid malignancy(pancytokeratin-, CD45+, CD3-, CD20-) and further immunohistochemistry studies(CD4+, CD43+, CD30+, ALK+) revealed ALK-positive ALCL. Rest of the lymphoma work-up was essentially normal and she had stage IE disease. She was treated with a combination of four cycles of cyclophosphamide , hydroxydaunorubicin , vincristine , and prednisolone ( CHOP ) regimen followed by local radiotherapy ( 36 Gray/20 fractions/4 weeks ) by three-dimensional conformal technique . She tolerated the treatment well without any severe toxicity and had complete clinical and radiological response. At last follow-up visit, 40 months from the initial diagnosis, she was alive and disease free. Sinonasal ALK-positive ALCL is a rare tumor, which can be effectively treated with a combination of multiagent CHOP/CHOP-like regimen and local conformal radiotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/30994389/"}
{"doc_id": "7b2d63dc01a8cf947fa8d797c1e4fbc7", "sentence": "We compared such treatment with docetaxel plus prednisone in men with this disease .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 32, "end": 41, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "prednisone", "start": 47, "end": 57, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease . ### methods From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone. ### results As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. ### conclusions When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.", "source": "https://pubmed.ncbi.nlm.nih.gov/15470213/"}
{"doc_id": "11ee75a48ed1d61aaaebf94dde6088f6", "sentence": "Magnocellular neurons of the hypothalamo-neurophypophysial system synthesize either vasopressin or oxytocin ; water deprivation and chronic saline ingestion are potent stimuli for the expression of both of the genes encoding these neuropeptides .", "spans": [{"span_id": 0, "text": "vasopressin", "start": 84, "end": 95, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "oxytocin", "start": 99, "end": 107, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Simultaneous detection of neuropeptides and messenger RNA in the magnocellular hypothalamo-neurohypophysial system by a combination of non-radioactive in situ hybridization histochemistry and immunohistochemistry. A protocol was developed combining non-radioactive in situ hybridization histochemistry with enzyme based immunohistochemistry, detect the expression of mRNA in phenotypically defined neurons. Free-floating brain sections were hybridized with the oligonucleotide probes which have been 3'-end labelled with biotin-11-dUTP. The hybridized probe was visualized by a combined avidin-biotin bridge method, anti-avidin immunohistochemistry, and horseradish peroxidase detection using diaminobenzidine as a substrate. The in situ hybridization step yielded a very stable reaction product enabling subsequent immunohistochemical reactions using horseradish peroxidase and benzidine dihydrochloride as a chromogen. Magnocellular neurons of the hypothalamo-neurophypophysial system synthesize either vasopressin or oxytocin ; water deprivation and chronic saline ingestion are potent stimuli for the expression of both of the genes encoding these neuropeptides . A number of other neuropeptides with putative transmitter action are synthesized in magnocellular neurons during such stimulation. Experiments were performed to explore whether neuropeptide y immunoreactivity is present within magnocellular vasopressin mRNA-expressing neurons of the hypothalamo-neurophypophysial system. The results clearly demonstrated that neuropeptide y-immunoreactive elements were present within a number of magnocellular vasopressin mRNA-containing cells. In addition, immunohistochemical detection of the neuropeptides ocytocin and cholecystokinin was carried out on sections hybridized non-radioactively for vasopressin; as expected vasopressin mRNA did not co-exist with cholecystokinin, whereas a few oxytocin immunoreactive neurons in osmotically stimulated animals also contained vasopressin mRNA. The developed method makes possible the immunohistochemical detection of intracellular antigens with concomitant detection of intracellular mRNA.", "source": "https://pubmed.ncbi.nlm.nih.gov/7698898/"}
{"doc_id": "fe4c90d21c59eca0e7c6c24e30779155", "sentence": "Combination chemotherapy has been established to have superior response rates and progression-free survival and -- in some instances , for fluorouracil and irinotecan combinations -- improved overall survival compared to fluorouracil alone .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 139, "end": 151, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "irinotecan", "start": 156, "end": 166, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "fluorouracil", "start": 221, "end": 233, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Update on chemotherapy for advanced colorectal cancer. Efforts to improve the length and quality of life, as well as to expand treatment options, for patients with metastatic colorectal cancer have only recently become more successful. With maximization of dose and schedule schemes for fluoropyrimidine therapy, new drugs such as irinotecan (CPT-11, Camptosar) and oxaliplatin have also become part of the standard therapy for patients. Combination chemotherapy has been established to have superior response rates and progression-free survival and -- in some instances , for fluorouracil and irinotecan combinations -- improved overall survival compared to fluorouracil alone . There is still much to be learned about the optimal management of patients with colorectal cancer, including the role of second- and third-line chemotherapy in the overall survival outcome, and the role of salvage therapy in patients with limited metastatic disease. Most importantly, the development of a biological marker of prognosis and response should help to select appropriate chemotherapy programs for patients on a rational and individual basis, not only in the setting of metastatic disease, but also in the adjuvant population.", "source": "https://pubmed.ncbi.nlm.nih.gov/11301834/"}
{"doc_id": "03eff5ead4fbffb23ee6efc363538950", "sentence": "Phase IV study of bevacizumab in combination with infusional fluorouracil , leucovorin and irinotecan ( FOLFIRI ) in first-line metastatic colorectal cancer .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 18, "end": 29, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "fluorouracil", "start": 61, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "leucovorin", "start": 76, "end": 86, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "irinotecan", "start": 91, "end": 101, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Phase IV study of bevacizumab in combination with infusional fluorouracil , leucovorin and irinotecan ( FOLFIRI ) in first-line metastatic colorectal cancer . bevacizumab (Avastin) significantly improves overall survival (OS) and progression-free survival (PFS) when combined with first-line irinotecan (IFL) plus bolus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer (CRC). This open-label, phase IV trial evaluated the efficacy and safety of first-line bevacizumab in combination with IFL and infusional 5-FU/LV (FOLFIRI). ### methods Two-hundred and nine treatment-na\u00efve metastatic CRC patients were enrolled and received bevacizumab and FOLFIRI every 2 weeks. Treatment was continued until disease progression. The primary objective was PFS, with additional determinations of OS, response and toxicity. ### results Median PFS was 11.1 months and is comparable to that observed in published phase III and community-based trials using first-line bevacizumab plus FOLFIRI, and to phase III trials using bevacizumab in combination with bolus 5-FU/LV plus IFL. Median OS was 22.2 months. Overall response rate was 53.1% and the disease control rate 85.6%. Most adverse events were grade 1/2 and were manageable. The most common grade 3/4 adverse events (> or =10%) were neutropenia, venous thromboembolic events, diarrhea, and fatigue. ### conclusion bevacizumab combined with first-line FOLFIRI is an effective and well-tolerated therapy option for patients with metastatic CRC.", "source": "https://pubmed.ncbi.nlm.nih.gov/19628950/"}
{"doc_id": "a83574308995e37ffd7007d1f457b04f", "sentence": "In addition , multidrug resistance of Hep-2-CSCs to vincristine , etoposide and doxorubicin was greatly improved after the cells were transfected with microRNA-125a mimics .", "spans": [{"span_id": 0, "text": "vincristine", "start": 52, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 66, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "doxorubicin", "start": 80, "end": 91, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Chemoresistance is a major obstacle in chemotherapy of laryngeal carcinoma. Recently, studies indicate that cancer stem cells are responsible for chemotherapy failure. In addition, microRNAs play important roles in tumor initiation, development and multidrug resistance. In the present study, we found that the expression of microRNA-125a was decreased in laryngeal carcinoma tissues and Hep-2 laryngeal cancer stem cells (Hep-2-CSCs). MicroRNA-125a gain-of-function significantly increased the sensitivity of Hep-2-CSCs to cisplatin in vitro and in vivo. Combination with microRNA-125a mimics can decrease the half maximal inhibitory concentration of Hep-2-CSCs to cisplatin. Mechanically, we found that microRNA-125a reverses cisplatin resistance in Hep-2-CSCs by targeting Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1). Inhibition of HAX-1 by microRNA-125a significantly promotes the cisplatin-induced apoptosis in Hep-2-CSCs through mitochondrial pathway. In addition , multidrug resistance of Hep-2-CSCs to vincristine , etoposide and doxorubicin was greatly improved after the cells were transfected with microRNA-125a mimics . These dates strongly suggested the promotion of microRNA-125a/HAX-1 axis on chemotherapy of laryngeal carcinoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/27880721/"}
{"doc_id": "c1eafdf83c00572f96e0bbd3f6615400", "sentence": "Nine patients received a combination of cisplatin and etoposide ( EP ) , 5 had cyclophosphamide , doxorubicin and vincristine , 1 had cyclophosphamide , etoposide and vincristine and 1 had monotherapy with oral etoposide .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 40, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "etoposide", "start": 54, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "cyclophosphamide", "start": 79, "end": 95, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "doxorubicin", "start": 98, "end": 109, "token_start": 17, "token_end": 18}, {"span_id": 4, "text": "vincristine", "start": 114, "end": 125, "token_start": 19, "token_end": 20}, {"span_id": 5, "text": "cyclophosphamide", "start": 134, "end": 150, "token_start": 23, "token_end": 24}, {"span_id": 6, "text": "etoposide", "start": 153, "end": 162, "token_start": 25, "token_end": 26}, {"span_id": 7, "text": "vincristine", "start": 167, "end": 178, "token_start": 27, "token_end": 28}, {"span_id": 8, "text": "etoposide", "start": 211, "end": 220, "token_start": 34, "token_end": 35}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3, 4], "is_context_needed": true}, {"class": "COMB", "spans": [5, 6, 7], "is_context_needed": true}], "paragraph": "Resolution of superior vena cava obstruction in small cell lung cancer patients treated with chemotherapy. Small cell lung cancer is a highly chemo-sensitive malignancy. As it often presents with a central lesion, superior vena cava obstruction (SVCO) is not an uncommon manifestation. From January 1990 to December 1993, 161 patients with small cell lung carcinoma were seen at our institution. Twenty (12.4%) of these patients presented with symptoms and signs of SVCO. Initial therapy consisted of radiotherapy in 4 patients and chemotherapy in 16 patients. Of those treated with chemotherapy, patient characteristics included 13 males, median age of 62.5 years (range 51 to 78 years), Eastern Co-operative Oncology Group (ECOG) performance status of 3 to 4 in 7 patients; 1 to 2 in 9 patients, and limited stage disease in 8 patients. The median period of follow-up was 5 months. Nine patients received a combination of cisplatin and etoposide ( EP ) , 5 had cyclophosphamide , doxorubicin and vincristine , 1 had cyclophosphamide , etoposide and vincristine and 1 had monotherapy with oral etoposide . Overall response to chemotherapy was 81% (with 31% complete responses). All responders had resolution of SVCO. Only 3 patients did not respond (1 patient defaulted, 1 patient died of neutropenic sepsis at week one and 1 patient had stable disease). Resolution of SVCO was noted within the first 2 weeks after the first cycle; the earliest being 3 days. The only patient given single-agent oral etoposide responded within 10 days after initiation of treatment. Of the 7 patients with poor performance status (ECOG 3 to 4), 3 died from treatment-related complications. Chemotherapy is highly effective as a primary treatment of small cell lung carcinoma despite presentation with SVCO. However, caution is advised in the use of combination chemotherapy for those presenting with poor performance status. Initial therapy with oral etoposide or radiotherapy should be considered as possible alternatives for these patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/8838986/"}
{"doc_id": "af8fae5caf46f6b613c1169c260a5c5c", "sentence": "Tetracycline ( TC ) and chlortetracycline ( CTC ) are used extensively for growth promotion and therapeutic purposes in livestock production .", "spans": [{"span_id": 0, "text": "Tetracycline", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "chlortetracycline", "start": 24, "end": 41, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Sorption of tetracycline and chlortetracycline on K- and Ca-saturated soil clays, humic substances, and clay-humic complexes.  Tetracycline ( TC ) and chlortetracycline ( CTC ) are used extensively for growth promotion and therapeutic purposes in livestock production . The sorption of TC and CTC on clays, humic substances (HS), and clay-humic complexes (clay-HC) derived from two agricultural soils was quantified using dilute CaCl2 (Ca) and KCI (K) as background solutions. In all systems, the soil components sorbed > 96% of added tetracyclines. Strongest sorption was observed for clays, followed by HS, and then clay-HC. Greater sorption by the Ca systems than the K systems and decreased sorption with increasing pH suggests that cation bridging and cation exchange contribute to sorption. X-ray diffraction analysis showed that TC and CTC were sorbed in the interlayers of smectites and that the presence of HS reduced interlayer sorption of tetracyclines by smectites in clay-HC. The results indicate that tetracyclines are dominantly sorbed on soil clays and that HS in clay-HC either mask sorption sites on clay surfaces or inhibit interlayer diffusion of tetracyclines.", "source": "https://pubmed.ncbi.nlm.nih.gov/17410786/"}
{"doc_id": "01fab8aba01515b6ee53f10614e5a77e", "sentence": "Comparing the combination of nalidixic acid and metronidazole with metronidazole alone , 17.5 % more children treated with the combination recovered by day 3 of treatment ( p = 0.08 ) and the mean stool frequency ascertained on day 7 for the previous 24 h was 26.8 % less in them ( p = 0.05 ) .", "spans": [{"span_id": 0, "text": "nalidixic acid", "start": 29, "end": 43, "token_start": 4, "token_end": 6}, {"span_id": 1, "text": "metronidazole", "start": 48, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "metronidazole", "start": 67, "end": 80, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. To determine the efficacy of antimicrobial treatment in non-dysenteric persistent diarrhoea in a community setting. ### methods In this double-blind field trial, 156 children aged 4-36 months with persistent diarrhoea not associated with Giardia lamblia infestation seeking treatment in a community outpatient clinic, were randomized to receive a combination of nalidixic acid and metronidazole, metronidazole alone, or placebo for 7 days. ### results In comparison with placebo, metronidazole treatment did not result in a significant reduction in the mean post-enrollment diarrhoeal duration and stool frequency, increase in the proportion of patients recovered by days 3, 5 and 7 of treatment, and increase in weight gain at days 7 and 14. Comparing the combination of nalidixic acid and metronidazole with metronidazole alone , 17.5 % more children treated with the combination recovered by day 3 of treatment ( p = 0.08 ) and the mean stool frequency ascertained on day 7 for the previous 24 h was 26.8 % less in them ( p = 0.05 ) . The weight gains at days 7 and 14 were similar in the two groups. ### conclusions These findings indicate that metronidazole offers no therapeutic benefit in persistent diarrhoea not associated with Giardia lamblia and nalidixic acid has only a modest clinical benefit, which is not substantial enough to warrant its routine use.", "source": "https://pubmed.ncbi.nlm.nih.gov/8955454/"}
{"doc_id": "4e07f5335a8ef944f397d3b0150c4384", "sentence": "The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy .", "spans": [{"span_id": 0, "text": "propranolol", "start": 85, "end": 96, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "primidone", "start": 101, "end": 110, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Topiramate for essential tremor. Essential tremor (ET) is one of the most common movement disorders. The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy . However, these treatments can be ineffective in 25% to 55% of people and are frequently associated with serious adverse events (AEs). For these reasons, it is worthwhile evaluating other treatments for ET. topiramate has been suggested as a potentially useful agent for the treatment of ET but there is uncertainty about its efficacy and safety. ### objectives To assess the efficacy and safety of topiramate in the treatment of ET. ### Search Methods We carried out a systematic search without language restrictions to identify all relevant trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to January 2017), Embase (January 1988 to January 2017), National Institute for Health and Care Excellence (1999 to January 2017), ClinicalTrials.gov (1997 to January 2017) and World Health Organization International Clinical Trials Registry Platform (ICTRP; 2004 to January 2017). We searched BIOSIS Citation Index (2000 to January 2017) for conference proceedings. We handsearched grey literature and the reference lists of identified studies and reviews. ### Selection Criteria We included all\u00a0randomised controlled trials (RCTs) of topiramate versus placebo/open control or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in people presenting with secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. ### Data Collection And Analysis Two review authors independently collected and extracted data using a data collection form. We assessed the risk of bias and the quality of evidence. We used a fixed-effect meta-analysis for data synthesis. ### Main Results This review included three trials comparing topiramate to placebo (309 participants). They were all at high overall risk of bias. The quality of evidence ranged from very low to low. Compared to placebo, participants treated with topiramate showed a significant improvement in functional disability and an increased risk of withdrawal (risk ratio (RR) 1.78, 95% confidence interval (CI) 1.23 to 2.60). There were more AEs for topiramate-treated participants, particularly paraesthesia, weight loss, appetite decrease and memory difficulty. ### Authors Conclusions This systematic review highlighted the presence of limited data and very low to low quality evidence to support the apparent efficacy and the occurrence of treatment-limiting AEs in people with ET treated with topiramate. Further research to assess topiramate efficacy and safety on ET is needed.", "source": "https://pubmed.ncbi.nlm.nih.gov/28409827/"}
{"doc_id": "85819fff08050e6eb88089ae579eed80", "sentence": "In vitro sensitivity of HT29 human colon cancer cells to doxorubicin ( DXR ) , vincristine ( VCR ) , etoposide ( VP16 ) , cisplatin ( CDDP ) , melphalan ( L-PAM ) and 5-fluorouracil ( 5FU ) was markedly reduced when cell-culture density increased .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 57, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "vincristine", "start": 79, "end": 90, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "etoposide", "start": 101, "end": 110, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "cisplatin", "start": 122, "end": 131, "token_start": 25, "token_end": 26}, {"span_id": 4, "text": "melphalan", "start": 143, "end": 152, "token_start": 30, "token_end": 31}], "rels": [], "paragraph": "Confluence-dependent resistance in human colon cancer cells: role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells.  In vitro sensitivity of HT29 human colon cancer cells to doxorubicin ( DXR ) , vincristine ( VCR ) , etoposide ( VP16 ) , cisplatin ( CDDP ) , melphalan ( L-PAM ) and 5-fluorouracil ( 5FU ) was markedly reduced when cell-culture density increased . For some drugs, confluence-dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L-PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR- and VP16-induced DNA breakage was also less important in confluent than in non-confluent cells. CDR appeared closely related to an increased proportion of non-cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/1544702/"}
{"doc_id": "d0e8063d3b74acc979234b2e580a4eb2", "sentence": "ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 113, "end": 124, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "fluorouracil", "start": 129, "end": 141, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy . To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and the excision cross-complementing (ERCC1) gene are associated with response to and survival of fluorouracil (5-FU)/oxaliplatin chemotherapy in metastatic colorectal cancer. ### Patients And Methods Patients had progressive stage IV disease after unsuccessful 5-FU and irinotecan chemotherapy. All patients were evaluated for eligibility for a compassionate 5-FU/oxaliplatin protocol. cDNA was derived from paraffin-embedded tumor specimens to determine TS and ERCC1 mRNA expression relative to the internal reference gene beta-actin using fluorescence-based, real-time reverse transcriptase polymerase chain reaction. ### results The median TS gene expression level from 50 metastasized tumors was 3.4 x 10(-3) (minimum expression, 0.18 x 10(-3);maximum expression, 11.5 x 10(-3)), and the median ERCC1 gene expression level was 2.53 x 10(-3) (minimum, 0.0; maximum, 14.61 x 10(-3)). The gene expression cutoff values for chemotherapy nonresponse were 7.5 x 10(-3) for TS and 4.9 x 10(-3) for ERCC1. The median survival time for patients with TS <or= 7.5 x 10(-3) (43 of 50 patients) was 10.2 months, compared with 1.5 months for patients with TS greater than 7.5 x 10(-3) (P < .001). Patients with ERCC1 expression <or= 4.9 x 10(-3) (40 of 50 patients) had a median survival time of 10.2 months, compared with 1.9 months for patients with ERCC1 expression greater than 4.9 x 10(-3) (P < .001). A TS of 7.5 x 10(-3) segregated significantly into response, stable disease, and progression (P = .02), whereas the association between ERCC1 and response did not reach statistical significance (P = .29). ### conclusion These data suggest that intratumoral ERCC1 mRNA and TS mRNA expression levels are independent predictive markers of survival for 5-FU and oxaliplatin combination chemotherapy in 5-FU-resistant metastatic colorectal cancer. Precise definition of the best TS cut point will require further analysis in a large, prospective study.", "source": "https://pubmed.ncbi.nlm.nih.gov/11731512/"}
{"doc_id": "9c7a78358ae8529066cbe99c14c5bccc", "sentence": "7 patients ( 53 % ) receiving pamidronate and thalidomide therapy demonstrated good response involving at least 25 % reduction of monoclonal protein levels in comparison with baseline .", "spans": [{"span_id": 0, "text": "pamidronate", "start": 30, "end": 41, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "thalidomide", "start": 46, "end": 57, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination of pamidronate and thalidomide in the therapy of treatment-resistant multiple myeloma. Bisphosphonates inhibit the activity of osteoclasts and demonstrate antitumor effect, involving induction of plasmocyte apoptosis, blocking of angiogenesis, stimulation of Tgd lymphocytes and inhibition of metalloproteinases. Bisphosphonates combined with thalidomide, a drug possessing confirmed anti-myeloma activity, seem to have potential favorable effect in patients with treatment-resistant multiple myeloma with advanced osteolytic lesions. ### Material Methods 13 patients with treatment-resistant multiple myeloma with advanced osteolytic lesions received combined pamidronate and thalidomide therapy. All the patients underwent detailed clinical and laboratory control once a month. pamidronate was used at 90 mg i.v. dose administered at 4-week intervals, and thalidomide at doses escalated from 200 mg/d in the first week to 400 mg/d after 3 weeks of the therapy. The mean duration of treatment was 12 weeks with a range of 3 to 36 weeks. ### results 7 patients ( 53 % ) receiving pamidronate and thalidomide therapy demonstrated good response involving at least 25 % reduction of monoclonal protein levels in comparison with baseline . All these patients reported improvement of osteodynia symptoms, and 3 of them - their complete regression. 70% patients experienced side effects (dizziness, constipation, somnolence, polyneuropathy) due to thalidomide administration ### conclusions Good response to combined pamidronate and thalidomide therapy can be expected in at least 50% of patients with treatment-resistant multiple myeloma with advanced osteolytic lesions.", "source": "https://pubmed.ncbi.nlm.nih.gov/11951079/"}
{"doc_id": "dd638765ce283cb888de1cf23ec47c17", "sentence": "Growth inhibition was measured by 3H-thymidine incorporation assays for doxorubicin hydrochloride ( ADM ) , mitomycin C ( MMC ) , cisplatin ( CDDP ) , and etoposide ( VP-16 ) , and by Alamar Blue assay for ( AB assay ) 5-fluorouracil ( 5-FU ) .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 72, "end": 83, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "mitomycin", "start": 108, "end": 117, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "cisplatin", "start": 130, "end": 139, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "etoposide", "start": 155, "end": 164, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "In vitro chemosensitivity of human pancreatic cancer cell lines. These results show that eight pancreatic cancer cell lines are broadly sensitive to CDDP, and that chemotherapy for pancreatic cancer may improve the prognosis by more effective drug delivery to cancer cells. ### background Chemotherapy for pancreatic cancer does not satisfactorily improve prognosis. The efficacy of chemotherapy depends on choosing sensitive anticancer drugs. ### methods The in vitro chemosensitivity of eight human pancreatic cancer cell lines was investigated. Growth inhibition was measured by 3H-thymidine incorporation assays for doxorubicin hydrochloride ( ADM ) , mitomycin C ( MMC ) , cisplatin ( CDDP ) , and etoposide ( VP-16 ) , and by Alamar Blue assay for ( AB assay ) 5-fluorouracil ( 5-FU ) . The cells were exposed to ADM, MMC, CDDP, and VP-16 for 2 h, and 5-FU for 72 h. From the dose-response curves, the 50% growth inhibition (IC50) level for each drug was estimated. ### results The IC50 after 2 h of exposure of each of the eight kinds of cell lines to each anticancer drug ranged from 0.12-8.2 micrograms/mL for ADM, 0.066-25 micrograms/mL for MMC, 0.57-7 micrograms/mL for CDDP, 0.68-300 micrograms/mL for VP-16. IC50 after 72 h of exposure to 5-FU ranged from 1.8-23 micrograms/mL.", "source": "https://pubmed.ncbi.nlm.nih.gov/9013279/"}
{"doc_id": "a873ff57f7d76116404d4cc23749820f", "sentence": "A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207 , moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide .", "spans": [{"span_id": 0, "text": "TMC207", "start": 90, "end": 96, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "moxifloxacin", "start": 99, "end": 111, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "pyrazinamide", "start": 116, "end": 128, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "amikacin", "start": 148, "end": 156, "token_start": 22, "token_end": 23}, {"span_id": 4, "text": "ethionamide", "start": 161, "end": 172, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "POS", "spans": [1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Sterilizing activity of second-line regimens containing TMC207 in a murine model of tuberculosis. The sterilizing activity of the regimen used to treat multidrug resistant tuberculosis (MDR TB) has not been studied in a mouse model. ### Objective And Methods Swiss mice were intravenously inoculated with 6 log10 of Mycobacterium tuberculosis (TB) strain H37Rv, treated with second-line drug combinations with or without the diarylquinoline TMC207, and then followed without treatment for 3 more months to determine relapse rates (modified Cornell model). ### measurements Bactericidal efficacy was assessed by quantitative lung colony-forming unit (CFU) counts. Sterilizing efficacy was assessed by measuring bacteriological relapse rates 3 months after the end of treatment. ### Main Results The relapse rate observed after 12 months treatment with the WHO recommended MDR TB regimen (amikacin, ethionamide, pyrazinamide and moxifloxacin) was equivalent to the relapse rate observed after 6 months treatment with the recommended drug susceptible TB regimen (rifampin, isoniazid and pyrazinamide). When TMC207 was added to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months. A similar relapse rate was also obtained with a 6-month completely oral regimen including TMC207 , moxifloxacin and pyrazinamide but excluding both amikacin and ethionamide . ### conclusions In this murine model the duration of the WHO MDR TB treatment could be reduced to 12 months instead of the recommended 18-24 months. The inclusion of TMC207 in the WHO MDR TB treatment regimen has the potential to further shorten the treatment duration and at the same time to simplify treatment by eliminating the need to include an injectable aminoglycoside.", "source": "https://pubmed.ncbi.nlm.nih.gov/21408613/"}
{"doc_id": "f034a10cf015ac9c562d19fd9cfd8396", "sentence": "Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma : Safety , Tolerability , and Preliminary Evidence of Antitumor Activity .", "spans": [{"span_id": 0, "text": "Propranolol", "start": 38, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "Pembrolizumab", "start": 54, "end": 67, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma : Safety , Tolerability , and Preliminary Evidence of Antitumor Activity . Increased \u03b2-adrenergic receptor (\u03b2-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly \u03b22-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective \u03b2-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. ### Patients And Methods A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. ### results Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade \u22653 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFN\u03b3 and a decrease in IL6 was noted in responders. ### conclusions Combination of propranolol with pembrolizumab in treatment-na\u00efve metastatic melanoma is safe and shows very promising activity. propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/33127652/"}
{"doc_id": "5be0c033561668e08e7c57384deed3e9", "sentence": "Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress .", "spans": [{"span_id": 0, "text": "Iohexol", "start": 0, "end": 7, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "iodixanol", "start": 12, "end": 21, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "A novel contrast-induced acute kidney injury model based on the 5/6-nephrectomy rat and nephrotoxicological evaluation of iohexol and iodixanol in vivo. Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10\u2009mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress . In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. iohexol induced more severe CI-AKI than iodixanol in this model.", "source": "https://pubmed.ncbi.nlm.nih.gov/25478060/"}
{"doc_id": "dd2afd1aa818c0374ac103916a263e56", "sentence": "Sequential exposure of vinorelbine preceding paclitaxel or prolonged exposure to both agents concurrently needs to be tested clinically to determine whether the antitumor activity of this combination can be enhanced .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 23, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "paclitaxel", "start": 45, "end": 55, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro. Empiric combinations of vinca alkaloids with taxanes have been recently used in clinical oncology. To enhance the activity of these two classes of agents, we evaluated the sequence and duration of exposure, looking for synergistic effects. Cell lines DU 145, PC 3, LnCaP, LL 86, MCF7wt, and MCF7/ADR (NCI/ADR-RES) were incubated with varying concentrations of paclitaxel or vinorelbine. Cytotoxicity was evaluated by a semiautomated MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) method. Synergism or antagonism of these two agents either sequentially or in combination was determined by median effect analysis. Prolonged exposure of cells to either drug enhanced cytotoxic effect. Synergism or antagonism with vinorelbine and paclitaxel were both sequence dependent and cell line specific. In the case of MCF7wt, synergism was seen when a 48-hr exposure to vinorelbine preceded paclitaxel, whereas antagonism was noted when both agents were applied simultaneously or when the sequence was reversed. Concurrent vinorelbine and paclitaxel were synergistic in four of six cell lines when the exposure was extended to 96 hr but not for shorter durations of exposure. Sequential exposure of vinorelbine preceding paclitaxel or prolonged exposure to both agents concurrently needs to be tested clinically to determine whether the antitumor activity of this combination can be enhanced . In addition, these studies suggest concurrent administration of these two agents may lead to a less than optimal cytotoxic result.", "source": "https://pubmed.ncbi.nlm.nih.gov/11107439/"}
{"doc_id": "2c73415d078bf6051c6a75b130a1dd05", "sentence": "On the other hand we observed that topoisomerase II ( Top2 ) poisons ( doxorubicin and etoposide ) did not affect 1 day post fertilization embryo viability , however in cells isolated from Top2 drug treated embryos the formation of DNA cleavage complexes was observed by comet assay .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 71, "end": 82, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "etoposide", "start": 87, "end": 96, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Genotoxic effects of topoisomerase poisoning and PARP inhibition on zebrafish embryos. Topoisomerase poisons are known to stabilize covalent enzyme-DNA intermediates forming covalent cleavage complexes, which are highly cytotoxic especially for dividing cells and thus, make topoisomerases targets for cancer therapy. Topoisomerases have been extensively studied in mammalian model systems, whereas in other vertebrate models including zebrafish, they still remain less characterized. Here we show similarities in the genotoxic effects of zebrafish and mammalian systems towards topoisomerase I (Top1) poisons and PARP inhibitor - olaparib. On the other hand we observed that topoisomerase II ( Top2 ) poisons ( doxorubicin and etoposide ) did not affect 1 day post fertilization embryo viability , however in cells isolated from Top2 drug treated embryos the formation of DNA cleavage complexes was observed by comet assay . We explain this by cellular drug uptake limitation in live zebrafish embryos versus unimpeded drug influx in cells isolated from Top2 poisons pre-treated embryos. We also demonstrate that EDTA facilitates the extraction of Top2 from zebrafish nuclei and recovers both, basal and Top2 poison induced DNA damage.", "source": "https://pubmed.ncbi.nlm.nih.gov/31877465/"}
{"doc_id": "5b6f3e829336b9bcf226bd4297fd9644", "sentence": "Favorable Response of Metastatic Hepatocellular Carcinoma to Treatment with Trans-arterial Radioembolization Followed by Sorafenib and Nivolumab .", "spans": [{"span_id": 0, "text": "Sorafenib", "start": 121, "end": 130, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "Nivolumab", "start": 135, "end": 144, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Favorable Response of Metastatic Hepatocellular Carcinoma to Treatment with Trans-arterial Radioembolization Followed by Sorafenib and Nivolumab . Trans-arterial radioembolization (TARE) with Y-90 microspheres is an endovascular, liver-directed therapy suitable for treatment of locally advanced hepatocellular carcinoma (HCC) often as a way to reduce tumor size and bridge patients to resection or liver transplant. Opdivo\u00ae, or nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, is an immunotherapeutic drug approved in September 2017 for the treatment of HCC in patients who have received prior sorafenib. We report on a patient with hepatocellular carcinoma with right and left portal vein involvement, bony metastasis, and possible lung metastasis. The patient showed a significant response following consecutive treatment with TARE, sorafenib,\u00a0and nivolumab. Our case suggests that TARE, sorafenib, and nivolumab may have a synergistic effect on the immune response to HCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/31019861/"}
{"doc_id": "a246eb2bf16c1c9f400688f585b2422f", "sentence": "In 23 adult patients , surgery , postoperative radiotherapy ( 60 Gy in 30 daily fractions within 6 weeks ) , and adjuvant modified chemotherapy ( procarbazine 60 mg/m(2 ) on Days 1 - 14 , lomustine 100 mg/m(2 ) on Day 1 , and vincristine 1.4 mg/m(2 ) [ maximum 2 mg ] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred .", "spans": [{"span_id": 0, "text": "procarbazine", "start": 146, "end": 158, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "lomustine", "start": 188, "end": 197, "token_start": 36, "token_end": 37}, {"span_id": 2, "text": "vincristine", "start": 226, "end": 237, "token_start": 45, "token_end": 46}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Combined treatment modality for anaplastic oligodendroglioma and oligoastrocytoma: a 10-year update of a phase II study. To provide updated outcome data (10 years) of a Phase II study of combined surgery, postoperative radiotherapy, and adjuvant chemotherapy in patients with anaplastic oligodendroglioma and oligoastrocytoma. ### Methods And Materials In 23 adult patients , surgery , postoperative radiotherapy ( 60 Gy in 30 daily fractions within 6 weeks ) , and adjuvant modified chemotherapy ( procarbazine 60 mg/m(2 ) on Days 1 - 14 , lomustine 100 mg/m(2 ) on Day 1 , and vincristine 1.4 mg/m(2 ) [ maximum 2 mg ] on Days 1 and 8) were administered every 6 weeks for up to six cycles or until progression occurred . ### results The median follow-up was 116 months for all patients. The median survival time was 118 months, and the 5-year and 10-year survival rate was 57% and 47%, respectively. The median time to tumor progression was 78 months, with a 5-year and 10-year progression-free survival rate of 52% and 39%, respectively. Gender, age, Karnofsky performance status, location, and histologic type did not influence survival. Patients with tumors <or=4 cm did better than those with tumors >4 cm (p = 0.0470), as did those with total tumor resection compared with those with subtotal tumor resection or biopsy only (p = 0.0024). Gender, Karnofsky performance status, location, and histologic type did not influence progression-free survival, but younger age (p = 0.0389), smaller tumor size (p = 0.0357), and more radical surgery (p = 0.0033) correlated positively with it. Acute high-grade (Grade 3 or worse) chemotherapy-related toxicity was mainly hematologic, with 3 patients (13%) experiencing acute Grade 4 toxicity. ### conclusion The results of this 10-year update confirmed that the trimodality approach is effective in patients with anaplastic oligodendroglioma and oligoastrocytoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/15145170/"}
{"doc_id": "df203d9ca4b844fad8c40f6b04f5901c", "sentence": "In addition to prolonged survival , these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit , compared with dacarbazine in patients with advanced melanoma .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 78, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "dacarbazine", "start": 185, "end": 196, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Effect of nivolumab on health-related quality of life in patients with treatment-na\u00efve advanced melanoma: results from the phase III CheckMate 066 study. nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-na\u00efve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. ### Patients And Methods HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus \u22651 post-baseline assessment. ### results Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. ### conclusions In addition to prolonged survival , these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit , compared with dacarbazine in patients with advanced melanoma .", "source": "https://pubmed.ncbi.nlm.nih.gov/27405322/"}
{"doc_id": "727e9b098f960d5805c6e24577853358", "sentence": "This phase 1 trial determined the safety , pharmacokinetics , and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments .", "spans": [{"span_id": 0, "text": "LY3022855", "start": 88, "end": 97, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "durvalumab", "start": 118, "end": 128, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "tremelimumab", "start": 132, "end": 144, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors. Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety , pharmacokinetics , and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments . Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100\u00a0mg once weekly (QW) combined with durvalumab 750\u00a0mg once every two weeks (Q2W) IV or LY3022855 50 or 100\u00a0mg QW IV with tremelimumab 75/225/750\u00a0mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750\u00a0mg Q2W. Results Seventy-two patients were enrolled (median age 61\u00a0years): Part A\u2009=\u200933, Part B\u2009=\u200939. In Part A, maximum tolerated dose was not reached, and LY3022855 100\u00a0mg QW and durvalumab 750\u00a0mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100\u00a0mg QW with durvalumab 750\u00a0mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011).", "source": "https://pubmed.ncbi.nlm.nih.gov/33852104/"}
{"doc_id": "c82aa2a58d6b83b380210f70b2de28e7", "sentence": "Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes .", "spans": [{"span_id": 0, "text": "vildagliptin", "start": 51, "end": 63, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "voglibose", "start": 68, "end": 77, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes . To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an \u03b1-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. ### methods In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. ### results Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUC\u03c4,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 \u00b1 1.4% (mean \u00b1 SD) for vildagliptin alone and 97.4 \u00b1 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). ### conclusions Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.", "source": "https://pubmed.ncbi.nlm.nih.gov/23782587/"}
{"doc_id": "0f70489fe451de475742c4dd8b30f15d", "sentence": "CD133 + cells ( CD133 is marker of CSC in some tumors ) isolated from NBL , osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin , carboplatin , etoposide and doxorubicin than the CD133- ones .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 135, "end": 144, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "carboplatin", "start": 147, "end": 158, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "etoposide", "start": 161, "end": 170, "token_start": 30, "token_end": 31}, {"span_id": 3, "text": "doxorubicin", "start": 175, "end": 186, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Neuroblastoma stem cells - mechanisms of chemoresistance and histone deacetylase inhibitors. Cancer stem cells (CSCs) form a small proportion of tumor cells that have stem cell properties: self-renewal capacity, the ability to develop into different lineages and proliferative potential. The interest in CSCs emerged from their expected role in initiation, progression and recurrence of many tumors. They are generally resistant to conventional chemotherapy and radiotherapy. There are two hypotheses about their origin: The first assumes that CSCs may arise from normal stem cells, and the second supposes that differentiated cells acquire the properties of CSCs. Both hypotheses are not mutually exclusive, as it is possible that CSCs have a diverse origin in different tumors. CD133 + cells ( CD133 is marker of CSC in some tumors ) isolated from NBL , osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin , carboplatin , etoposide and doxorubicin than the CD133- ones . Being resistant to chemotherapy, there were many attempts to target CSCs epigenetically including the use of histone deacetylase inhibitors. The diverse influence of valproic acid (histone deacetylase inhibitor) on normal and cancer stem cells was proved in different experiments. We have found an increase percentage of CD133+ NBL cells after their incubation with VPA in a dose that does not induce apoptosis. Further researches on CSCs and clinical application for their detection are necessary: (i) to define the CSC function in carcinogenesis, cancer development and their role in metastasis; (ii) to find a specific marker for CSCs in different tumors; (iii) to explain the role of different pathways that determine their behavior and (iv) to explain mechanisms of chemoresistance of CSCs.", "source": "https://pubmed.ncbi.nlm.nih.gov/22862175/"}
{"doc_id": "6989a1930bd6246fc018940dbfb91dae", "sentence": "The epidermal growth factor receptor ( EGFR ) inhibitors , gefitinib , erlotinib and afatinib ; the anaplastic lymphoma kinase ( ALK ) inhibitor , crizotinib ; and the anti-vascular endothelial growth factor receptor monoclonal antibody , bevacizumab , are already providing improved survival for patients with NSCLC .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 59, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "erlotinib", "start": 71, "end": 80, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "afatinib", "start": 85, "end": 93, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "crizotinib", "start": 147, "end": 157, "token_start": 25, "token_end": 26}, {"span_id": 4, "text": "bevacizumab", "start": 239, "end": 250, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Targeted therapies for treatment of non-small cell lung cancer--Recent advances and future perspectives. Non-small cell lung cancer (NSCLC) is one of the most deadly cancers worldwide, with poor prognosis once the disease has progressed past the point at which surgery is a viable option. Whilst chemotherapy has improved survival over recent decades, there is still great need for improvements in treatments for patients with advanced disease. Over the last decade, a variety of such drugs have received market approval for treating NSCLC, with a variety of others in the pipeline. Here, we review the development of targeted therapies for the treatment of advanced or metastatic NSCLC, including those already in clinical practice and those in early trials. The epidermal growth factor receptor ( EGFR ) inhibitors , gefitinib , erlotinib and afatinib ; the anaplastic lymphoma kinase ( ALK ) inhibitor , crizotinib ; and the anti-vascular endothelial growth factor receptor monoclonal antibody , bevacizumab , are already providing improved survival for patients with NSCLC . Moreover, the discovery of EGFR mutations and ALK rearrangements has enabled the identification of patients who are more likely to benefit from a specific drug. The recent approval of the immune checkpoint inhibitor nivolumab, along with the designation of alectinib and MPDL3280A as breakthrough therapies by the FDA, demonstrates how rapidly this area of research is expanding. Over the last decade there has been significant progress made in the treatment of advanced NSCLC, and the large and varied selection of drugs currently undergoing trials provide great promise for improving the prognosis of this highly prevalent and deadly form of cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/26537995/"}
{"doc_id": "d11330ba239670dfe84d3d8c19f4bbce", "sentence": "Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning .", "spans": [{"span_id": 0, "text": "paroxetine", "start": 40, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "fluvoxamine", "start": 55, "end": 66, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning . The acute and chronic effects of paroxetine and fluvoxamine on naloxone withdrawal-induced place aversion in morphine dependent rats were investigated. Acutely administered fluvoxamine (25 mg/kg s.c. given 30 min prior to naloxone withdrawal pairing) and chronic daily paroxetine (10 mg/kg s.c.) coadministration with a morphine induction protocol, both attenuated morphine withdrawal place aversion. Conversely, acutely administered paroxetine (up to 25 mg/kg s.c.) or chronic daily fluvoxamine (10 mg/kg s.c.) coadministration with morphine did not modify subsequent withdrawal place aversion. Previous radioligand binding studies indicate that fluvoxamine has opioid-displacing properties. It is suggested therefore that acute fluvoxamine may have decreased withdrawal aversion, probably through serotonin and also, in part, via an opioid-like mechanism whereas chronic paroxetine decreased withdrawal aversion by a serotonergic mechanism, but it is not clear whether opioid systems play any role in the action of paroxetine.", "source": "https://pubmed.ncbi.nlm.nih.gov/7796854/"}
{"doc_id": "795b47de736ed4d9bb01e83a9296d968", "sentence": "Phase 3 data support the use of sunitinib , bevacizumab plus interferon-\u03b1 and pazopanib for patients with low and intermediate risk of clear-cell renal cell carcinoma .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 32, "end": 41, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "bevacizumab", "start": 44, "end": 55, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "pazopanib", "start": 78, "end": 87, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "interferon-\u03b1", "start": 61, "end": 73, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Advances in renal cell carcinoma treatment. The treatment of advanced renal cell carcinoma has been completely changed by the development of new therapeutic modalities during the past 3 years. In this time period six targeted agents have been approved for the treatment of advanced or metastatic disease. Phase 3 data support the use of sunitinib , bevacizumab plus interferon-\u03b1 and pazopanib for patients with low and intermediate risk of clear-cell renal cell carcinoma . In the pivotal study of temsirolimus a significant longer overall survival compared with interferon-\u03b1 in high-risk disease including non-clear-cell histology was observed. Patients pretreated with cytokines will benefit from sorafenib and pazopanib while everolimus has been shown to increase significantly progression-free survival after previous anti-angiogenesis therapy. In addition to these phase 3 data-based recommendations, several other factors have to be considered for treatment selection, for example, side effect profile and patients' comorbidities. Currently, the sequential use of the available targeted drugs and adjuvant treatment are the subject of ongoing clinical trials. However, medical treatment of renal cell carcinoma remains palliative and surgery remains the only curative approach in patients with localized, locally advanced and limited metastatic disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/21789079/"}
{"doc_id": "bbc240b3838d705d6c0cd2afafb5a4ae", "sentence": "This study is designed to find out the efficacy and toxicity of the combination of oxaliplatin and gemcitabine in the treatment of advanced non-small cell lung cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 83, "end": 94, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "gemcitabine", "start": 99, "end": 110, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[Oxaliplatin combined with gemcitabine in the treatment of patients with advanced non-small cell lung cancer]. The use of oxaliplatin is very little in the treatment of lung can- cer . This study is designed to find out the efficacy and toxicity of the combination of oxaliplatin and gemcitabine in the treatment of advanced non-small cell lung cancer ( NSCLC ) . ### methods There were 32 cases of advanced NSCLC patients who were treated with oxaliplatin 65mg/m\u00b2 by intravenous infusion on the 1st and 8th days, and gemcitabine 800-1000mg/m\u00b2 by intravenous infusion on the 1st and 8th days every 21 days. After 2 cycles the efficacy was evaluated. ### results There were 31 cases that could be evaluated. No complete response was observed and the overall response rate was 22.6% (7 partial response). The disease control rate was 71.0%. The median time to diease progression was 7 months and the median survival time was 14.5 months. The 1-year survival rate was 59.0% and 2-year survival rate was 45.8%. The main toxicities were myelosuppression and nausea and vomiting. ### conclusions The combination of oxaliplatin and gemcitabine is effective and well tolerated in the treatment of advanced NSCLC. The quality of life is little influenced and the regimen also can prolong the survival time in some patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/21110933/"}
{"doc_id": "f6894ba00cbe854d18f5f0e2df20e5b3", "sentence": "All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h ( 50 mg/m2/d ) .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 41, "end": 57, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "paclitaxel", "start": 144, "end": 154, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Paclitaxel plus high-dose cyclophosphamide with G-CSF support in patients with relapsed and refractory aggressive non-Hodgkin's lymphoma. Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h ( 50 mg/m2/d ) . 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL.", "source": "https://pubmed.ncbi.nlm.nih.gov/9858216/"}
{"doc_id": "4a7c5133266617e25068a30212208935", "sentence": "Rituximab combined with a small dose of melphalan for a refractory follicular lymphoma patient .", "spans": [{"span_id": 0, "text": "Rituximab", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "melphalan", "start": 40, "end": 49, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Rituximab combined with a small dose of melphalan for a refractory follicular lymphoma patient . A 48-year-old male patient with follicular lymphoma, grade II, stage IV, was treated with CHOP, ESHAP and MACOP-B, resulting in partial remission. After 9 months, the disease progressed and several chemotherapy agents, including three courses of rituximab combined with etoposide, sobuzoxane or methotrexate, only resulted in a stable disease response. However, the fourth course of rituximab combined with a small dose of melphalan produced excellent results and the complete response continued for more than 15 months. It is possible that these two drugs may act synergistically.", "source": "https://pubmed.ncbi.nlm.nih.gov/16321871/"}
{"doc_id": "f1d130a68922106ba443ad5d6b0a1df5", "sentence": "In this study , the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 57, "end": 67, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "azithromycin", "start": 72, "end": 84, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Anti-bacterial activity of intermittent preventive treatment of malaria in pregnancy: comparative in vitro study of sulphadoxine-pyrimethamine, mefloquine, and azithromycin. Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine (SP) is recommended for the prevention of malaria in pregnancy in sub-Saharan Africa. Increasing drug resistance necessitates the urgent evaluation of alternative drugs. Currently, the most promising candidates in clinical development are mefloquine and azithromycin. Besides the anti-malarial activity, SP is also a potent antibiotic and incurs significant anti-microbial activity when given as IPTp - though systematic clinical evaluation of this action is still lacking. ### methods In this study , the intrinsic anti-bacterial activity of mefloquine and azithromycin was assessed in comparison to sulphadoxine-pyrimethamine against bacterial pathogens with clinical importance in pregnancy in a standard microdilution assay . ### results SP was highly active against Staphylococcus aureus and Streptococcus pneumoniae. All tested Gram-positive bacteria, except Enterococcus faecalis, were sensitive to azithromycin. Additionally, azithromycin was active against Neisseria gonorrhoeae. mefloquine showed good activity against pneumococci but lower in vitro action against all other tested pathogens. ### conclusion These data indicate important differences in the spectrum of anti-bacterial activity for the evaluated anti-malarial drugs. Given the large scale use of IPTp in Africa, the need for prospective clinical trials evaluating the impact of antibiotic activity of anti-malarials on maternal and foetal health and on the risk of promoting specific drug resistance of bacterial pathogens is discussed.", "source": "https://pubmed.ncbi.nlm.nih.gov/21029476/"}
{"doc_id": "c7be1464e80f8842f897858a9f0a3a67", "sentence": "Pirfenidone has a beneficial effect on morphological changes in anti-GBM GN comparable with candesartan", "spans": [{"span_id": 0, "text": "Pirfenidone", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "candesartan", "start": 92, "end": 103, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. The antifibrotic substance pirfenidone and the angiotensin II type I receptor antagonist candesartan cilexetil, given alone and in combination, were tested in rats with chronic anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). ### methods Male Wistar rats with anti-GBM GN were treated for 8 weeks with candesartan (4 mg/kg body weight/day), pirfenidone (500 mg/kg body weight/day) or a combination of both drugs. One GN group received no treatment and untreated non-GN-rats were used as controls. Blood pressure and urinary protein excretion were measured after 3 and 7 weeks. Kidney histology was complemented by ultrastructural investigation and by quantification of collagen Ialpha mRNA. ### results The percentage of glomeruli with adsorption droplets in podocytes correlated well with the amount of proteinuria (r = 0.873, P<0.01) and was significantly lowered in rats treated with candesartan (8.3 vs GN 24.6%), pirfenidone (9.8%) and combined treatment (2.6%, P<0.05 vs candesartan alone). A comparable lowering was seen for segmental sclerosis (GN 11%, candesartan 0.7%, P<0.05 vs GN, pirfenidone 1.8%, P = 0.09 vs GN, candesartan/pirfenidone 0.1%, P>0.5 vs candesartan alone). Cortical collagen Ialpha mRNA expression was significantly decreased in all treatment groups. Ultrastructural investigation showed an amelioration of basement membrane alterations and podocyte damage in the treatment groups. candesartan caused significant blood pressure reduction and the effect was significantly enhanced by combination therapy after 3 weeks. Rats treated with pirfenidone showed blood pressure values similar to control rats. ### conclusion Pirfenidone has a beneficial effect on morphological changes in anti-GBM GN comparable with candesartan although with a trend to slightly better results with candesartan treatment. Moreover, our results suggest an additive effect of combination treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/15561744/"}
{"doc_id": "04dacdd4af1e82ee9156f2d141a35ddd", "sentence": "Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients : a randomized safety and efficacy study .", "spans": [{"span_id": 0, "text": "Difluprednate", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "prednisolone", "start": 21, "end": 33, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients : a randomized safety and efficacy study . PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3\u2009mm\u2009Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).Conclusionsdifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery.", "source": "https://pubmed.ncbi.nlm.nih.gov/27367745/"}
{"doc_id": "6da861a53f0a3f9e21425877fed8b5c7", "sentence": "Accumulated doses of cyclophosphamide , procarbazine , doxorubicin , mitoxantrone , and etoposide were 18,300 mg , 3000 mg , 580 mg , 100 mg , and 4150 mg , respectively , which had been administered for the treatment of NHL .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 21, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "procarbazine", "start": 40, "end": 52, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "doxorubicin", "start": 55, "end": 66, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "mitoxantrone", "start": 69, "end": 81, "token_start": 9, "token_end": 10}, {"span_id": 4, "text": "etoposide", "start": 88, "end": 97, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Therapy-related leukemia with a novel 21q22 rearrangement. We present a case of a 59-year-old Japanese man with therapy-related acute myeloblastic leukemia (AML) after the chemotherapy for non-Hodgkin's lymphoma (NHL). Accumulated doses of cyclophosphamide , procarbazine , doxorubicin , mitoxantrone , and etoposide were 18,300 mg , 3000 mg , 580 mg , 100 mg , and 4150 mg , respectively , which had been administered for the treatment of NHL . Myeloblasts in the peripheral blood increased 43 months after the onset of NHL. He was diagnosed as having AML (M2; FAB classification). The karyotype of the bone marrow cells in the present case contained the following abnormalities: t(2;21)(q21;q22), t(8;21)(q22;q22), and add(13)(q34). In the present case, 645 base pairs of chimeric mRNA were detected by reverse transcription-polymerase chain reaction, indicating the presence of AML1/MTG8 rearrangement. Translocation (2;21)(q21;q22) has not been described previously to our knowledge. It is interesting that the breakpoint of 21q22 existed both in t(2;21) and t(8;21). The disrupted AML1 gene resulting from two 21q22 rearrangements may be involved in the pathogenesis of AML in the present case. The clinical importance of therapy-related AML having the 21q22 rearrangement remains to be examined.", "source": "https://pubmed.ncbi.nlm.nih.gov/8780746/"}
{"doc_id": "629ee4e216dcdc05f98202ea86148bde", "sentence": "In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance .", "spans": [{"span_id": 0, "text": "rituximab", "start": 130, "end": 139, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "cyclophosphamide", "start": 142, "end": 158, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "doxorubicin", "start": 161, "end": 172, "token_start": 24, "token_end": 25}, {"span_id": 3, "text": "vincristine", "start": 175, "end": 186, "token_start": 26, "token_end": 27}, {"span_id": 4, "text": "prednisone", "start": 193, "end": 203, "token_start": 29, "token_end": 30}, {"span_id": 5, "text": "rituximab", "start": 220, "end": 229, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": false}], "paragraph": "Mantle cell lymphoma: therapeutic options in transplant-ineligible patients. Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT , the standard-of-care has generally been R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , and prednisone ) , followed by rituximab , maintenance . In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Novel targeted agents now offer more promise than traditional chemotherapy or immunochemotherapy for both previously treated and untreated disease, and should also improve outcomes for older MCL patients. Here, we review standard therapies currently in use and novel agents that may soon be available for MCL patients and particularly for those unsuitable for ASCT.", "source": "https://pubmed.ncbi.nlm.nih.gov/31018735/"}
{"doc_id": "671a98fbcc6aa7636084ec1b0a365f03", "sentence": "Here , we analyze the effects of the broad-spectrum HDAC inhibitors ( HDACi ) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity ( Transcription factor EB-TFEB , forkhead boxO-FOXO ) and autophagic flux in neuroblastoma cells .", "spans": [{"span_id": 0, "text": "panobinostat", "start": 78, "end": 90, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "vorinostat", "start": 95, "end": 105, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma. Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here , we analyze the effects of the broad-spectrum HDAC inhibitors ( HDACi ) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity ( Transcription factor EB-TFEB , forkhead boxO-FOXO ) and autophagic flux in neuroblastoma cells . In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/33923163/"}
{"doc_id": "2f4b519ad0cb470a172c725c002d462c", "sentence": "The postischemic decrease in total intensity and frequency index in EEG recovered rapidly when nitrendipine was pretreated , whereas the recovery of EEG parameters was not obtained by the nicardipine pretreatment .", "spans": [{"span_id": 0, "text": "nitrendipine", "start": 95, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "nicardipine", "start": 188, "end": 199, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Nitrendipine facilitates recovery of cerebral blood flow, EEG and metabolites following cerebral ischemia in anesthetized rabbits. The effect of nitrendipine, an antihypertensive calcium antagonist, on the impairment of cerebral blood flow and EEG observed after 10-min complete cerebral ischemia in anesthetized rabbits was compared with those of nicardipine. The ischemia was produced by neck tourniquet in combination with hypotension (50-60 mmHg). Blood flow was measured by hydrogen-clearance method. Transient reactive hyperemia was observed immediately after the cessation of ischemic procedure, and was followed by a decrease in blood flow in the range of 58-73% of corresponding basal values in the total brain, cortex and thalamus. The postischemic decrease in blood flow was suppressed when nitrendipine (0.3-1 mg/kg) or nicardipine (3-10 mg/kg) was given intraduodenally before ischemia. The postischemic decrease in total intensity and frequency index in EEG recovered rapidly when nitrendipine was pretreated , whereas the recovery of EEG parameters was not obtained by the nicardipine pretreatment . These results suggest that the effect of nitrendipine and nicardipine on the postischemic cerebral blood flow may be due to the inhibition of calcium-induced contraction in cerebral vessels, whereas the discrepancy between the effects of these agents on EEG may not be due solely to the improvement in cerebral circulation. Furthermore, the improvement in postischemic cerebral energy metabolism was confirmed by nitrendipine pretreatment (0.3 mg/kg).", "source": "https://pubmed.ncbi.nlm.nih.gov/1798973/"}
{"doc_id": "72710c472e00e8c0ebba324e82696897", "sentence": "The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels .", "spans": [{"span_id": 0, "text": "BU", "start": 26, "end": 28, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "IPSA", "start": 33, "end": 37, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "verapamil", "start": 61, "end": 70, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "carbamazepine", "start": 75, "end": 88, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Effects of the serotonin-1A agonists buspirone and ipsapirone on field potentials in the hippocampus slice: comparison with carbamzepine and verapamil. The serotonin-1A agonists buspirone (BU) and ipsapirone (IPSA) have been demonstrated to exert antidepressant and anxiolytic effects. Since some antidepressant drugs and the antiepileptic substance carbamazepine have calcium antagonistic properties, the interaction of BU and IPSA with carbamazepine and the organic calcium channel blocker verapamil was analyzed in the low Mg2+ induced model epilepsy which has been shown to be suppressed specifically by organic calcium antagonists. BU and IPSA reduced the frequency of occurrence of low magnesium induced field potentials in CA1 and CA3 areas of the hippocampus slice preparation (guinea pigs) in a dose dependent manner. The subthreshold concentrations which yielded no effect were 5 mumol/l for BU and IPSA, 10 mumol/l for carbamazepine and 2 mumol/l for verapamil. Combinations of these subthreshold concentrations elicited a reduction in the repetition rate of field potentials. The results indicate that BU and IPSA behave additively with verapamil and carbamazepine , which may be due to a common action on the same subtype of calcium channels . It may be assumed that besides their action on 5-HT1A receptors BU and IPSA may also have calcium antagonistic properties.", "source": "https://pubmed.ncbi.nlm.nih.gov/7613104/"}
{"doc_id": "2a13a782996d6a4eb247ccb83958e7a6", "sentence": "The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "trastuzumab", "start": 33, "end": 44, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study. We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity .", "source": "https://pubmed.ncbi.nlm.nih.gov/12576933/"}
{"doc_id": "42aef7f95da0233dda2f19ac2be2ae91", "sentence": "Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume .", "spans": [{"span_id": 0, "text": "insulin-like growth factor-I", "start": 25, "end": 53, "token_start": 3, "token_end": 6}, {"span_id": 1, "text": "prednisolone", "start": 59, "end": 71, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "ursodeoxycholic acid", "start": 75, "end": 95, "token_start": 9, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Choleretic actions of insulin-like growth factor-I, prednisolone, and ursodeoxycholic acid in rats. A recent study by our group demonstrated that a 1-week infusion of insulin-like growth factor-I increases bile flow volume and bile acid secretion in rats, suggesting it is important in in vivo choleresis. In the present study, the effect in rats of a single administration of insulin-like growth factor-I on bile flow volume was investigated and compared with the choleretic drugs prednisolone and ursodeoxycholic acid. A significant and long-lasting increase in bile flow volume was observed in rats treated with insulin-like growth factor-I or prednisolone. Ursodeoxycholic acid significantly, but transiently increased. Combined treatment using insulin-like growth factor-I with prednisolone or ursodeoxycholic acid additively increased bile flow volume . Overall, this study demonstrated that the stimulatory effect of insulin-like growth factor-I on bile flow volume is almost equally potent to that of prednisolone and ursodeoxycholic acid, indicating the possible therapeutic potential of insulin-like growth factor-I in cholestatic liver diseases.", "source": "https://pubmed.ncbi.nlm.nih.gov/12870804/"}
{"doc_id": "7725b444e1f548fd763cf55a50c903ea", "sentence": "The AV3V-lesioned group of animals were characterized by an inability to excrete the excess sodium load and by a failure to increase secretion of both oxytocin and vasopressin into the general circulation in response to the salt-stimulus .", "spans": [{"span_id": 0, "text": "oxytocin", "start": 151, "end": 159, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "vasopressin", "start": 164, "end": 175, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "The effect of anteroventral third ventricular lesions on the changes in cholecystokinin receptor density in the rat supraoptic nucleus following saline drinking. Abstract Autoradiography and computerized image analysis were used to study the density of Cholecystokinin binding sites in the supraoptic nucleus of sham-lesioned and anteroventral third ventricle (AV3V)-lesioned animals in which the magnocellular system had been activated by salt-loading with 2% saline for 48 h. Rats were maintained in metabolic cages for 5 to 7 days prior to a sham- or AV3V-lesioning procedure, and the ratio of sodium intake:urinary sodium output used as a measure of sodium excretion. Following the sham or lesion procedure half of the rats had their drinking water replaced with 2% saline and the other half were maintained on normal drinking water. Neurohypophysial hormone levels were measured by specific radioimmunoassay in trunk blood samples taken 48 h after the saline or water treatment. The AV3V-lesioned group of animals were characterized by an inability to excrete the excess sodium load and by a failure to increase secretion of both oxytocin and vasopressin into the general circulation in response to the salt-stimulus . Despite this inappropriate response, [(125) l]cholecystokinin octapeptide binding in the oxytocin-rich dorsal portion of the supraoptic nucleus was similarly elevated in both sham- and AV3V-lesioned rats following 2 days of saline treatment. These results suggest that the magnocellular oxytocin system is capable of responding to an osmotic stimulus even when the release of hormone has been severely impaired.", "source": "https://pubmed.ncbi.nlm.nih.gov/19215354/"}
{"doc_id": "7add9dfc666dea880db503fa86a2fc53", "sentence": "Patients received BBFC ( n = 193 ) , brinzolamide 1 % ( n = 192 ) , or brimonidine 0.2 % ( n = 175 ) BID .", "spans": [{"span_id": 0, "text": "brinzolamide", "start": 37, "end": 49, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "brimonidine", "start": 71, "end": 82, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Twice-daily brinzolamide/brimonidine fixed combination versus brinzolamide or brimonidine in open-angle glaucoma or ocular hypertension. To compare the intraocular pressure (IOP)-lowering efficacy and safety of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) with that of brinzolamide 1% or brimonidine 0.2% monotherapy, all dosed 2 times per day (BID). ### design Six-month, phase 3, randomized, multicenter, double-masked clinical trial. ### participants A total of 560 patients with primary open-angle glaucoma or ocular hypertension who had insufficient IOP reduction with their current therapeutic regimen or who were receiving \u2265 2 IOP-lowering medications. ### intervention Patients received BBFC ( n = 193 ) , brinzolamide 1 % ( n = 192 ) , or brimonidine 0.2 % ( n = 175 ) BID . ### Main Outcome Measures The primary end point was mean change in diurnal IOP from baseline to month 3. Supportive end points included mean diurnal IOP change from baseline at week 2, week 6, and month 6; and mean IOP, mean IOP change from baseline, mean percentage IOP change from baseline, and percentage of patients with IOP <18 mmHg at week 2, week 6, month 3, and month 6 at each assessment time point (i.e., 9 am, 11 am, and 4 pm). Adverse events were recorded throughout the study. ### results Baseline diurnal IOP was similar among groups (mean \u00b1 standard deviation: BBFC, 25.9 \u00b1 0.19 mmHg; brinzolamide, 25.9 \u00b1 0.20 mmHg; brimonidine, 26.0 \u00b1 0.19 mmHg). At month 3, BBFC lowered mean diurnal IOP from baseline to a significantly greater extent than brinzolamide (least squares [LS] mean difference: -1.4 mmHg; P < 0.0001; t test) and brimonidine (LS mean difference: -1.5 mmHg; P < 0.0001). All supportive end points corroborated the results of the primary efficacy analysis. Mean percentage reductions in IOP from baseline were 26.7% to 36.0% with BBFC, 22.4% to 27.9% with brinzolamide, and 20.6% to 31.3% with brimonidine. The most common adverse drug reactions were ocular side effects, including hyperemia, blurred vision, allergic-type reactions, and discomfort. The incidence of hyperemia of the eye was slightly lower with brinzolamide than with BBFC and brimonidine, whereas blurred vision and ocular discomfort were slightly more common with BBFC than with brinzolamide or brimonidine. ### conclusions brinzolamide 1% and brimonidine 0.2% fixed combination administered BID had a significantly greater IOP-lowering effect than either brinzolamide or brimonidine alone and displayed a safety profile consistent with its individual components.", "source": "https://pubmed.ncbi.nlm.nih.gov/25064721/"}
{"doc_id": "721a25c7ca5bc4f07e322c7320c43e11", "sentence": "Artemisinin ( ART ) is a sesquiterpene lactone extracted from Chinese herb qinghao , and artemether ( ARM ) , artesunate ( ARS ) and dihydroartemisinin ( DHA ) were synthesized derivatives of artemisinin , which also have anti-malarial and anti-cancer effects such as artemisinin .", "spans": [{"span_id": 0, "text": "Artemisinin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "artemether", "start": 89, "end": 99, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "artesunate", "start": 110, "end": 120, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "dihydroartemisinin", "start": 133, "end": 151, "token_start": 25, "token_end": 26}, {"span_id": 4, "text": "artemisinin", "start": 192, "end": 203, "token_start": 33, "token_end": 34}, {"span_id": 5, "text": "artemisinin", "start": 268, "end": 279, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-\u03b2 signaling in breast cancer. Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin ( ART ) is a sesquiterpene lactone extracted from Chinese herb qinghao , and artemether ( ARM ) , artesunate ( ARS ) and dihydroartemisinin ( DHA ) were synthesized derivatives of artemisinin , which also have anti-malarial and anti-cancer effects such as artemisinin . ### methods In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. ### results We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-\u03b2 signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-\u03b2 signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. ### conclusions artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/30477536/"}
{"doc_id": "815c59e8446f996f0e187eba6304b302", "sentence": "Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 95, "end": 106, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "trabectedin", "start": 111, "end": 122, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells . This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions. ### methods Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter \u03c8 was used to quantify the effects of the individual drugs and combinations. ### results Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter \u03c8 was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects. ### conclusions The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations.", "source": "https://pubmed.ncbi.nlm.nih.gov/26604207/"}
{"doc_id": "6795bdc912a74f3c0792c3e8ec20011d", "sentence": "Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis .", "spans": [{"span_id": 0, "text": "dinaciclib", "start": 135, "end": 145, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "flavopiridol", "start": 157, "end": 169, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "regorafenib", "start": 194, "end": 205, "token_start": 31, "token_end": 32}, {"span_id": 3, "text": "sorafenib", "start": 210, "end": 219, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Inhibition of cyclin E1 sensitizes hepatocellular carcinoma cells to regorafenib by mcl-1 suppression. To clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition. ### methods Western blotting for caspase-3 and Hoechst 33225 staining was used to measure the expression level of apoptosis-related proteins under drug treatment. ### results Our results showed that enhanced expression of cyclin E1 after transfection compromised apoptosis in HCC cells induced by regorafenib or sorafenib. Conversely , down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase ( CDK ) inhibitors dinaciclib ( DIN ) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis . The expression of Mcl-1, which is modulated by STAT3, plays a key role in regulating the therapeutic effects of CDK inhibitors. Xenograft experiments conducted to test the efficacy of regorafenib combined with DIN showed dramatic tumor inhibitory effects due to induction of apoptosis. Our results suggested that the level of cyclin E1 expression in HCCs may be used as a pharmacodynamic biomarker to assess the antitumor effects of regorafenib or sorafenib. ### conclusions Combining regorafenib and CDK inhibitors may enhance the clinical efficiency of the treatment of HCCs.", "source": "https://pubmed.ncbi.nlm.nih.gov/31349793/"}
{"doc_id": "fc15eb12c35c136b2d8960b1ef35e819", "sentence": "Levofloxacin hemihydrate ( LEV ) and ambroxol HCl ( AMB ) are available for the treatment of upper and lower respiratory tract infections .", "spans": [{"span_id": 0, "text": "Levofloxacin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "ambroxol", "start": 37, "end": 45, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Micellar liquid chromatographic method for the simultaneous determination of Levofloxacin and Ambroxol in combined tablets: Application to biological fluids.  Levofloxacin hemihydrate ( LEV ) and ambroxol HCl ( AMB ) are available for the treatment of upper and lower respiratory tract infections . A survey of the literature reveals that two reversed phase HPLC methods were e reported for the simultaneous determination of LEV and AMB in pharmaceutical preparations. However the reported methods suffers from the low sensitivity, no application of the method in the combined tablets and no application to biological fluids. Also the toxic effects of the used solvents which are harmful to human beings. For this reason, our target was to develop a simple sensitive, less hazardous micellar HPLC method for the simultaneous determination of LEV and AMB in their combined dosage forms and plasma. ### results The method showed good linearity over the ranges of 1-44 \u03bcg/mL and 1-20 \u03bcg/mL with limits of detection 0.26 and 0.07 \u03bcg/mL and limits of quantification 0.80 and 0.20 \u03bcg/mL for LEV and AMB, respectively. The method was further extended to the determination of LEV in spiked human plasma with mean percentage recoveries of 100.10% \u00b1\u20091.14 as well as determination of LEV in real human plasma without prior extraction. Statistical evaluation of the data was performed according to ICH Guidelines. ### conclusion The suggested method was successfully applied for the simultaneous analysis of the studied drugs in their co-formulated tablets and human plasma. The mean percentage recoveries in combined tablets were 100.20\u2009\u00b1\u20091.64 and 100.72\u2009\u00b1\u20091.11 for LEV and AMB, respectively and 100.10\u2009\u00b1\u20091.14 for LEV in spiked human plasma. Statistical comparison of the results with those of the comparison method revealed good agreement and proved that there were no significant difference in the accuracy and precision between the two methods respectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/24079576/"}
{"doc_id": "2416572d3a4560a066355df81040dcd2", "sentence": "Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % .", "spans": [{"span_id": 0, "text": "Cytarabine", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "etoposide", "start": 15, "end": 24, "token_start": 2, "token_end": 3}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. ### Patients And Methods Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. ### results mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10 % . The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). ### conclusion mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/12885813/"}
{"doc_id": "cb064ac7581f1895a51363066960d6b8", "sentence": "After initiating warfarin plus lenvatinib , INR assays are necessary .", "spans": [{"span_id": 0, "text": "warfarin", "start": 17, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "lenvatinib", "start": 31, "end": 41, "token_start": 4, "token_end": 5}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Drug interactions between warfarin and lenvatinib in a patient with the CYP2C9*1/*3 and VKORC1-1639G/A genotype. lenvatinib inhibits CYP2C8. (S)-warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C9*1/*3. ### Case Summary The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12\u00a0mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33.3\u00a0ng/mL and 0.67\u00a0\u03bcg/mL, respectively. On day 10, his INR increased to 3.48. ### What Is New And Conclusion lenvatinib-dependent (S)-warfarin inhibition could involve CYP2C9 and CYP2C8. After initiating warfarin plus lenvatinib , INR assays are necessary .", "source": "https://pubmed.ncbi.nlm.nih.gov/31468576/"}
{"doc_id": "ace8dd79aefc245c868d9dfd7db7224a", "sentence": "Treatment with the DNA topoisomerase inhibitors etoposide , doxorubicin , and camptothecin , and with the alkylating agents cisplatin and melphalan , caused peroxide accumulation and apoptosis in U-937 human promonocytic cells .", "spans": [{"span_id": 0, "text": "etoposide", "start": 48, "end": 57, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "doxorubicin", "start": 60, "end": 71, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "cisplatin", "start": 124, "end": 133, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "melphalan", "start": 138, "end": 147, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation.  Treatment with the DNA topoisomerase inhibitors etoposide , doxorubicin , and camptothecin , and with the alkylating agents cisplatin and melphalan , caused peroxide accumulation and apoptosis in U-937 human promonocytic cells . Preincubation with the reduced glutathione (GSH) synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) always potentiated peroxide accumulation. However, although GSH depletion potentiated the toxicity of cisplatin and melphalan, occasionally switching the mode of death from apoptosis to necrosis, it did not affect the toxicity of the other antitumor drugs. Hypoxia or preincubation with antioxidant agents attenuated death induction, apoptotic and necrotic, by alkylating drugs. The generation of necrosis by cisplatin could not be mimicked by addition of exogenous H(2)O(2) instead of BSO and was not adequately explained by caspase inactivation nor by a selective fall in ATP content. Treatment with cisplatin and melphalan caused a late decrease in mitochondrial transmembrane potential (DeltaPsim), which was much greater during necrosis than during apoptosis. The administration of the antioxidant agents N-acetyl-l-cysteine and butylated hydroxyanisole after pulse treatment with cisplatin or melphalan did not affect apoptosis but attenuated necrosis. Under these conditions, both antioxidants attenuated the necrosis-associated DeltaPsim decrease. These results indicate that oxidation-mediated alterations in mitochondrial function regulate the selection between apoptosis and necrosis in alkylating drug-treated human promonocytic cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/11602574/"}
{"doc_id": "427f3561697bddffb6580da3c3b40bfd", "sentence": "We retrospectively analyzed 76 patients with LD SCLC who received combination cisplatin or carboplatin of etoposide or irinotecan .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 78, "end": 87, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "carboplatin", "start": 91, "end": 102, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "etoposide", "start": 106, "end": 115, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "irinotecan", "start": 119, "end": 129, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "[Chemotherapy-induced myelosuppression and treatment efficacy in limited-stage disease small cell lung cancer]. We examined the association between chemotherapy-induced myelosuppression and prognosis in limited-stage disease small cell lung cancer (LD SCLC). We retrospectively analyzed 76 patients with LD SCLC who received combination cisplatin or carboplatin of etoposide or irinotecan . Patients were categorized into two groups (grade 0 to 2 or grade 3 to 4) according to the worst neutropenia, anemia, or thrombocytopenia during first-line chemotherapy and were analyzed for overall survival (OS) and time to progression (TTP). From univariate analysis, OS was significantly better in patients who developed grade 0 to 2 anemia or thrombocytopenia than those who developed grade 3 to 4. In addition, performance status, neuron-specific enolase (NSE), and pro-gastrin-releasing protein were identified as prognostic factors. By multi-variate analysis, NSE was an independent prognostic factor for OS. There were no independent prognostic factors for TTP. Myelosuppression during chemotherapy is not a prognostic factor in LD SCLC. Our results show doses of platinum doublet chemotherapy were adequate in patients with LD SCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/20154478/"}
{"doc_id": "a7445d337ce87106b31b40f827cfe077", "sentence": "MCF-7 cells which expressed a constitutively-activated Akt-1 gene [ \u2206Akt-1(CA ) ] were more resistant to doxorubicin , etoposide and 4-OH-tamoxifen ( 4HT ) than cells lacking \u2206Akt-1(CA ) .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 105, "end": 116, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "etoposide", "start": 119, "end": 128, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "4-OH-tamoxifen", "start": 133, "end": 147, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo- and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascades. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF-7 breast cancer cells to chemotherapeutic- and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [ \u2206Akt-1(CA ) ] were more resistant to doxorubicin , etoposide and 4-OH-tamoxifen ( 4HT ) than cells lacking \u2206Akt-1(CA ) . Cells which expressed \u2206Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC50s for doxorubicin, etoposide and 4HT in the cells which expressed \u2206Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo- and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/21730367/"}
{"doc_id": "5f21f1c49c6de43c2bcdd11b02ee1b73", "sentence": "that , in response to mitomycin C and doxorubicin , human hepatocellular carcinoma cells generate conflicting signals , mediated by cyclin E and p21WAF1/CIP1 , which respectively accelerates and represses cell cycle transition .", "spans": [{"span_id": 0, "text": "mitomycin", "start": 22, "end": 31, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "doxorubicin", "start": 38, "end": 49, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Mitomycin C and doxorubicin elicit conflicting signals by causing accumulation             of cyclin E prior to p21WAF1/CIP1 elevation in human hepatocellular carcinoma             cells. Proteins involved in the G1 phase of the cell cycle are aberrantly expressed,             sometimes in mutated forms, in human cancers including human hepatocellular carcinoma.             Upon attack by a DNA-damaging anticancer drug, a cell arrests at the G1 phase;             this is a safety feature prohibiting entry of DNA-damaged cells into S-phase.             p21WAF1/CIP1 prevents damaged cells from progressing to the next cell cycle. Here,             we show that , in response to mitomycin C and doxorubicin , human hepatocellular carcinoma cells generate conflicting signals , mediated by cyclin E and p21WAF1/CIP1 , which respectively accelerates and represses cell cycle transition . Exposure to             these anticancer drugs led to rapid accumulation of cyclin E in both p53-proficient             HepG2 and p53-deficient Hep3B cells. Such anticancer drug-induced cyclin\u00a0E accumulation             influenced the G1-S-phase transition, but not DNA fragmentation-mediated death.             In p53-proficient HepG2 cells, accumulation of cyclin E was followed by an increase             in the level of p53-dependent p21WAF1/CIP1, thereby inhibiting further the G1-S-phase             transition. Sublethal drug concentrations also induced rapid accumulation of cyclin             E, but p21WAF1/CIP1 accumulation was delayed, further facilitating the G1-S-phase             transition. Eventually, most cells arrested in G2/M. Thus, mitomycin C- or doxorubicin-induced             conflicting signals, mediated by cyclin E and p21WAF1/CIP1, are in play in human             hepatocellular carcinoma cells. Damaged G1 cells either immediately enter S-phase,             or do not do so at all, depending on the extent of DNA damage.", "source": "https://pubmed.ncbi.nlm.nih.gov/21887464/"}
{"doc_id": "b04b7ef796a12ef625cad5773c25d555", "sentence": "In the last years , the main topoisomerase I inhibitors ( TP1-I ) ( i.e. topotecan and irinotecan ) have been used in combination chemotherapy in non-small cell lung cancer .", "spans": [{"span_id": 0, "text": "topotecan", "start": 73, "end": 82, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "irinotecan", "start": 87, "end": 97, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Topoisomerase I inhibitors combination chemotherapy in non-small cell lung cancer.  In the last years , the main topoisomerase I inhibitors ( TP1-I ) ( i.e. topotecan and irinotecan ) have been used in combination chemotherapy in non-small cell lung cancer . Several drugs (also alternative to cisplatin) have been used in combination with TP1-I, but to date the higher remission rate obtained with combinations is not translated into a more prolonged survival in comparison with TP1-I given alone. On the other hand, the toxicity of TP1-I combinations is greater than those of TP1-I used alone. The superior efficacy of combinations versus TP1-I used alone remains an open question. Furthermore, the best schedule for TP1-I has not been completely elucidated. Randomised studies are few (only two phase III trials) and only controlled studies will be able to clarify the best TP1-I combination regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/11742701/"}
{"doc_id": "f4558f7eed0e676239a76530501a8b34", "sentence": "Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) .", "spans": [{"span_id": 0, "text": "inosine", "start": 49, "end": 56, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "interferon alfa", "start": 208, "end": 223, "token_start": 31, "token_end": 33}, {"span_id": 2, "text": "ribavirin", "start": 251, "end": 260, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "Merimepodib", "start": 0, "end": 11, "token_start": 0, "token_end": 1}], "rels": [{"class": "POS", "spans": [1, 2, 3], "is_context_needed": false}], "paragraph": "Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders.  Merimepodib ( MMPD ) is an orally administered , inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C ( CHC ) when combined with pegylated interferon alfa 2a ( Peg-IFN-alfa-2a ) and ribavirin ( RBV ) . We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. ### conclusion The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.", "source": "https://pubmed.ncbi.nlm.nih.gov/19852040/"}
{"doc_id": "f64fae61c888b6de0c2525dec44a77f4", "sentence": "Of the antibacterial agents examined , only carbenicillin and , to a lesser extent , gentamicin were active against the bacteria usually encountered whilst still permitting normal protoplast metabolism and regeneration .", "spans": [{"span_id": 0, "text": "carbenicillin", "start": 44, "end": 57, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "gentamicin", "start": 85, "end": 95, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "The use of antibiotics in the culture of non-sterile plant protoplasts. The use of antibiotics to control infections in cultures of protoplasts of leaf mesophyll cells has been examined. The antifungal agents nystatin and amphotericin B were non-toxic to protoplasts at concentrations that controlled fungal growth (25 units and 2.5 \u03bcg/ml respectively). Of the antibacterial agents examined , only carbenicillin and , to a lesser extent , gentamicin were active against the bacteria usually encountered whilst still permitting normal protoplast metabolism and regeneration . The most satisfactory control of contaminating microorganisms was obtained with a combination of nystatin (25 units/ml) or amphotericin B (2.5 \u03bcg/ml) and carbenicillin (250 \u03bcg/ml).", "source": "https://pubmed.ncbi.nlm.nih.gov/24468958/"}
{"doc_id": "58ae13fafd1ae26654f91eecd42f14ca", "sentence": "Chemosensitization is one of the anti-tumor effects of E1A , increasing in vitro and in vivo sensitization of anti-cancer drugs , including cisplatin , gemcitabine , etoposide , doxorubicin , paclitaxel , and tumor necrosis factor-related apoptosis-inducing ligand and histone deacetylase inhibitors in different types of cancer cells .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 140, "end": 149, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "gemcitabine", "start": 152, "end": 163, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "etoposide", "start": 166, "end": 175, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "doxorubicin", "start": 178, "end": 189, "token_start": 28, "token_end": 29}, {"span_id": 4, "text": "paclitaxel", "start": 192, "end": 202, "token_start": 30, "token_end": 31}], "rels": [], "paragraph": "The anti-tumor activity of E1A and its implications in cancer therapy. The adenovirus type 5 E1A protein (E1A) plays a critical role in anti-cancer gene therapy and has been tested in clinical trials. The expression of E1A significantly reduces tumorigenesis, promotes cell death, and inhibits cancer cell mobility. Chemosensitization is one of the anti-tumor effects of E1A , increasing in vitro and in vivo sensitization of anti-cancer drugs , including cisplatin , gemcitabine , etoposide , doxorubicin , paclitaxel , and tumor necrosis factor-related apoptosis-inducing ligand and histone deacetylase inhibitors in different types of cancer cells . E1A also demonstrates anti-metastasis activity through various molecular mechanisms such as the repression of protease expression, suppression of HER2/neu and downregulation of microRNA (miR-520h). Moreover, E1A has been reported to reprogram transcription in tumor cells and stabilize tumor suppressors such as PP2A/C, p21 and p53. Because E1A plays a potentially significant role in anti-tumor therapy, there exists an urgent need to study the anti-cancer activities of E1A. This paper presents a review of our current understanding of the tumor-suppressive functions and molecular regulation of E1A, as well as the potential clinical applications of E1A.", "source": "https://pubmed.ncbi.nlm.nih.gov/24504082/"}
{"doc_id": "14798260886c7b0c8d279b38d05b4cc5", "sentence": "A strong correlation was only found between the level of MRP3 expression and the IC(50 ) values of etoposide , doxorubicin and pirarubicin ( r = 0.86 - 0.98 , P<0.05 ) .", "spans": [{"span_id": 0, "text": "etoposide", "start": 99, "end": 108, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "doxorubicin", "start": 111, "end": 122, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "pirarubicin", "start": 127, "end": 138, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined. ### methods Five human CCA cell lines (KKU-100, KKU-M055, KKU-M156, KKU-M214 and KKU-OCA17) were treated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC(50) values and the ratios of gene expression were analyzed by linear regression to predict their relationship. ### results Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC(50) values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC(50) values (<5 mumol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC(50 ) values of etoposide , doxorubicin and pirarubicin ( r = 0.86 - 0.98 , P<0.05 ) . ### conclusion Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug sensitivity. MRP3 was correlated with resistance of CCA cell lines to etoposide, doxorubicin and pirarubicin, whereas other chemotherapeutic drugs showed no association. The role of this multidrug resistance-associated protein, MRP3, in chemotherapeutic resistance in CCA patients needs to be further investigated.", "source": "https://pubmed.ncbi.nlm.nih.gov/15884115/"}
{"doc_id": "6dc0a36ba66aeb79ec26c4be2bc068c5", "sentence": "In addition to the typical cross-resistance to doxorubicin , daunorubicin , vincristine and etoposide , we observed a significant resistance of the C6,5 x 10(-7 ) Dox cell line to irradiation , which can not be explained by Pgp-expression .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 47, "end": 58, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "daunorubicin", "start": 61, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "vincristine", "start": 76, "end": 87, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "etoposide", "start": 92, "end": 101, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Multiple drug-resistant C6 glioma cells cross-resistant to irradiation. Although many advances in antineoplastic therapy have taken place, a clinical breakthrough in the therapy of malignant gliomas is still required. One of the reasons for this is the poor response to cytotoxic drugs and irradiation. We established a subline of the rat glioma cell line C6, named C6,5 x 10(-7) Dox, by exposure to increasing doses of doxorubicin for 5 months. C6,5 x 10(-7) Dox cells expressed high levels of P-glycoprotein (Pgp), known to function as an energy-dependent efflux pump for lipophilic drugs causing the multidrug resistance phenotype. Pgp, which normally has a molecular weight of 170 to 180 kd, appears in C6,5 x 10(-7) Dox cells as two bands with a molecular weight of 140 and 120 kd in western blots. In addition to the typical cross-resistance to doxorubicin , daunorubicin , vincristine and etoposide , we observed a significant resistance of the C6,5 x 10(-7 ) Dox cell line to irradiation , which can not be explained by Pgp-expression .", "source": "https://pubmed.ncbi.nlm.nih.gov/9494563/"}
{"doc_id": "cfc8d72201c15e205dfa65f372a8228a", "sentence": "[ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] .", "spans": [{"span_id": 0, "text": "endostatin", "start": 13, "end": 23, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxycycline", "start": 28, "end": 39, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Effects of endostatin and doxycycline on microcirculation patterns in melanoma and their relevant molecular mechanisms ] . To investigate the effects of endostatin and doxycycline on microcirculation patterns in melanoma and their molecular mechanisms. ### methods To establish mouse B16 melanoma model by subcutaneous injection of B16 melanoma cell suspension. The mice were divided into 3 experimental groups and 1 control group. To treat the mice in the 3 experimental groups with endostatin, doxycycline, endostatin and doxycycline, respectively, and the control group without any treatment. The tumor volume was measured and recorded to make comparison of their growth rate. To assess the expression of MMP-2, MMP-9 and TIMP-2 by immunohistochemical staining. The three microcirculation patterns of endothelium-dependent vessels, mosaic vessels and vasculogenic mimicry were counted. The activity of MMP-2, MMP-9 between different groups was examined by gelatin zymography. ### results Tumor growth in the three experimental groups was statistically significantly slower than that in the control group. The expression of MMP-2, MMP-9 and TIMP-2 in each treated group was significantly different with that in the control group. The amount of three microcirculation patterns in three experimental groups was less than that of the control group, and the amount of MV and VM in each experimental group was significantly less than that in the control group. By gelatin zymography, the enzyme activity of MMP-9, actived-MMP-2 and MMP-2/proMMP-2 in ES, DOX and ES + DOX group was lower than that in the control group, but the enzyme activity of pro-MMP-2 among the four groups was not significantly different. ### conclusion The combined use of doxycycline and endostatin in melanoma can inhibit the expression of MMPs, influencing the formation of different microcirculation patterns in melanoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/18069628/"}
{"doc_id": "8048a8eef6fed20013431209617b227c", "sentence": "It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy , potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 183, "end": 192, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "everolimus", "start": 211, "end": 221, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "temsirolimus", "start": 225, "end": 237, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "FLT3 inhibitors for the treatment of acute myeloid leukemia. The fms-like receptor tyrosine kinase-3 (FLT3), which is important for the normal development of hematopoietic stem cells and cells of the immune system, is frequently mutated in patients with acute myeloid leukemia (AML). FLT3 is, therefore, a potential therapeutic target in AML. Recently, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations. sorafenib and sunitinib were the first FLT3 inhibitors to be studied in the clinic and have the most clinically relevant data. Limited data are available for midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), AC220, and KW-2449. It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy , potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus . This review discusses the theoretical rationale for the use of these agents and summarizes the relevant clinical data.", "source": "https://pubmed.ncbi.nlm.nih.gov/20733555/"}
{"doc_id": "7c1045ff7227c040eb9dcd75a533501d", "sentence": "Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively .", "spans": [{"span_id": 0, "text": "etoposide", "start": 118, "end": 127, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "doxorubicin", "start": 130, "end": 141, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "cisplatin", "start": 144, "end": 153, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "mitotane", "start": 158, "end": 166, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation. In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3\u03b2HSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M ( etoposide , doxorubicin , cisplatin and mitotane ) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively . In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.", "source": "https://pubmed.ncbi.nlm.nih.gov/27764813/"}
{"doc_id": "47a943623f242fd6dc450c698de16055", "sentence": "Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine .", "spans": [{"span_id": 0, "text": "Oxaliplatin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gemcitabine", "start": 98, "end": 109, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Gemcitabine and oxaliplatin: a safe and active regimen in poor prognosis advanced non-small cell lung cancer patients. Most patients with non-small cell lung cancer (NSCLC) cannot tolerate a cisplatin-based chemotherapy because of old age, general conditions, and/or multiorgan metastatic sites. Oxaliplatin is active in NSCLC , offers advantage in terms of toxicity , and shows synergism with gemcitabine . The aims of this phase II study were to evaluate the response rate and toxicity of the gemcitabine-oxaliplatin combination in patients with advanced NSCLC and poor prognosis. ### methods Patients were given a gemcitabine infusion (1000 mg/m(2) over 30 min on days 1 and 8) followed by oxaliplatin (65 mg/m(2) over 120 min on days 1 and 8) every 21 days for six cycles. ### results Thirty-two patients with poor-prognosis advanced NSCLC received 136 cycles. There were 25 males and seven females, and the median age was 65 years (range 29-76). Fifty-six percent of patients had adenocarcinoma, and 31% had squamous cell carcinoma. Sixty-six percent of patients had stage IV disease, and 34% had stage IIIB disease. Eastern cooperative oncology group (ECOG) performance status was 2-3 in 50%, 1 in 44%, and 0 in 6% of patients. Eight patients (25%) had been previously treated with cisplatin or carboplatin. All patients were symptomatic. Of the 32 patients who received study drug, five (16%) achieved partial response, six (19%) had minor response, three (9%) had stable disease, and 15 (47%) progressed. The median overall survival was 27 weeks. Thirty-one patients were evaluable for toxicity: seven patients (23%) had grade 3-4 thrombocytopenia with no bleeding; four patients (13%) had grade 3-4 neutropenia with no febrile neutropenia, and three patients (10%) had grade 3 anemia. Two patients (6%) had grade 3, and six patients (19%) had grade 1-2 neurotoxicity. ### conclusion The combination of gemcitabine and oxaliplatin seems to be well tolerated and active in patients with poor prognosis advanced NSCLC and deserves further evaluation in phase II clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/12826318/"}
{"doc_id": "9f520f0a2b7375cbd106d2b03d54c8fd", "sentence": "A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel , abiraterone acetate , enzalutamide , cabozantinib , carboplatin or cabazitaxel .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 105, "end": 114, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "abiraterone", "start": 117, "end": 128, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "enzalutamide", "start": 139, "end": 151, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "cabozantinib", "start": 154, "end": 166, "token_start": 24, "token_end": 25}, {"span_id": 4, "text": "carboplatin", "start": 169, "end": 180, "token_start": 26, "token_end": 27}, {"span_id": 5, "text": "cabazitaxel", "start": 184, "end": 195, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Role of free testosterone levels in patients with metastatic castration-resistant prostate cancer receiving second-line therapy. A range of new treatment options has recently become available for patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone is continued when performing chemotherapy or androgen deprivation with new second-generation therapeutic agents such as enzalutamide or abiraterone acetate. Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only. The aim of the present study was to evaluate the role of FT as a prognostic biomarker for cancer-specific survival (CSS) and its feasibility as an ADT monitoring biomarker in patients with mCRPC for the first time. The requirement for continued ADT in mCRPC patients is discussed within the basis of the current literature. A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel , abiraterone acetate , enzalutamide , cabozantinib , carboplatin or cabazitaxel . Data were obtained from the Departments of Urology and Urological Oncology, Hannover Medical School (Hannover, Germany) between March 2009 and April 2014. A cutoff point of 0.5 pg/ml was used to discriminate between patients according to FT levels. Statistical evaluation of CSS was performed by applying Kaplan Meier survival estimates, multivariate Cox regression analyses and log-rank tests. The median age of all 34 patients was 72 years (range, 51-86 years). The mean follow-up interval was 16.1 months (range, 0.7-55.6 months). Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml. A notable difference with regard to CSS was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively, P=0.0063). Upon multivariate Cox regression analysis, the mean FT concentration during treatment remained a significant prognostic factor for CSS (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43; P=0.0182). In conclusion, in patients with mCRPC, the serum FT level is a strong predictor of CSS in patients under therapy with second-line anti-hormonal therapeutic medication and chemotherapy. It may be concluded that FT levels should be included into the routine control of androgen suppression while under treatment with ADT and second-generation hormonal therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/28123517/"}
{"doc_id": "640a3c9a82e16798bccd7249bd3a43ca", "sentence": "Pharmacological interventions with a proton pump inhibitor ( PPI ) , H2 receptor antagonist ( H2RA ) , antacid , bismuth and sucralfate may have effects on both the prevention and treatment of upper gastrointestinal bleeding in infants .", "spans": [{"span_id": 0, "text": "bismuth", "start": 113, "end": 120, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "sucralfate", "start": 125, "end": 135, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Pharmacological interventions for prevention and treatment of upper gastrointestinal bleeding in newborn infants. Upper gastrointestinal bleeding is typically a mild, self-limiting condition that can affect both preterm and term neonates, although it can be severe particularly when associated with co-morbidities. Pharmacological interventions with a proton pump inhibitor ( PPI ) , H2 receptor antagonist ( H2RA ) , antacid , bismuth and sucralfate may have effects on both the prevention and treatment of upper gastrointestinal bleeding in infants . ### objectives To assess how different pharmacological interventions (PPIs, H2RAs, antacids, sucralfate or bismuth salts) administered to preterm and term neonates for the prevention or treatment of upper gastrointestinal bleeding to reduce morbidity and mortality compare with placebo or no treatment, supportive care, or each other. ### Search Methods We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 6), MEDLINE via PubMed (1966 to 12 July 2018), Embase (1980 to 12 July 2018), and CINAHL (1982 to 12 July 2018). We also searched clinical trial databases, conference proceedings, the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials, and online for Chinese literature articles. ### Selection Criteria We selected randomised, quasi-randomised and cluster-randomised trials involving preterm and term neonates. Trials were included if they used a proton pump inhibitor, H2 receptor antagonist, antacid, sucralfate or bismuth either for the prevention or treatment of upper gastrointestinal bleeding. ### Data Collection And Analysis Two review authors independently assessed the eligibility of studies for inclusion, extracted data and assessed methodological quality. We conducted meta-analysis using a fixed-effect model. We used the GRADE approach to assess quality of evidence. ### Main Results Eleven studies with 818 infants met the criteria for inclusion in this review.Four trials with 329 infants assessed the use of an H2 receptor antagonist for prevention of upper gastrointestinal bleeding in high-risk newborn infants. Meta-analysis of these four trials identified a reduction in any upper gastrointestinal bleeding when using an H2 receptor antagonist (typical risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.58; typical risk difference (RD) -0.20, 95% CI -0.28 to -0.11; number needed to treat for an additional beneficial outcome (NNTB) 5, 95% CI 4 to 9). The quality of evidence was moderate. A single trial with 53 infants assessing prevention of upper gastrointestinal bleeding reported no difference in mortality in infants assigned H2 receptor antagonist versus no treatment; however the quality of evidence was very low.Seven trials with 489 infants assessed an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) for treatment of gastrointestinal bleeding in newborn infants. Meta-analysis of two trials (131 infants) showed no difference in mortality from use of a H2 receptor antagonist compared to no treatment. The quality of evidence was low. Meta-analysis of two trials (104 infants) showed a reduction in duration of upper gastrointestinal bleeding from use of an inhibitor of gastric acid compared to no treatment (mean difference -1.06 days, 95% CI -1.28 to -0.84). The quality of evidence was very low. Meta-analysis of six trials (451 infants) showed a reduction in continued upper gastrointestinal bleeding from use of any inhibitor of gastric acid compared to no treatment (typical RR 0.36, 95% CI 0.26 to 0.49; typical RD -0.26, 95% CI -0.33, -0.19; NNTB 4, 95% CI 3 to 5). The quality of evidence was low. There were no significant subgroup differences in duration of upper gastrointestinal bleeding or of continued upper gastrointestinal bleeding according to type of inhibitor of gastric acid. A single trial (38 infants) reported no difference in anaemia requiring blood transfusion from use of a H2 receptor antagonist compared to no treatment.Although no serious adverse events were reported from the use of a H2 receptor antagonist or proton pump inhibitor, some neonatal morbidities - including necrotising enterocolitis, ventilator-associated pneumonia, duration of ventilation and respiratory support, and duration of hospital stay - were not reported. Long-term outcome was not reported. ### Authors Conclusions There is moderate-quality evidence that use of an H2 receptor antagonist reduces the risk of gastrointestinal bleeding in newborn infants at high risk of gastrointestinal bleeding. There is low-quality evidence that use of an inhibitor of gastric acid (H2 receptor antagonist or proton pump inhibitor) reduces the duration of upper gastrointestinal bleeding and the incidence of continued gastric bleeding in newborn infants with gastrointestinal bleeding. However, there is no evidence that use of an inhibitor of gastric acid in newborn infants affects mortality or the need for blood transfusion. As no study reported the incidence of necrotising enterocolitis, ventilator- or hospital-associated pneumonia, sepsis, or long-term outcome, the safety of inhibitors of gastric acid secretion is unclear.", "source": "https://pubmed.ncbi.nlm.nih.gov/31265739/"}
{"doc_id": "77d8064af9c3e21a554ef1c5daf0a918", "sentence": "Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer .", "spans": [{"span_id": 0, "text": "Doxorubicin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "lapatinib", "start": 16, "end": 25, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Doxorubicin and lapatinib combination nanomedicine for treating resistant breast cancer . Our objective was to design a polymeric micelle-based doxorubicin and lapatinib combination therapy for treating multidrug resistant (MDR) breast cancers. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) (PEG-PBC) polymers were synthesized for preparing doxorubicin and lapatinib loaded micelles using a film dispersion method. Micelles were characterized by determining critical micelle concentration (CMC), particle size distribution, and drug loading. The anticancer effects were determined in vitro with MTT assays as well as with lactate dehydrogenase (LDH) release studies. In addition, the cellular uptake of drug-loaded micelles was determined with fluorescence microscopy and flow cytometry. Finally, in vivo anticancer activity and tolerance of developed formulations were evaluated in resistant breast tumor bearing mice. PEG5K-PBC7K polymer synthesized in this study had a low CMC value (1.5 mg/L) indicating an excellent dynamic stability. PEG-PBC micelles could efficiently load both doxorubicin and lapatinib drugs with a loading density of 21% and 8.4%, respectively. The mean particle size of these micelles was 100 nm and was not affected by drug loading. The use of lapatinib as an adjuvant sensitized drug resistant MCF-7/ADR cells to doxorubicin treatment. Cellular uptake studies showed enhanced doxorubicin accumulation in MCF-7/ADR cells in the presence of lapatinib. The doxorubicin and lapatinib combination therapy showed a significant decrease in tumor growth compared to doxorubicin monotherapy. In conclusion, we have developed PEG-PBC micelle formulations for the delivery of doxorubicin and lapatinib. The combination therapy of doxorubicin plus lapatinib has a great potential for treating MDR breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/24405470/"}
{"doc_id": "e4e17068283d443afce7f6f729118c40", "sentence": "The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel .", "spans": [{"span_id": 0, "text": "ritonavir", "start": 27, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "docetaxel", "start": 122, "end": 131, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Ritonavir inhibits intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model. docetaxel (Taxotere(\u00ae)) is currently used intravenously as an anticancer agent and is primarily metabolized by Cytochrome P450 3A (CYP3A). The HIV protease inhibitor ritonavir , a strong CYP3A4 inhibitor , decreased first-pass metabolism of orally administered docetaxel . Anticancer effects of ritonavir itself have also been described. We here aimed to test whether ritonavir co-administration could decrease intratumoral metabolism of intravenously administered docetaxel and thus increase the antitumor activity of docetaxel in an orthotopic, immunocompetent mouse model for breast cancer. Spontaneously arising K14cre;Brca1(F/F) ;p53(F/F) mouse mammary tumors were orthotopically implanted in syngeneic mice lacking Cyp3a (Cyp3a(-/-)) to limit ritonavir effects on systemic docetaxel clearance. Over 3 weeks, docetaxel (20 mg/kg) was administered intravenously once weekly, with or without ritonavir (12.5 mg/kg) administered orally for 5 days per week. Untreated mice were used as control for tumor growth. ritonavir treatment alone did not significantly affect the median time of survival (14 vs. 10 days). Median time of survival in docetaxel-treated mice was 54 days. ritonavir co-treatment significantly increased this to 66 days, and substantially reduced relative average tumor size, without altering tumor histology. Concentrations of the major docetaxel metabolite M2 in tumor tissue were reduced by ritonavir co-administration, whereas tumor RNA expression of Cyp3a was unaltered. In this breast cancer model, we observed no direct antitumor effect of ritonavir alone, but we found enhanced efficacy of docetaxel treatment when combined with ritonavir. Our data, therefore, suggest that decreased docetaxel metabolism inside the tumor as a result of Cyp3a inhibition contributes to increased antitumor activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/26297509/"}
{"doc_id": "33c10cbad0525179d74c6d25b5e93bfa", "sentence": "Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC .", "spans": [{"span_id": 0, "text": "Ramucirumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "osimertinib", "start": 17, "end": 28, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Phase 1 Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer. We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR TKI osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant NSCLC. ### Experimental Design This open-label, single-arm phase 1 study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-na\u00efve. A dose-limiting toxicity (DLT) period with as-needed dose de-escalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. ### results Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common Grade 3 or higher treatment-related adverse events (TRAEs) were hypertension (8%) and platelet count decreased (16%); Grade 5 TRAE (subdural hemorrhage) occurred in one patient. Patients with (N=10) and without CNS metastasis (N=15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months (90% CI: 9.6-21.2). Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations post progression included C797S, MET amplification, and EGFR amplification. ### conclusions Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC .", "source": "https://pubmed.ncbi.nlm.nih.gov/33046516/"}
{"doc_id": "dedf04d0b8a7521028b1091c88e41780", "sentence": "The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone .", "spans": [{"span_id": 0, "text": "etoposide", "start": 164, "end": 173, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "cytarabine", "start": 176, "end": 186, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "mitoxantrone", "start": 193, "end": 205, "token_start": 27, "token_end": 28}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Refractory acute myeloid leukemia developed malignancy-associated hemophagocytic lymphohistiocytosis during treatment of invasive fungal infection]. We here report a 2-year-old female with relapsed acute myeloid leukemia (AML) with MLL gene rearrangement in the bone marrow and central nervous system. The 3'-RACE (Rapid Amplification of cDNA Ends) method identified the MLLT10 gene as a fusion partner of the MLL gene. The patient was complicated with hemophagocytic lymphohistiocytosis ( HLH ) and invasive aspergillosis ( IPA ) after re-induction treatment with FLAG-IDA following etoposide , cytarabine , and mitoxantrone . Although treatment with systemic anti-fungal drugs was effective for IPA, HLH did not improve. We considered tumor-associated HLH to be initiated from leukemic stem cells (LSCs) in the bone marrow niche because reverse transcription-polymerase chain reaction (RT-PCR) analysis of a bone marrow biopsy sample was positive for MLL-MLLT10. gemtuzumab ozogamicin and sorafenib had no major effect on acquiring complete remission, and the patient died of progressive AML with an exacerbation of HLH and aspergillosis. LSCs are known to be resistant to conventional chemotherapy due to their quiescence in the cell cycle. Novel therapeutic concepts are important to eradicate LSCs in order to cure AML patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/23666221/"}
{"doc_id": "4b3bb26a64999b4abc090d469be4cad8", "sentence": "On the other hand , cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 20, "end": 32, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "tacrolimus", "start": 37, "end": 47, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "tacrolimus", "start": 108, "end": 118, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "cyclosporine", "start": 188, "end": 200, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Cyclosporine: advantages versus disadvantages vis-\u00e0-vis tacrolimus. Despite a different molecular structure and biochemical properties, cyclosporine and tacrolimus--by inhibiting calcineurin activity--have been shown in the previous two decades of solid organ transplantation to be well tolerated and effective immunosuppressants. Initial randomized clinical trials showed a lower incidence of acute rejection in tacrolimus than in cyclosporine-treated patients, in combination with steroids and azathioprine. But in conjunction with mycophenolate mofetil, the difference in the incidence of acute rejection episodes is less clear. In general, short- and medium-term outcome variables (1-year serum creatinine, graft and patient survival) with cyclosporine and tacrolimus are excellent, and (almost) identical, with both substances having the same intrinsic nephrotoxic potential. On the other hand , cyclosporine and tacrolimus have a different impact on cardiovascular risk factors with tacrolimus having a better profile on arterial tension and lipid metabolism and cyclosporine on glucose metabolism . However, at present no data are available to discern that these differences in risk profile alter patient or graft survival or long-term cardiovascular morbidity/mortality. Therefore, prospective long-term trials are needed to study the quantitative impact of different immunosuppressive agents and concomitant cardiovascular risk factors on long-term patient and graft survival, before evidence-based (patient, graft, or cardiovascular) risk reduction can be firmly claimed by tailoring calcineurin inhibitors.", "source": "https://pubmed.ncbi.nlm.nih.gov/15041305/"}
{"doc_id": "4a2741e8f251bf34f99d7969b7f536cb", "sentence": "Isoniazid , streptomycin , rifampin , and ethambutol were each tested at 3 concentrations by the radiometric method and the reference ( agar dilution ) method .", "spans": [{"span_id": 0, "text": "Isoniazid", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "streptomycin", "start": 12, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "rifampin", "start": 27, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "ethambutol", "start": 42, "end": 52, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Rapid radiometric susceptibility testing of Mycobacterium tuberculosis. A 48-hour radiometric test for determining the drug susceptibility of Mycobacterium tuberculosis has been developed. The test is based on the measurement of 14CO2 produced by the oxidation of formate labeled with carbon-14. The test system uses 5 X 10(7) organisms in 1 ml of Middlebrook 7H9 medium plus albumin-dextrose-catalase enrichment and 1 muCi of [14C]formate. The 14CO2 produced is measured in an ionization chamber at 24-, 48-, and 72-hour intervals, with and without the addition of antituberculous drugs. Isoniazid , streptomycin , rifampin , and ethambutol were each tested at 3 concentrations by the radiometric method and the reference ( agar dilution ) method . Six standard strains and 21 patient isolates were compared by both methods. Production of 14CO2 was quantitatively decreased in the presence of drugs that inhibit the organism. The radiometric method requires 2 days; the agar dilution, 14 to 21 days.", "source": "https://pubmed.ncbi.nlm.nih.gov/417650/"}
{"doc_id": "14560985da268f584dee6d70f4a91607", "sentence": "Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas .", "spans": [{"span_id": 0, "text": "methamphetamine", "start": 30, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "haloperidol", "start": 82, "end": 93, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "haloperidol", "start": 175, "end": 186, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Enhancement of haloperidol-induced increase in rat striatal or mesolimbic 3,4-dihydroxyphenylacetic acid and homovanillic acid by pretreatment with chronic methamphetamine. After a drug-free period of 1 week following 2 weeks of haloperidol treatment, the increased response of striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) to a challenge dose of haloperidol was significantly reduced. Tolerance to this effect was not, however, seen in the mesolimbic system. Pretreatment of the rats with methamphetamine ( MAP ) for 8 days prior to chronic haloperidol significantly enhanced the DOPAC and HVA increase produced by the challenge with haloperidol in both brain areas . The reduced response of striatal DOPAC or HVA after chronic haloperidol was prevented by pretreatment with MAP. The data suggest that the long-term dopamine receptor stimulation induced by MAP may antagonize the tolerance produced by chronic haloperidol treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/6794073/"}
{"doc_id": "62abad5bc762dd8e9abb9a04fd693feb", "sentence": "The patients participated in three clinical trials that combined tumor vaccines with potential Treg-depleting agents : low-dose cyclophosphamide , anti-CD25 monoclonal antibody daclizumab , and the IL-2/diphtheria toxin fusion protein denileukin diftitox .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 128, "end": 144, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "daclizumab", "start": 177, "end": 187, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "denileukin diftitox", "start": 235, "end": 254, "token_start": 30, "token_end": 32}], "rels": [], "paragraph": "Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Regulatory T cells (Tregs) are thought to inhibit antitumor immune responses, and their depletion could therefore have a synergistic effect with therapeutic cancer vaccines. We investigated the impact of three medications on blood Treg frequency in vaccinated cancer patients. ### Experimental Design To date, the most specific marker for human Tregs is demethylation in the DNA that encodes the transcription factor FOXP3. Thus, we used a FOXP3 methylation-specific quantitative PCR assay (MS-qPCR) to measure Treg frequencies in the peripheral blood mononuclear cells (PBMCs) of melanoma patients. The patients participated in three clinical trials that combined tumor vaccines with potential Treg-depleting agents : low-dose cyclophosphamide , anti-CD25 monoclonal antibody daclizumab , and the IL-2/diphtheria toxin fusion protein denileukin diftitox . ### results In the nine control patients, blood Treg frequencies varied over time; there was a 46% reduction in one patient. In treated patients, a more than 2-fold decrease in Tregs was observed in one out of 11 patients receiving cyclophosphamide and in four out of 13 receiving daclizumab, but there was no such Treg decrease in any of the six patients who received denileukin diftitox. As a positive control, a more than 2-fold increase in blood Tregs was detected in four out of nine patients who were treated with interleukin-2. ### conclusions We used a MS-qPCR method that detects Tregs but not other activated T lymphocytes; however, none of the Treg-depleting strategies that we tested led, in the majority of patients, to a conservative 50% reduction in blood Tregs.", "source": "https://pubmed.ncbi.nlm.nih.gov/21177412/"}
{"doc_id": "6d7c9fb77c622f5e2f023fe97b07a848", "sentence": "The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin .", "spans": [{"span_id": 0, "text": "vancomycin", "start": 136, "end": 146, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "ampicillin", "start": 151, "end": 161, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Related Enteric Viruses Have Different Requirements for Host Microbiota in Mice. Accumulating evidence suggests that intestinal bacteria promote enteric virus infection in mice. For example, previous work demonstrated that antibiotic treatment of mice prior to oral infection with poliovirus reduced viral replication and pathogenesis. Here, we examined the effect of antibiotic treatment on infection with coxsackievirus B3 (CVB3), a picornavirus closely related to poliovirus. We treated mice with a mixture of five antibiotics to deplete host microbiota and examined CVB3 replication and pathogenesis following oral inoculation. We found that, as seen with poliovirus, CVB3 shedding and pathogenesis were reduced in antibiotic-treated mice. While treatment with just two antibiotics, vancomycin and ampicillin, was sufficient to reduce CVB3 replication and pathogenesis, this treatment had no effect on poliovirus. The quantity and composition of bacterial communities were altered by treatment with the five-antibiotic cocktail and by treatment with vancomycin and ampicillin . To determine whether more-subtle changes in bacterial populations impact viral replication, we examined viral infection in mice treated with milder antibiotic regimens. Mice treated with one-tenth the standard concentration of the normal antibiotic cocktail supported replication of poliovirus but not CVB3. Importantly, a single dose of one antibiotic, streptomycin, was sufficient to reduce CVB3 shedding and pathogenesis while having no effect on poliovirus shedding and pathogenesis. Overall, replication and pathogenesis of CVB3 are more sensitive to antibiotic treatment than poliovirus, indicating that closely related viruses may differ with respect to their reliance on microbiota.", "source": "https://pubmed.ncbi.nlm.nih.gov/31511379/"}
{"doc_id": "a2fcf8649db52726b1ccb01786b9ba09", "sentence": "Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy .", "spans": [{"span_id": 0, "text": "etoposide", "start": 78, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "prednisone", "start": 90, "end": 100, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "vincristine", "start": 103, "end": 114, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "cyclophosphamide", "start": 117, "end": 133, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "doxorubicin", "start": 140, "end": 151, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": false}], "paragraph": "Successful treatment of an elderly Langerhans cell sarcoma patient by EPOCH ( etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ) chemotherapy . ", "source": "https://pubmed.ncbi.nlm.nih.gov/30305476/"}
{"doc_id": "4fe7ef8a981494fabcb16d1a1dc34a73", "sentence": "Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer .", "spans": [{"span_id": 0, "text": "Tremelimumab", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gemcitabine", "start": 18, "end": 29, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer. ### Patients And Methods gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab. ### results From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%). ### conclusion Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile , warranting further study in patients with metastatic pancreatic cancer . ### Clinicaltrialsgov Id NCT00556023.", "source": "https://pubmed.ncbi.nlm.nih.gov/24907635/"}
{"doc_id": "406cc45dcc6f28cc137e7b4ea45a2236", "sentence": "The sensitivity of a panel of short-term cultures derived from 22 malignant astrocytoma and four malignant oligodendroglioma was assessed to aziridinylbenzoquinone ( AZQ ) , etoposide and doxorubicin ( DOX ) using a [ (35)S ] methione uptake assay .", "spans": [{"span_id": 0, "text": "etoposide", "start": 174, "end": 183, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "doxorubicin", "start": 188, "end": 199, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Response of short-term cultures derived from human malignant glioma to aziridinylbenzoquinone, etoposide and doxorubicin: an in vitro phase II trial. The relative resistance of malignant glioma to chemotherapy makes the identification of new cytotoxic drugs critically important. The use of short-term cultures derived from these tumors to screen drugs at doses that can be attained within human intracranial tumors provides a model system that should be capable of identifying effective drugs suitable for clinical evaluation. The sensitivity of a panel of short-term cultures derived from 22 malignant astrocytoma and four malignant oligodendroglioma was assessed to aziridinylbenzoquinone ( AZQ ) , etoposide and doxorubicin ( DOX ) using a [ (35)S ] methione uptake assay . The ID(50) of each culture was compared to the levels of drug which could be achieved in the tumor using standard doses. There was marked heterogeneity between cultures in response to each drug. Whilst there was no evidence that cultures derived from grade III astrocytoma were more sensitive to any of the drugs than cultures derived from grade IV astrocytoma, cultures derived from oligodendroglioma tended to be more sensitive to the alkylating agent AZQ, but not to either of the other drugs. The sensitivity of these short-term cultures at concentrations that can be achieved in situ corresponded well with the clinical efficacy of AZQ and etoposide. Although DOX appeared to be toxic to human gliomas cells in vitro, its limited penetration into the intact brain would seem to preclude its use i.v., but it is likely to be effective if local drug delivery techniques could be employed. The study suggests that short-term cultures derived from malignant glioma should be used to screen investigational agents for potential clinical efficacy.", "source": "https://pubmed.ncbi.nlm.nih.gov/11593057/"}
{"doc_id": "39a8733290490861e7886845d3222f69", "sentence": "Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 108, "end": 120, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "lapatinib", "start": 126, "end": 135, "token_start": 20, "token_end": 21}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer. HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. ### Experimental Design Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. ### results Longer progression-free survival ( PFS ) and overall survival ( OS ) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups . PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. ### conclusions Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. \u00a92016 AACR.", "source": "https://pubmed.ncbi.nlm.nih.gov/26920887/"}
{"doc_id": "6cde22570e75d729825322fcd3bb8706", "sentence": "Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study .", "spans": [{"span_id": 0, "text": "Apalutamide", "start": 52, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "Abiraterone", "start": 69, "end": 80, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "Prednisone", "start": 94, "end": 104, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Pharmacokinetics , Safety , and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer : Phase Ib Study . apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC). ### Patients And Methods Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8. ### results Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of \u226550% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-na\u00efve patients and 14% (6/42) of AR signaling inhibitor-treated patients. ### conclusions Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.", "source": "https://pubmed.ncbi.nlm.nih.gov/32366670/"}
{"doc_id": "e94d4ba7604e7b25944f13484e92fbe8", "sentence": "Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials .", "spans": [{"span_id": 0, "text": "nintedanib", "start": 24, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "letrozole", "start": 55, "end": 64, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Nintedanib plus letrozole in early breast cancer: a phase 0/I pharmacodynamic, pharmacokinetic, and safety clinical trial of combined FGFR1 and aromatase inhibition. The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. ### Patients And Methods Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150\u2009mg/bid) plus letrozole (2.5\u2009mg/day) administered for a single 28-day\u2009cycle (DLT assessment period), followed by a classic 3\u2009+\u20093 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6\u2009cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). ### results A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200\u2009mg/bid plus letrozole 2.5\u2009mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. ### conclusion Combined treatment with nintedanib ( 200 mg/bid ) plus letrozole ( 2.5 mg/day ) effectively suppressed FGFR1 and aromatase activity , and these respective doses can be used as starting doses in any subsequent trials . However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6\u2009months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions. ### Trial Registration This trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015.", "source": "https://pubmed.ncbi.nlm.nih.gov/31126332/"}
{"doc_id": "ded8a5fdc1e6b60a2cbad5fbf2761e9e", "sentence": "A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 43, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "vinorelbine", "start": 59, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A significant response to a combination of trastuzumab and vinorelbine in HER2-negative metastatic breast cancer with HER2 V777L mutation . Metastatic breast cancer (MBC) is the most life-threatening disease in women worldwide. HER2-mutated breast carcinoma has been reported to benefit from HER2-targeted tyrosine kinase inhibitors recently. Here, we presented a heavy pretreated and harbored HER2 V777L mutation de novo stage IV Luminal B (HER2 unamplified) breast cancer patient who achieved an unexpected good response to trastuzumab combined with vinorelbine therapy. Although HER2-unamplified MBC patients do not regularly benefit from anti-HER2 target therapy, HER2 V777L mutation detected by next-generation sequencing from ctDNA may present as a predictive biomarker for anti-HER2-based strategy therapy in HER2-negative MBC patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/31118664/"}
{"doc_id": "8653897a48e7d6eb3f5dcfc08388cfa3", "sentence": "Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 154, "end": 165, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "ifosfamide", "start": 170, "end": 180, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "Dex", "start": 94, "end": 97, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "GM-CSF", "start": 101, "end": 107, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "POS", "spans": [0, 1, 3], "is_context_needed": true}], "paragraph": "Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide. Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients ( n = 28 ) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide . No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/14528069/"}
{"doc_id": "3214d11b86f9a3f4d5b6f1d4973dc814", "sentence": "After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy .", "spans": [{"span_id": 0, "text": "methylprednisolone", "start": 57, "end": 75, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "prednisolone", "start": 99, "end": 111, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "tacrolimus", "start": 124, "end": 134, "token_start": 17, "token_end": 18}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "The association between dermatomyositis and papillary thyroid cancer: a case report. We report the case of a 66-year-old woman who developed progressive proximal muscle weakness and papillary thyroid cancer. After a thyroidectomy , she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy . However, her clinical symptoms and laboratory data did not improve sufficiently. Therefore, we administered intravenous immunoglobulin. As a result, she regained substantial muscle strength along with complete normalization of serum muscle enzymes and showed no evidence of recurrence of papillary thyroid cancer or exacerbation of dermatomyositis (DM). Although there is controversy as to whether papillary thyroid cancer is involved in DM, the results of this study support a connection between these two conditions.", "source": "https://pubmed.ncbi.nlm.nih.gov/21243494/"}
{"doc_id": "4db36c9c0dfcd102155276b3f8deaf81", "sentence": "The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 21, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "pemetrexed", "start": 68, "end": 78, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "imexon", "start": 100, "end": 106, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. This study evaluated the cytotoxic effects of imexon (NSC-714597) in tumor cells when combined with a broad panel of chemotherapeutic drugs. ### methods The sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays were used to analyze the degree of growth inhibition for the combination studies in the A375 human malignant melanoma and RPMI 8226 human multiple myeloma cell lines, respectively. Cells were continuously exposed to both drugs at a constant molar ratio for 4-5 days. Combination effects were analyzed using the Median Effect method. Statistical significance was inferred if the 95% confidence interval for the combination interaction (C.I.) values for a particular two-drug combination did not include 1.0 (additivity). Synergy was inferred for C.I. values<1.0 and antagonism for CI values>1.0. ### results Imexon was synergistic when combined with DNA-binding agents (cisplatin, dacarbazine, melphalan) and pyrimidine-based antimetabolites (cytarabine, fluorouracil, gemcitabine) in both cell lines. Antagonistic combinations with imexon included methotrexate and the topoisomerase I (TOPO I) and II (TOPO II) inhibitors irinotecan, doxorubicin, mitoxantrone and etoposide. docetaxel was synergistic with imexon in both cell lines whereas paclitaxel and fludarabine showed a mixed result. dexamethasone and the proteasome inhibitor bortezomib showed synergy in myeloma cells and additivity in the melanoma cells. The vinca alkaloid , vinorelbine , and the multi-targeted antifol , pemetrexed , were additive with imexon in both cell lines . ### discussion The consistent synergy seen for imexon and alkylating agents may relate to the sulfhydryl-lowering effect of imexon, which would render cells more sensitive to electrophilic species from the alkylators. The marked synergy noted with pyrimidine-based antimetabolites was unexpected and may relate to the induction of cell cycle arrest in S-phase. The strong antagonism noted for imexon with topoisomerase I and II inhibitors may be due to the effect of imexon at increasing oxidant levels which are known to antagonize the cytotoxic effects of topoisomerase poisons. In contrast, the synergy seen with bortezomib in myeloma cells may be related to an increase in reactive oxygen species (ROS) from both drugs. These results suggest that combinations of imexon with alkylating agents and pyrimidine-based antimetabolites are rational to pursue in therapeutic studies in vivo.", "source": "https://pubmed.ncbi.nlm.nih.gov/17333195/"}
{"doc_id": "c97520cf4ea0ffbd75af6ff891594eee", "sentence": "Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) .", "spans": [{"span_id": 0, "text": "enalapril", "start": 74, "end": 83, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "atenolol", "start": 97, "end": 105, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "enalapril", "start": 121, "end": 130, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "atenolol", "start": 136, "end": 144, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "enalapril", "start": 244, "end": 253, "token_start": 49, "token_end": 50}, {"span_id": 5, "text": "atenolol", "start": 267, "end": 275, "token_start": 54, "token_end": 55}, {"span_id": 6, "text": "enalapril", "start": 291, "end": 300, "token_start": 59, "token_end": 60}, {"span_id": 7, "text": "atenolol", "start": 306, "end": 314, "token_start": 61, "token_end": 62}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination. In 16 patients with essential hypertension the effects of enalapril 20 mg once daily were compared with those of atenolol 50 mg once daily, with the two drugs in combination and with placebo using a double-blind cross-over design with allocation of treatment order by randomised Latin squares. For each patient there were four treatment phases, each of four weeks duration, which together comprised a 2 x 2 factorial experiment. All blood pressure parameters were reduced in the three active treatment phases compared to placebo (p less than 0.001). Supine blood pressures ( group means ) were 171/97 ( placebo ) , 147/85 ( enalapril ) , 154/84 ( atenolol ) and 144/78 ( enalapril plus atenolol ) ( S.E.M. + /- 2/+/- 1-ANOVA ) , and standing blood pressures were 170/105 ( placebo ) , 146/92 ( enalapril ) , 154/92 ( atenolol ) and 147/86 ( enalapril plus atenolol ) ( S.E.M. + /- 3/+/- 1 ) . In the combination phase there was an additional hypotensive response but the potential fully additive effects of the two agents were attenuated by 30-50%. The mechanism of the attenuated hypotensive effect of the combined agents has not been determined. Plasma atrial natriuretic peptide (ANP) concentration was doubled in the presence of atenolol (P less than 0.01) suggesting that ANP may contribute to the hypotensive effect of the beta-blocker.", "source": "https://pubmed.ncbi.nlm.nih.gov/2832102/"}
{"doc_id": "da53ead9de194fbbbfd4fbf115119337", "sentence": "To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 52, "end": 64, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "folinic acid", "start": 74, "end": 86, "token_start": 13, "token_end": 15}, {"span_id": 2, "text": "oxaliplatin", "start": 100, "end": 111, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer.  To evaluate the toxicity and activity of infusional fluorouracil ( FU ) , folinic acid ( FA ) , and oxaliplatin , administered every 2 weeks in patients with metastatic gastric cancer . ### Patients And Methods Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. ### results All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. ### conclusion Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/14966088/"}
{"doc_id": "2b4b20609f32c318d94165458d3ead40", "sentence": "Bevacizumab in combination with interferon alfa is now approved for treatment-na\u00efve advanced renal cell carcinoma ( RCC ) in both the US and Europe .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "interferon alfa", "start": 32, "end": 47, "token_start": 4, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The bevacizumab experience in advanced renal cell carcinoma.  Bevacizumab in combination with interferon alfa is now approved for treatment-na\u00efve advanced renal cell carcinoma ( RCC ) in both the US and Europe . Its objective response rates of 30% and progression-free survival rates of 9-10 months are comparable to the other approved first-line multityrosine kinase inhibitors, sunitinib and pazopanib. Its advantages include a different toxicity profile and assurance of administration compliance given its intravenous formulation. Enthusiasm for its use is blunted by the increased costs, the potential infusion-related reactions, the associated interferon-related toxicities, and the inconvenience of its nonoral formulation. Further study is warranted to assess its efficacy both as a single agent and in combination with the targeted agents and other immunotherapies. With multiple agents now available for the treatment of advanced RCC, identification of patient and tumor-specific biomarkers to inform our choice of first-line therapy and the proper sequence of subsequent therapies is imperative.", "source": "https://pubmed.ncbi.nlm.nih.gov/21049084/"}
{"doc_id": "393f92352c19f9ae226d09ba0b920e66", "sentence": "YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients .", "spans": [{"span_id": 0, "text": "YM155", "start": 0, "end": 5, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "rituximab", "start": 26, "end": 35, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. This phase II study evaluated ym155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received ym155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n\u2009=\u200934), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients .", "source": "https://pubmed.ncbi.nlm.nih.gov/26857688/"}
{"doc_id": "4d375de169095f455d7feec13343392b", "sentence": "Both , droperidol and the new 5-HT3-antagonist ( e.g. dolasetron ) are effective drugs in the prevention of postoperative nausea and vomiting ( PONV ) .", "spans": [{"span_id": 0, "text": "droperidol", "start": 7, "end": 17, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "dolasetron", "start": 54, "end": 64, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "[Dolasetron, droperidol and a combination of both in prevention of postoperative nausea and vomiting after extracapsular cataract extraction under general anesthesia].  Both , droperidol and the new 5-HT3-antagonist ( e.g. dolasetron ) are effective drugs in the prevention of postoperative nausea and vomiting ( PONV ) . It was the aim of this prospective double blind placebo controlled study to determine the efficacy of low-dose droperidol, dolasetron, and a combination of both drugs in the prevention of PONV after extracapsular cataract extraction. ### methods 148 inpatients undergoing cataract surgery were stratified according to gender and then randomised to receive one of four antiemetic regimens: placebo, droperiodol (10 micrograms x kg-1), dolasetron (12.5 mg), or the combination of both drugs (10 micrograms x kg-1 + 12.5 mg). The drugs were administered intravenously 5-10 minutes before the end of anaesthesia. General anaesthesia and the perioperative management of the patients were standardised: benzodiazepine premedication, induction with etomidate, alfentanil and mivacurium. Maintenance using desflurane in N2O/O2, and a continuous infusion of mivacurium was used. Postoperative analgesia (diclofenac or paracetamol) and antiemetic rescue medication (dimenhydrinate and metoclopramide) was standardised. Nausea, episodes of vomiting, retching and the need for additional antiemetics were recorded for 24-hours. The severity of PONV was categorised using a standardised scoring algorithm. The main aim of the study was the number of patients who stayed completely free from PONV. ### results There were no differences between the two groups with regard to biometric data, type of surgery, and distribution of risk factors for developing PONV. In all three treatment groups significantly less patients suffered from PONV (placebo: 66%; droperidol: 89%, dolasetron: 92%, combination: 89%; p = 0.011). Furthermore, the severity of PONV was reduced (p = 0.012). ### conclusion Low-dose droperidol and dolasetron are equally effective to reduce the incidence of PONV after cataract surgery under general anaesthesia. The combination of both drugs revealed no additional effect.", "source": "https://pubmed.ncbi.nlm.nih.gov/10429772/"}
{"doc_id": "a7970e11e38af84aa3c563f2b60c7e06", "sentence": "Use of doxycycline or azithromycin had little effect on the likelihood of removal of the IUD within 90 days of insertion ( OR 1.05 ; 95 % CI 0.68 - 1.63 ) .", "spans": [{"span_id": 0, "text": "doxycycline", "start": 7, "end": 18, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "azithromycin", "start": 22, "end": 34, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Antibiotic prophylaxis for intrauterine contraceptive device insertion. Concern about the risk of upper genital tract infection (pelvic inflammatory disease) often limits use of the IUD, a highly effective contraceptive. Prophylactic antibiotic administration around the time of induced abortion significantly reduces the risk of postoperative endometritis.(Sawaya, 1996) Since the risk of IUD-related infection is limited to the first few weeks to months after insertion,(Lee, 1983; Farley, 1992) contamination of the endometrial cavity at the time of insertion(Mishell, 1966) appears to be the mechanism, rather than the IUD or string itself. Thus, antibiotic administration before IUD insertion might reduce the risk of upper genital tract infection from passive introduction of bacteria at insertion. ### objectives To assess the effectiveness of prophylactic antibiotic administration before IUD insertion in reducing IUD-related complications and discontinuations within three months of insertion. The primary outcome was pelvic inflammatory disease (four reports) or early removals of the device (two reports). ### Search Strategy We searched both MEDLINE and EMBASE, handsearches of journals through CENTRAL, and lists of references. We also wrote to international experts in the field to identify unpublished studies. ### Selection Criteria We included randomized controlled trials using any antibiotic compared with a placebo. We found four such trials; two had pilot study data available. ### Data Extraction We used searches of MEDLINE, EMBASE, and handsearches of journals available through CENTRAL. We also reviewed lists of references in original research and in review articles. We wrote to experts to identify unpublished trials and made telephone calls to authors to supply missing information. Two independent reviewers abstracted data. We assessed the validity of each study using methods suggested in the Cochrane Handbook. ### Data Synthesis We generated 2x2 tables for the principal outcome measures. We used the Peto modified Mantel-Haenszel technique to calculate odds ratios and assessed statistical heterogeneity between studies. ### Main Results The odds ratios for pelvic inflammatory disease associated with use of prophylactic doxycycline or azithromycin compared with placebo or no treatment was 0.89 (95%CI 0.53-1.51). Use of prophylaxis was associated with a small reduction in unscheduled vists to the provider (OR 0.82; 95% CI 0.70-0.98). Use of doxycycline or azithromycin had little effect on the likelihood of removal of the IUD within 90 days of insertion ( OR 1.05 ; 95 % CI 0.68 - 1.63 ) . Significant heterogeneity did not exist between studies. ### Reviewer S Conclusions Use of either doxycycline 200 mg or azithromycin 500 mg by mouth before IUD insertion confers little benefit. While the reduction in unscheduled visits to the provider was marginally significant, the cost-effectiveness of routine prophylaxis remains questionable. A uniform finding in these trials was the low risk of IUD-associated infection, with or without use of antibiotic prophylaxis.", "source": "https://pubmed.ncbi.nlm.nih.gov/10796777/"}
{"doc_id": "185a0df36f0bbe26afde08a20ba31179", "sentence": "Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 67, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "gemcitabine", "start": 84, "end": 95, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "carboplatin", "start": 103, "end": 114, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Management of platinum-sensitive recurrent ovarian cancer. The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinum-sensitive disease. Re-treatment with single-agent platinum has long been considered standard therapy for patients with platinum-sensitive disease, and, based on its favorable therapeutic profile, carboplatin has become the treatment agent of choice. High response rates are seen with platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft f\u00fcr Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined. Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly , a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial . The toxicity profiles and schedules of carboplatin plus paclitaxel and carboplatin plus gemcitabine are different, with the taxane combination having greater neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions (although fewer days of treatment per cycle) than the gemcitabine combination. Based on the results of these two trials, combination chemotherapy should be considered the standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two combination regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/16716798/"}
{"doc_id": "e43d4d1e7e7b7d7db5fa281723b77e6a", "sentence": "We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared .", "spans": [{"span_id": 0, "text": "betamethasone", "start": 62, "end": 75, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "tazarotene", "start": 128, "end": 138, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Tazarotene cream (0.1%) in combination with betamethasone valerate foam (0.12%) for plaque-type psoriasis. A combination of multiple agents is often required to achieve treatment success for plaque-type psoriasis. We report a case series of 10 patients that were treated with betamethasone valerate foam ( 0.12 % ) in the morning and topical tazarotene cream ( 0.1 % ) in the evening for a total of 12 weeks or until plaques cleared . Erythema, scale, and thickness along with an aggregate severity score were determined at weeks 4, 8, and 12. One patient was lost to follow-up. Eight of the other 9 patients experienced improvement in their disease by week 12. Two patients were clear of their psoriasis at week 4 and 4 were clear at week 8. No adverse events, including irritation were reported; the use of the corticosteroid foam may protect against potential local irritation reported with tazarotene. The combination of tazarotene cream and betamethasone valerate foam is an effective combination approach to treating localized plaque-type psoriasis.", "source": "https://pubmed.ncbi.nlm.nih.gov/15776784/"}
{"doc_id": "f4bbaf3dafcd80da3dde3ed4380d023c", "sentence": "Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration .", "spans": [{"span_id": 0, "text": "Valsartan", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "sulfasalazine", "start": 14, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis. Inflammatory bowel disease (IBD) is defined by the chronic inflammation of the digestive tract. Ulcerative colitis is one of the most prevalent chronic IBDs. The increase in the mucosal expression of angiotensin II (AT-II) in colitis suggests a possible role of AT-II in colitis-associated inflammation. Here, we examined the potential therapeutic effects of combination therapy regarding valsartan (Val), as an AT-II receptor blocker, with sulfasalazine (SSZ) in a murine colitis model. DSS induced colitis was initiated by the administration of dextran sodium sulfate (DSS) in male C57BL/6 mice for 1 week. Val (160 mg/kg/day, gavage) was given on the third day and continued for seven days. SSZ (100 mg/kg/day) was used as reference drug and also used in combination in one group (Val; 160 mg/kg/day and/or SSZ; 100 mg/kg/day). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The disease activity index in DSS-treated mice, including weight loss, stool consistency, and rectal bleeding, were significantly lower in the group of mice receiving the combination of valsartan and sulfasalazine compared to the DSS-treated group. valsartan and sulfasalazine treatment was associated with a lower reduction in colon length, diminished colon weight, and high sensitivity C-reactive protein level in mice with DSS-induced colitis. Valsartan and sulfasalazine also reduced markers of oxidative stress after DSS administration . Our findings demonstrate the anti-inflammatory and anti-fibrotic activities of a combination therapy with sulfasalazine and valsartan in experimentally induced colitis, indicating its value as a potential therapeutic option for the treatment of colitis.", "source": "https://pubmed.ncbi.nlm.nih.gov/33628160/"}
{"doc_id": "2b68661394691dcb80f0b77a179ad330", "sentence": "Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone , occurring in the two patients who had previously been treated with Glatiramer Acetate .", "spans": [{"span_id": 0, "text": "Mitoxantrone", "start": 66, "end": 78, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "Glatiramer", "start": 148, "end": 158, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis. mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone , occurring in the two patients who had previously been treated with Glatiramer Acetate . In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of mitoxantrone, no enhancing lesions were identified on MRI brain scans. glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.", "source": "https://pubmed.ncbi.nlm.nih.gov/16990994/"}
{"doc_id": "8ca4537381cf706758f57cc0a9ac5516", "sentence": "Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer .", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 11, "end": 25, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "oxaliplatin", "start": 28, "end": 39, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "irinotecan", "start": 44, "end": 54, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Metronomic 5-fluorouracil , oxaliplatin and irinotecan in colorectal cancer . Metronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.", "source": "https://pubmed.ncbi.nlm.nih.gov/19695243/"}
{"doc_id": "699f2e2cf2eb7133facfc4ee10aab5ca", "sentence": "Several epidemiological , clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs ( NSAIDs ) ( aspirin , naproxen , sulindac , celecoxib , and licofelone ) , statins and other natural agents-both individually , and in combinations .", "spans": [{"span_id": 0, "text": "aspirin", "start": 207, "end": 214, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "naproxen", "start": 217, "end": 225, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "sulindac", "start": 228, "end": 236, "token_start": 31, "token_end": 32}, {"span_id": 3, "text": "celecoxib", "start": 239, "end": 248, "token_start": 33, "token_end": 34}, {"span_id": 4, "text": "licofelone", "start": 255, "end": 265, "token_start": 36, "token_end": 37}], "rels": [], "paragraph": "Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives. Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological , clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs ( NSAIDs ) ( aspirin , naproxen , sulindac , celecoxib , and licofelone ) , statins and other natural agents-both individually , and in combinations . Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.", "source": "https://pubmed.ncbi.nlm.nih.gov/30096840/"}
{"doc_id": "21b69c12af9158b87a5b0f5917acfdb5", "sentence": "Lenalidomide is an approved medication for relapsed mantle cell lymphoma in patients who received at least two lines of therapy , including bortezomib .", "spans": [{"span_id": 0, "text": "Lenalidomide", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bortezomib", "start": 140, "end": 150, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Lenalidomide for mantle cell lymphoma. Mantle cell lymphoma accounts for 6% of all non-Hodgkin lymphomas. It is a biologically and clinically heterogeneous disease and treatment may be difficult, since most patients present at an older age, being unable to undergo intensive chemotherapy. Lenalidomide is an approved medication for relapsed mantle cell lymphoma in patients who received at least two lines of therapy , including bortezomib . New insights into the mechanisms of action of lenalidomide provided ground for novel combinations that may be more tolerable, while still efficient, for this patient population. In this review, we evaluate the current paradigm for lenalidomide in mantle cell lymphoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/25952533/"}
{"doc_id": "1af53bee0469e8864ff0d747d76a9c51", "sentence": "Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 15, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "praziquantel", "start": 30, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "praziquantel", "start": 77, "end": 89, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "mefloquine", "start": 93, "end": 103, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Therapeutic effect of mefloquine on Schistosoma mansoni in experimental infection in mice. Schistosomiasis is one of the most prevalent parasitic infections worldwide. praziquantel is the drug of choice for treatment of schistosomiasis for its high efficacy. The present work was carried out on 160 mice to evaluate the therapeutic effect of mefloquine on experimental schistosomiasis mansoni. Mice were classified into 3 groups; group I (20 infected non-treated mice), group II included 60 infected mice which were further divided into group IIm (20 mice treated with 400\u00a0mg/kg mefloquine), group IIp (20 mice treated with 1,000\u00a0mg/kg/2\u00a0days praziquantel) and group IIpm (20 mice treated with 200\u00a0mg/kg mefloquine and 500\u00a0mg/kg praziquantel), group III included 80 non-infected mice subdivided into group IIIn (20 non-treated mice), group IIIm (20 mice treated with 400\u00a0mg/kg mefloquine), group IIIp (20 mice treated with 1,000\u00a0mg/kg/2\u00a0days praziquantel), group IIIpm (20 mice treated with 200\u00a0mg mefloquine and 500\u00a0mg praziquantel). mefloquine significantly reduced worm burden, tissue egg load, number of liver granulomas and increased the percent of dead ova within granulomas. Combination of mefloquine and praziquantel gave better curative effects than praziquantel or mefloquine given alone .", "source": "https://pubmed.ncbi.nlm.nih.gov/27413290/"}
{"doc_id": "d0b32ba93cfb030781614840a4f9e9eb", "sentence": "The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 46, "end": 57, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "epirubicin", "start": 91, "end": 101, "token_start": 14, "token_end": 15}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Influence of trastuzumab on epirubicin pharmacokinetics in metastatic breast cancer patients. Anthracycline cardiotoxicity is increased by the contemporaneous administration of trastuzumab. The mechanism by which it occurs is as yet unknown. The aim of this study was to evaluate whether trastuzumab modifies the pharmacokinetics of epirubicin and its metabolites . ### Patients And Methods Women with HER2-positive metastatic breast cancer were treated with epirubicin 75 mg/m(2) i.v. bolus followed by docetaxel 75 mg/m(2) in a 1-h infusion, every 3 weeks for six cycles, and trastuzumab (once at 4 mg/m(2), then 2 mg/m(2) weekly thereafter) in a 30-min infusion. epirubicin pharmacokinetic data of seven patients were evaluated at the first cycle of therapy (baseline, with trastuzumab administered 24 h after epirubicin), and at the sixth cycle (i.e. 15 weeks after baseline, with trastuzumab administered immediately before epirubicin). ### results No pharmacokinetic change in the parent compound epirubicin was detected. The area under the plasma concentration-time curve (AUC(0-24 h)) was 1230 +/- 318 [mean +/- standard deviation (SD)] at the first cycle and 1287 +/- 385 h. micro g/l at the sixth. The mean (+/-SD) maximum plasma concentration (C(max)) and the terminal elimination half-life at the first cycle (1303 +/- 490 micro g/l and 12.5 +/- 3.1 h, respectively) were similar to those obtained at the sixth cycle (1229 +/- 580 micro g/l and 11.5 +/- 2.9 h, respectively). Pharmacokinetic data of epirubicin metabolites evaluated at the first and sixth cycle of chemotherapy were superimposable without any statistical difference. ### conclusion Enhanced anthracycline cardiotoxicity related to trastuzumab administration was not linked to pharmacokinetic interferences with epirubicin and its metabolites.", "source": "https://pubmed.ncbi.nlm.nih.gov/12881383/"}
{"doc_id": "7500cc285dc26dbd5642ffff0b28d687", "sentence": "Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 27, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "cyclophosphamide", "start": 43, "end": 59, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "paclitaxel", "start": 72, "end": 82, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "trastuzumab", "start": 99, "end": 110, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "NEG", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial . To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. ### Patients And Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. ### results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. ### conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.", "source": "https://pubmed.ncbi.nlm.nih.gov/18250349/"}
{"doc_id": "69aab0d7ca9444e4b1295a8f4ea70482", "sentence": "Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice .", "spans": [{"span_id": 0, "text": "Bupropion", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "nicotine", "start": 85, "end": 93, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Bupropion differentially alters the aversive , locomotor and rewarding properties of nicotine in CD-1 mice . The present experiments determined the effects of bupropion on the motivational (aversive and rewarding) and locomotor properties of nicotine in CD-1 mice. Preliminary experiments determined effective nicotine doses (0.1-2.0 mg/kg) to produce a conditioned taste aversion (CTA) or conditioned place preference (CPP; Experiments 1a and 2a, respectively). Mice were administered vehicle or bupropion (1-20 mg/kg) followed by vehicle or nicotine after drinking saccharin during CTA training (Experiment 1b). Mice were administered vehicle or bupropion (1-20 mg/kg) 15 (Experiment 2b) or 30 (Experiment 2c) minutes (min) prior to vehicle or nicotine during CPP training. The two highest nicotine doses produced CTAs and a moderate nicotine dose (0.4 mg/kg) produced a CPP. bupropion dose-dependently blocked nicotine CTA. For the 15-min pretreatment interval, bupropion dose-dependently increased locomotor activity and produced CPPs when administered alone; whereas for the 30-min pretreatment interval, only the highest bupropion dose increased locomotor activity and produced a CPP. However, bupropion failed to alter nicotine CPP and the co-administration of bupropion and nicotine did not increase locomotor activity more so than when bupropion was administered alone regardless as to the pretreatment interval. Thus, bupropion selectively altered the aversive properties of nicotine in CD-1 mice.", "source": "https://pubmed.ncbi.nlm.nih.gov/18556053/"}
{"doc_id": "798ec9703dcfe46033a3f97ad645abba", "sentence": "We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin , clarithromycin , metronidazole , tetracycline and levofloxacin in Bangladesh .", "spans": [{"span_id": 0, "text": "amoxicillin", "start": 86, "end": 97, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "clarithromycin", "start": 100, "end": 114, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "metronidazole", "start": 117, "end": 130, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "tetracycline", "start": 133, "end": 145, "token_start": 19, "token_end": 20}, {"span_id": 4, "text": "levofloxacin", "start": 150, "end": 162, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Helicobacter pylori antibiotic susceptibility patterns in Bangladesh: Emerging levofloxacin resistance. The most recent study to report Helicobacter pylori antibiotic resistance rates in Bangladesh was published 15 years ago and did not include levofloxacin. We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin , clarithromycin , metronidazole , tetracycline and levofloxacin in Bangladesh . ### methodology This study included 133 consecutive patients who underwent endoscopy examination at Dhaka Medical College in November 2014. The serial two-fold agar dilution method was used to determine the minimum inhibitory concentrations of the five antibiotics. ### results Among 56 cultured strains, H. pylori showed high rates of resistance to clarithromycin and metronidazole (39.3% and 94.6%, respectively). Moreover, levofloxacin showed an emerging antimicrobial resistance pattern (66.1%), which was higher in patients with gastritis than that in those with peptic ulcers (p = 0.02). The resistance rate of levofloxacin was significantly higher in patients living in Dhaka city compared to those living in the village (p = 0.049). However, amoxicillin and tetracycline resistance rates were very low. Resistance to both metronidazole and levofloxacin was most commonly observed. ### conclusions The rates of resistance to clarithromycin, metronidazole, and levofloxacin were high in Bangladesh, which suggests that triple therapy based on these drugs may not be useful as first-line therapies in Bangladesh. Alternative strategies such as furazolidone-based triple therapy, bismuth-based quadruple therapies, or sequential therapy may be more effective for patients in in Bangladesh.", "source": "https://pubmed.ncbi.nlm.nih.gov/27031456/"}
{"doc_id": "a6bdd8378e693d7a72d57a3b0d89f174", "sentence": "With the exception of one Y. enterocolitica isolate which was resistant to tetracycline and streptomycin , the isolates were sensitive to the non-beta-lactam antibiotics .", "spans": [{"span_id": 0, "text": "tetracycline", "start": 75, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "streptomycin", "start": 92, "end": 104, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Antibiotic susceptibilities of Yersinia enterocolitica and Y. intermedia isolates from aquatic environments. Of 37 Yersinia isolates from various aquatic environments, seven were Y. enterocolitica and 30 Y. intermedia. These isolates were biotyped, serotyped and tested for their susceptibility to 20 antibiotics. All Y. enterocolitica isolates were of biovar 1; those of Y. intermedia were distributed amongst four biovars (1, 2, 4 and 6). On the basis of combined biotyping and serotyping results, Y. enterocolitica isolates were distributed in five and Y. intermedia in 17 groups. With the exception of one Y. enterocolitica isolate which was resistant to tetracycline and streptomycin , the isolates were sensitive to the non-beta-lactam antibiotics . In contrast, various patterns of beta-lactam insensitivity were detected, including ampicillin and ticarcillin (35 isolates), cephalothin (33 isolates), carbenicillin (32 isolates), amoxycillin/clavulanate (23 isolates) and cefoxitin (22 isolates). No correlation between biotype or serotype and the susceptibility pattern of the isolates was apparent. Both inducible cephalosporinase activity against third-generation cephalosporins and inhibition of resistance to penicillins were detected in all Y. enterocolitica and Y. intermedia isolates by double-disk tests.", "source": "https://pubmed.ncbi.nlm.nih.gov/9989643/"}
{"doc_id": "d962e3a836ee82e855e8c51bd15f7b82", "sentence": "Meropenem ( 84.5 % ) and vancomycin ( 100 % ) remain the most effective antimicrobial agents against Gram negative and Gram positive bacteria , respectively .", "spans": [{"span_id": 0, "text": "Meropenem", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "vancomycin", "start": 25, "end": 35, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "[Colonization of cental venous catheter in the Intensive Care Units at the Institute of Cardiovascular Disease \"Dedinje\"--one year study]. The application of Central Venous Catheters (CVC) is associated with increased risk of microbial colonization and infection. The aim of present study was to assess the frequency of pathogens colonizing CVC and to determine their susceptibility pattern to various antimicrobial agents. ### Materials And Methods A total of 253 samples of CVC from intensive care units (ICU) patients were received for culture during 2003. All microorganisms were identified by standard microbiological methods and the susceptibility to antimicrobial agents was determined according to NCCLS recommendations. ### results A total of 184 (72.7%) cultures were positive and 223 pathogens were isolated. Coagulase negative staphylococci (CNS) were the dominant isolates (24.7%), followed by Enterobacter spp. (12.1%), Pseudomonas spp. (11.7%), Enterococcus spp. (9.9%), Klebsiella spp. (8.6%), Candida spp. (7.6%), Acinetobacter spp. (7.6%), other Gram negative nonfermentative bacilli (5.8%), Serratia spp. (4.5%), Staphylococcus aureus (2.6%), Proteus mirabilis (2.2%), E. coli (1.8%) and Citrobacter spp. (0.9%). Meropenem ( 84.5 % ) and vancomycin ( 100 % ) remain the most effective antimicrobial agents against Gram negative and Gram positive bacteria , respectively . ### conclusion Gram negative bacilli and CNS are the commonest microorganisms colonizing CVC from ICU patients. The increasing resistance of the bacteria to antimicrobial agents is the major problem in spite of restricted policy of using antimicrobial agents in ICU.", "source": "https://pubmed.ncbi.nlm.nih.gov/16812991/"}
{"doc_id": "22493c5e296bf637da1a3a4d317c9fe2", "sentence": "Troublesome coughing , as observed by the operator , was less frequent with glycopyrrolate ( control 51 % , atropine 42 % , glycopyrrolate 30 % ) , as was patient movement ( 40 % , 32 % , 19 % , respectively ) .", "spans": [{"span_id": 0, "text": "glycopyrrolate", "start": 76, "end": 90, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "atropine", "start": 108, "end": 116, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "glycopyrrolate", "start": 124, "end": 138, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Anticholinergic premedication for fibreoptic bronchoscopy. atropine is routinely used as part of the premedication regimen for fibreoptic bronchoscopy. This study was performed, firstly, to evaluate the effect of anticholinergic agents on the ease of bronchoscopy, haemodynamic parameters and patient comfort during the procedure; and secondly, to compare atropine with glycopyrrolate, a newer acetylcholine antagonist which is claimed to cause less tachycardia and sedation, whilst suppressing salivation more effectively. One hundred and ninety consecutive patients were randomly allocated to three treatment groups: diazepam 5 mg; diazepam 5 mg + atropine 600 micrograms; and diazepam 5 mg + glycopyrrolate 300 micrograms. Diazepam was given orally one hour before bronchoscopy, and glycopyrrolate/atropine intramuscularly 30 min before bronchoscopy. All patients received thalamonal intravenously, lignocaine gel into one nostril, and lignocaine by transtracheal injection just prior to the procedure. The incidence of bronchoscopy related haemodynamic problems was similar in all three groups. Troublesome coughing , as observed by the operator , was less frequent with glycopyrrolate ( control 51 % , atropine 42 % , glycopyrrolate 30 % ) , as was patient movement ( 40 % , 32 % , 19 % , respectively ) . Uncomfortable dryness of the mouth was most common with glycopyrrolate (37%, 32%, 66%, respectively), but overall assessment of discomfort, and the number of patients who would agree to a repeat bronchoscopy (73%, 76%, 70%, respectively) were very similar in all three groups. In conclusion, the differences between the three groups were slight. glycopyrrolate made the bronchoscopy slightly easier for the operator because of significantly improved cough and movement suppression, though atropine was marginally preferable in terms of patient comfort.", "source": "https://pubmed.ncbi.nlm.nih.gov/8049691/"}
{"doc_id": "fb2aef24db7a72de42f51884b108ba26", "sentence": "The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab .", "spans": [{"span_id": 0, "text": "doxorubicin/cyclophosphamide", "start": 79, "end": 107, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "paclitaxel", "start": 111, "end": 121, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "trastuzumab", "start": 129, "end": 140, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "vinorelbine", "start": 194, "end": 205, "token_start": 31, "token_end": 32}, {"span_id": 4, "text": "trastuzumab", "start": 208, "end": 219, "token_start": 33, "token_end": 34}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [3, 4], "is_context_needed": true}], "paragraph": "Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. ### methods The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy ( doxorubicin/cyclophosphamide or paclitaxel ) + /- trastuzumab , and the second was a multicenter phase II trial of vinorelbine + trastuzumab . All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. ### results Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. ### conclusions Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.", "source": "https://pubmed.ncbi.nlm.nih.gov/16150805/"}
{"doc_id": "96a9fd8b397223abbea02baa3dfbe9fc", "sentence": "Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients .", "spans": [{"span_id": 0, "text": "Peginterferon alfa-2a", "start": 0, "end": 21, "token_start": 0, "token_end": 2}, {"span_id": 1, "text": "ribavirin", "start": 36, "end": 45, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy. Peginterferon alfa plus ribavirin is currently the treatment of choice for chronic hepatitis C. Peginterferon alfa-2a ( 40KD ) plus ribavirin has given an overall sustained virological response of 18 % in F3/F4 previous nonresponder US patients . We evaluated the effectiveness of peginterferon alfa-2a (40KD) plus ribavirin in Brazilian patients who were relapsers or nonresponders to previous interferon-based therapy. One-hundred-thirty-four patients with biopsy-proven chronic hepatitis C, HCV RNA positive, elevated ALT and who were either relapsers (n=37) or nonresponders (n=97) to at least 24 weeks of conventional interferon/ribavirin therapy were retreated with peginterferon alfa-2a (40KD) 180mg/qw and ribavirin 800 mg bid for 48 weeks. Efficacy was assessed as virological response (defined as undetectable HCV RNA) at the end of treatment (EoT) and at the end of follow-up (SVR - Sustained Virological Response). Safety assessments consisted of clinical and laboratory evaluations. In the patient sample, 72% were genotype 1 and 34% were cirrhotic. In an intention-to-treat analysis, relapser patients showed 78% EoT response and 51% SVR. Nonresponders showed 57% EoT response and 26% SVR. Positive predictive factors of SVR were non-1 genotype and relapser state. Six percent of the patients interrupted treatment because of adverse events and 45% had dose reduction (mainly associated with leucopenia and anemia). Brazilian patient relapsers and nonresponders to conventional interferon and ribavirin treatment can achieve a sustained virological response when retreated with peginterferon alfa-2a (40KD) and ribavirin. The safety profile is similar to that of naive patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/16767309/"}
{"doc_id": "1c3e878969df3a2cbcad911937d77bd6", "sentence": "Simultaneous determination of pyrimethamine and mefloquine in human plasma by high-performance liquid chromatography with ultraviolet detection .", "spans": [{"span_id": 0, "text": "pyrimethamine", "start": 30, "end": 43, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "mefloquine", "start": 48, "end": 58, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Simultaneous determination of pyrimethamine and mefloquine in human plasma by high-performance liquid chromatography with ultraviolet detection . A rapid, sensitive and selective method was developed for the simultaneous determination of pyrimethamine and mefloquine, two of the active ingredients of Fansimef, in human plasma. The procedure involved extraction of the compounds and the internal standard nitrazepam from basified plasma with dichloromethane and chromatography on a C18 column (microBondapak, 300 X 3.9 mm I.D.) with acetonitrile-phosphate buffer as the mobile phase and UV detection at 222 nm. The limit of quantification was 10 ng/ml for both substances, using a 1-ml plasma specimen. The mean inter-assay precision was 2.8% for pyrimethamine and 4.7% for mefloquine up to 800 ng/ml. The practicability of the method was demonstrated by the analysis of more than 1200 plasma samples from several pharmacokinetic studies involving single-dose administration of Fansimef to both patients and volunteers.", "source": "https://pubmed.ncbi.nlm.nih.gov/2584319/"}
{"doc_id": "9a67aa7bd71f87b823a2f61c598580c8", "sentence": "We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 58, "end": 67, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "celecoxib", "start": 72, "end": 81, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study. Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions . Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.", "source": "https://pubmed.ncbi.nlm.nih.gov/24085777/"}
{"doc_id": "1354ecde1f0efa09e4ae9da54b16a013", "sentence": "Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel , cetuximab , methotrexate , carboplatin , 5-fluorouracil and everolimus .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 108, "end": 117, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "cetuximab", "start": 120, "end": 129, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "methotrexate", "start": 132, "end": 144, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "carboplatin", "start": 147, "end": 158, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "5-fluorouracil", "start": 161, "end": 175, "token_start": 25, "token_end": 26}, {"span_id": 5, "text": "everolimus", "start": 180, "end": 190, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option. Patient-derived xenograft (PDX) models have shown to reflect original patient tumors better than any other preclinical model. We embarked in a study establishing a large panel of head and neck squamous cell carcinomas PDX for biomarker analysis and evaluation of established and novel compounds. Out of 115 transplanted specimens 52 models were established of which 29 were characterized for response to docetaxel , cetuximab , methotrexate , carboplatin , 5-fluorouracil and everolimus . Further, tumors were subjected to sequencing analysis and gene expression profiling of selected mTOR pathway members. Most frequent response was observed for docetaxel and cetuximab. Responses to carboplatin, 5-fluorouracil and methotrexate were moderate. everolimus revealed activity in the majority of PDX. Mutational profiling and gene expression analysis did not reveal a predictive biomarker for everolimus even though by trend RPS6KB1 mRNA expression was associated with response. In conclusion we demonstrate a comprehensively characterized panel of head and neck cancer PDX models, which represent a valuable and renewable tissue resource for evaluation of novel compounds and associated biomarkers.", "source": "https://pubmed.ncbi.nlm.nih.gov/25404014/"}
{"doc_id": "a5a37111778a7e5eac53c5f529927814", "sentence": "Apart from progesterone , the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil , trifluoperazine and reserpine .", "spans": [{"span_id": 0, "text": "verapamil", "start": 133, "end": 142, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "trifluoperazine", "start": 145, "end": 160, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "reserpine", "start": 165, "end": 174, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Comparison of effects of surfactants with other MDR reversing agents on intracellular uptake of epirubicin in Caco-2 cell line. P-glycoprotein (P-gp) actively pumps out a number of anticancer drugs, such as epirubicin, from tumor cells. P-gp is also expressed in the small intestine under normal physiological conditions. Inhibition of intestinal P-gp function using MDR reversing agents may enhance the oral bioavailability of some chemotherapeutic agents. Human colon adenocarcinoma (Caco-2) cell line expresses many characteristics of differentiated cells of the normal small intestine. Using Caco-2 as an in vitro intestinal model, the overall goal of the present study was to evaluate the MDR-reversing effects of some commonly used nonabsorptive pharmaceutical surfactants, such as Tween 20, Tween 80 and acacia on the intracellular accumulation of epirubicin by flow cytometry. Tween 20, Tween 80 or acacia all significantly increased intracellular accumulation of epirubicin with the highest enhancing effect for acacia and the lowest for Tween 20. Apart from progesterone , the enhancing effects of surfactants were better than those of non-surfactant MDR reversing agents such as verapamil , trifluoperazine and reserpine . In conclusion, our results demonstrate that progesterone, acacia, Tween 20 and Tween 80 are potent MDR modifiers of epirubicin in Caco-2 at concentrations that could be achieved in vivo. Use of surfactants in excipients may increase the intestinal absorption of some drugs through P-gp inhibition and thus improve drug bioavailability for P-gp substrate.", "source": "https://pubmed.ncbi.nlm.nih.gov/9713500/"}
{"doc_id": "8fdaeaa5a546d9cdb6e3f2ad87336e00", "sentence": "A549-Gem is cross-resistant to vincristine and etoposide , but not resistant to adriamycin , cisplatin , cytarabine and paclitaxel .", "spans": [{"span_id": 0, "text": "vincristine", "start": 31, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "etoposide", "start": 47, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "cisplatin", "start": 93, "end": 102, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "cytarabine", "start": 105, "end": 115, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "paclitaxel", "start": 120, "end": 130, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "[Development and characterization of a gemcitabine-resistant variant of human lung adenocarcinoma cell line A549]. gemcitabine (2',2-difluorodeo- xycytide) has antitumor activity in both experimental and clinical treatment of solid tumors. Although resistance to gemcitabine in ovarian cancer cell line and erythroleukemic cell line was described, there was no report on the lung cancer resistant variant. In order to elucidate the mechanism by which gemcitabine induce resistance in lung cancer, we have established the resistance to gemcitabine in human lung adenocarcinoma cell line A549 and described the characteristics of its resistant variant. ### methods Resistance to gemcitabine was established by exposing A549 cells to increasing concentration of gemcitabine, which was designated as A549-Gem. The IC(50) and resistance index(RI) were tested by MTT assay and colony formation test. The growth curve and cell cycle of A549 and A549-Gem were compared. The cross-resistance profile of A549-Gem was also tested. ### results The IC(50) increased from 6.56+/-1.19 micromol/L in A549 to 921.09+/-225.27 micromol/L in A549-Gem as tested by MTT assay at 72h exposure, the RI was 140.52 (P=0.019 5). The RI of colony formation test was 132.95. Double time of A549 and A549-Gem were 29.7 h and 36.4 h, respectively, as evaluated by the growth curve. A549-Gem was cross-resistant to vincristine and etoposide(54.38-fold and 6.18-fold)(P< 0.01), but not to adriamycin, cisplatin, cytarabine, and paclitaxel. ### conclusion A549-Gem, the gemcitabine resistant phenotype, is stable and suitable for the study of gemcitabine resistance in lung cancer. A549-Gem is cross-resistant to vincristine and etoposide , but not resistant to adriamycin , cisplatin , cytarabine and paclitaxel .", "source": "https://pubmed.ncbi.nlm.nih.gov/15191667/"}
{"doc_id": "20514f75a386ccc202c4c1745f22bc91", "sentence": "[ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] .", "spans": [{"span_id": 0, "text": "lamivudine", "start": 37, "end": 47, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "adefovir", "start": 52, "end": 60, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Efficacy of combination therapy of lamivudine and adefovir dipivoxyl for patients with hepatitis B-induced decompensated liver cirrhosis ] . To evaluate the efficacy of combination therapy of lamivudine (LAM) and adefovir dipivoxyl (ADV) for patients with hepatitis B-induced decompensated cirrhosis. ### methods A total of 81 patients were randomly divided into a combination group and an ADV group over 48 week treatment course. The combination group were treated with LAM (100 mg/d) plus ADV (10 mg/d), and the ADV group with ADV (10 mg/d ) for 48 weeks. All patients received hepatic function support and symptomatic treatment. The levels of HBV DNA, liver function, Child-Pugh scores and HBV DNA indicators were observed before and after the treatment. ### results At week 4, the mean reduction of HBV DNA was 1.83 lgIU/mL, 17.9% of the patients achieved undetectable HBV DNA and 28.2% showed normal ALT in the combination group. The counterpart in the ADV group was 0.96 lgIU/mL, 5.3% and 10.5%. At week 4, 12, 24 and 48, the differences in the mean reduction of HBV DNA, undetectable HBV DNA and ALT normalization were statistically significant between the 2 groups. The difference in HBeAg negative conversion rates and HBeAg seroconversion at week 24 and 48 was not significant. ### conclusion The combination therapy results in HBV suppression and improved liver function and Child-Pugh score. The combination treatment has an advantage over ADV due to low drug resistance rate and good tolerance.", "source": "https://pubmed.ncbi.nlm.nih.gov/23281382/"}
{"doc_id": "18d0d9d7869efb79ddddcc8959b06715", "sentence": "The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects .", "spans": [{"span_id": 0, "text": "aspirin", "start": 17, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "aspirin", "start": 84, "end": 91, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "metoclopramide", "start": 97, "end": 111, "token_start": 15, "token_end": 16}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Aspirin in the treatment of acute migraine attacks. Acetylsalicylic acid (aspirin or ASA) has been used for many years as an analgesic, antipyretic and anti-inflammatory drug. In recent years, evidence for its effectiveness in migraine headache has been demonstrated in several clinical trials. The effervescent highly buffered preparation of aspirin was shown to be effective, safe and well tolerated compared with placebo or other treatment options. The effervescent aspirin preparation is at least as effective as the combination of aspirin plus metoclopramide , but has fewer side effects . This review summarizes and analyzes clinical data of aspirin in the treatment of acute migraine attacks with respect to the different galenic formulations.", "source": "https://pubmed.ncbi.nlm.nih.gov/16623655/"}
{"doc_id": "8661d62eebfe82d61a8747df95d0c3d1", "sentence": "Several agents are now available in this setting , including neratinib , tucatinib , ado-trastuzumab emtansine , and trastuzumab deruxtecan .", "spans": [{"span_id": 0, "text": "neratinib", "start": 61, "end": 70, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "emtansine", "start": 101, "end": 110, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "trastuzumab deruxtecan", "start": 117, "end": 139, "token_start": 18, "token_end": 20}], "rels": [], "paragraph": "Neratinib: an option for HER2-positive metastatic breast cancer. Metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is currently incurable. The primary goals of treatment are to prolong survival while optimizing quality of life. Several agents are now available in this setting , including neratinib , tucatinib , ado-trastuzumab emtansine , and trastuzumab deruxtecan . neratinib in combination with capecitabine was recently approved for the treatment of adult patients with advanced or metastatic breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. neratinib is an oral pan-HER inhibitor that binds covalently to the kinase site, providing irreversible binding. Phase 3 data showed that the combination of neratinib plus capecitabine improved progression-free survival vs lapatinib plus capecitabine. The duration of response was longer among patients in the neratinib arm. neratinib plus capecitabine was also active against brain metastases associated with refractory, HER2-positive breast cancer, and this combination is listed in guidelines from the National Comprehensive Cancer Network for this indication. When combined with fulvestrant, neratinib demonstrated efficacy in patients with HER2-positive breast cancer, regardless of their hormone receptor status. Ongoing trials are evaluating the ability of neratinib to treat brain metastases, as well as the efficacy and safety of the triplet combination of neratinib, fulvestrant, and trastuzumab in this setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/33843838/"}
{"doc_id": "a33444511331956df6350a73604e4fa2", "sentence": "This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis .", "spans": [{"span_id": 0, "text": "adalimumab", "start": 133, "end": 143, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "methotrexate", "start": 148, "end": 160, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "adalimumab", "start": 166, "end": 176, "token_start": 23, "token_end": 24}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial. The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. ### methods This is an investigator-initiated , multicenter randomized controlled trial ( RCT ) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis . The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. ### discussion OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. ### Trial Registration NTR4499 . Registered on 7 April 2014.", "source": "https://pubmed.ncbi.nlm.nih.gov/28148280/"}
{"doc_id": "fb3968457142d3e200753ba423dd76e6", "sentence": "These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 66, "end": 75, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "irinotecan", "start": 149, "end": 159, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08-11.7 muM; SN-38 range 3.6-256 nM). lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas .", "source": "https://pubmed.ncbi.nlm.nih.gov/19536776/"}
{"doc_id": "9c6dd86cf42be0dc6db7778db1fcd651", "sentence": "In order to investigate the effects of a realistic pharmaceutical mixture on an ecosystem , a study utilizing 15 of 12,000 L aquatic microcosms treated with eight common pharmaceuticals ( atorvastatin , acetaminophen , caffeine , sulfamethoxazole , carbamazepine , levofloxacin , sertraline , and trimethoprim ) at total ( summed ) molar concentrations of 0 , 0.044 , 0.608 , 2.664 , and 24.538 micromol/L ( n = 3 ) was conducted .", "spans": [{"span_id": 0, "text": "atorvastatin", "start": 188, "end": 200, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "sulfamethoxazole", "start": 230, "end": 246, "token_start": 36, "token_end": 37}, {"span_id": 2, "text": "carbamazepine", "start": 249, "end": 262, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "levofloxacin", "start": 265, "end": 277, "token_start": 40, "token_end": 41}, {"span_id": 4, "text": "sertraline", "start": 280, "end": 290, "token_start": 42, "token_end": 43}, {"span_id": 5, "text": "trimethoprim", "start": 297, "end": 309, "token_start": 45, "token_end": 46}], "rels": [], "paragraph": "Microcosm evaluation of the effects of an eight pharmaceutical mixture to the aquatic macrophytes Lemna gibba and Myriophyllum sibiricum. Pharmaceuticals have been detected in surface waters of the US and Europe, originating largely from two sources, sewage effluent and agricultural runoff. These compounds often occur as mixtures leading to potential combined effects. In order to investigate the effects of a realistic pharmaceutical mixture on an ecosystem , a study utilizing 15 of 12,000 L aquatic microcosms treated with eight common pharmaceuticals ( atorvastatin , acetaminophen , caffeine , sulfamethoxazole , carbamazepine , levofloxacin , sertraline , and trimethoprim ) at total ( summed ) molar concentrations of 0 , 0.044 , 0.608 , 2.664 , and 24.538 micromol/L ( n = 3 ) was conducted . Phytotoxicity was assessed on a variety of somatic and pigment endpoints in rooted (Myriophyllum sibiricum) and floating (Lemna gibba) macrophytes over a 35-day period. EC10, EC25 and EC50 values were calculated for each endpoint exhibiting a concentration-dependent response. Generally, M. sibiricum and L. gibba displayed similar sensitivity to the pharmaceutical mixture, with phytotoxic injury evident in both species, which was concentration dependent. Through single compound 7-day daily static renewal toxicity tests with L. gibba, the sulfonamide antibiotic sulfamethoxazole, the fluoroquinolone antibiotic levofloxacin and the blood lipid regulator atorvastatin were found to be the only compounds to elicit phytotoxic effects in the concentration range utilized (0-1000 microg/L). atorvastatin concentration was highly correlated to decreased pigment content in L. gibba, likely inhibiting the known target enzyme HMGR, the rate-limiting enzyme in isoprenoid biosynthesis. Hazard quotients were calculated for both microcosm and laboratory studies; the highest HQ values were 0.235 (L. gibba) and 0.051 (L. gibba), which are below the threshold value of 1 for chronic risks. The microcosm data suggest that at an ecological effect size of >20%, biologically significant risks are low for L. gibba and M. sibiricum exposed to similar mixtures of pharmaceutical compounds. For M. sibiricum and L. gibba, respective minimum differences of 5 and 1%, were detectable, however, these effect sizes are not considered ecologically significant.", "source": "https://pubmed.ncbi.nlm.nih.gov/15451605/"}
{"doc_id": "025b8825ec9c2ac2b1b6c82763b21d3d", "sentence": "The enhancement characteristics in different portions of the liver during dynamic sequential bolus computed tomography ( CT ) with iodinated contrast material ( DSBCT ) were prospectively evaluated in 75 patients by using iothalamate meglumine , iopamidol , and iohexol ( 25 patients received each agent ) .", "spans": [{"span_id": 0, "text": "meglumine", "start": 234, "end": 243, "token_start": 34, "token_end": 35}, {"span_id": 1, "text": "iopamidol", "start": 246, "end": 255, "token_start": 36, "token_end": 37}, {"span_id": 2, "text": "iohexol", "start": 262, "end": 269, "token_start": 39, "token_end": 40}], "rels": [], "paragraph": "Hepatic dynamic sequential CT: section enhancement profiles with a bolus of ionic and nonionic contrast agents.  The enhancement characteristics in different portions of the liver during dynamic sequential bolus computed tomography ( CT ) with iodinated contrast material ( DSBCT ) were prospectively evaluated in 75 patients by using iothalamate meglumine , iopamidol , and iohexol ( 25 patients received each agent ) . After baseline noncontrast CT was performed, DSBCT was performed with a 180-mL intravenous bolus administered at 2 mL/sec. Scanning was started 25 seconds after the bolus was initiated, by using a 3-second scan time and rapid cephalocaudal table incrementation, yielding contiguous 8-mm-thick sections at a rate of nine sections per minute. On postcontrast images, peak enhancement was 115% for iopamidol and 117% for iohexol, both of which were superior to iothalamate meglumine at 95% (P less than .05). After peaking, enhancement then decreased for all three contrast agents, although the decline was more precipitous for iothalamate meglumine. Enhancement on the more caudal sections with both iopamidol and iohexol was superior to that with iothalamate meglumine (P less than .05). The data suggest that the enhancement characteristics for the two nonionic agents may be more optimal for detection of focal hepatic lesions than the ionic agent.", "source": "https://pubmed.ncbi.nlm.nih.gov/1987614/"}
{"doc_id": "0576c71d7dcc9e0dea83264897cdb410", "sentence": "Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 170, "end": 179, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "vincristine", "start": 196, "end": 207, "token_start": 34, "token_end": 35}, {"span_id": 2, "text": "bleomycin", "start": 233, "end": 242, "token_start": 42, "token_end": 43}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer. ### Patients And Methods Women with previously untreated bulky ( primary tumor > /= 4 cm ) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2 ) and vincristine 1 mg/m(2 ) for 1 day and bleomycin 25 mg/m(2 ) for 3 days for three cycles followed by radical hysterectomy ( NAC arm ) or receive primary pelvic radiotherapy only ( R/T arm ) . The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative. ### results Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. ### conclusion NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.", "source": "https://pubmed.ncbi.nlm.nih.gov/10764435/"}
{"doc_id": "11606721daca6e4dbd9d993400db75bc", "sentence": "The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment .", "spans": [{"span_id": 0, "text": "bupropion", "start": 75, "end": 84, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "nicotine", "start": 116, "end": 124, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo.  The purpose of this study was to evaluate the efficacy of long-term use of bupropion sustained release ( SR ) , the nicotine patch , and the combination of these 2 treatments in patients who initially failed treatment . ### methods This was a post hoc analysis of a multicenter, double-blind, randomized, placebo-controlled clinical trial in 893 smokers. Patients were randomly assigned to 9 weeks of treatment with placebo (n = 160), bupropion SR (n = 244), nicotine patch (n = 244), or a combination of nicotine patch and bupropion SR (n = 245). The study was originally designed with a follow-up period of 52 weeks. In this analysis, short-term success was defined as smoking cessation after 14 or 21 days of therapy and long-term success was defined as smoking cessation after >21 days of therapy. Patients who did not achieve short-term success were evaluated for long-term success at week 9 (end of treatment), 6 months, and 1 year after the start of the study. ### results The mean age of the smokers was 44 years. The majority (93%) of patients were white, and 52% were female. The study subjects smoked an average of 27 cigarettes per day. Among the 467 patients who initially failed treatment in the first 3 weeks, treatment with bupropion SR alone and in combination with the nicotine patch produced significant increases in successful smoking cessation rates from weeks 4 to 9 (19% bupropion SR or combination, 7% nicotine patch, 7% placebo), at month 6 (11% bupropion SR, 13% combination, 2% nicotine patch, 3% placebo), and at month 12 (10% bupropion SR, 7% combination, 2% nicotine patch, 1% placebo) (P < 0.05 for bupropion SR and combination vs nicotine patch or placebo). ### conclusion Among patients who initially failed treatment, continued therapy with bupropion SR, either alone or in combination with the nicotine patch, resulted in significantly higher short- and long-term smoking cessation rates than treatment with the nicotine patch alone or placebo.", "source": "https://pubmed.ncbi.nlm.nih.gov/11394732/"}
{"doc_id": "b3091e36da5861d17b4bb73004c91646", "sentence": "Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 112, "end": 124, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "doxycycline", "start": 129, "end": 140, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial. azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline. ### methods From January 2007 to July 2011, English-speaking males \u226516 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or \u22655 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks. ### results Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%-85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%-82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred. ### conclusions Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline . Mycoplasma genitalium treatment failure was extremely common. Clinical Trials Registration.NCT00358462.", "source": "https://pubmed.ncbi.nlm.nih.gov/23223595/"}
{"doc_id": "e50ad95ee57016b82dec8134f6f4b203", "sentence": "In the main study submitted for this application , a 2.4-month longer median overall survival time and a 30 % lower risk for death were observed for cabazitaxel , compared with mitoxantrone .", "spans": [{"span_id": 0, "text": "cabazitaxel", "start": 149, "end": 160, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "mitoxantrone", "start": 177, "end": 189, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "The European Medicines Agency review of cabazitaxel (Jevtana\u00ae) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use. On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana\u00ae (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana\u00ae is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application , a 2.4-month longer median overall survival time and a 30 % lower risk for death were observed for cabazitaxel , compared with mitoxantrone . The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).", "source": "https://pubmed.ncbi.nlm.nih.gov/22477727/"}
{"doc_id": "6437f27dae4e4543db96a39e19b72d17", "sentence": "Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 .", "spans": [{"span_id": 0, "text": "vincristine", "start": 27, "end": 38, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "actinomycin D", "start": 41, "end": 54, "token_start": 5, "token_end": 7}, {"span_id": 2, "text": "cyclophosphamide", "start": 62, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "etoposide", "start": 101, "end": 110, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "cisplatin", "start": 116, "end": 125, "token_start": 18, "token_end": 19}], "rels": [{"class": "NEG", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "[Intrascrotal rhabdomyosarcoma in adult: a case report]. The patient was a 34-year-old man presenting with the right intra-scrotal painless mass. With a diagnosis of right intrascrotal tumor, the patient underwent right high orchiectomy. The pathological diagnosis of pleomorphic rhabdomyosarcoma arisen from the right spermatic cord was made. Computed tomography revealed a single metastasis in the para-vena cava lymph node. Systemic chemotherapy with vincristine , actinomycin D , plus cyclophosphamide ( VAC therapy ) , and etoposide plus cisplatin ( EP therapy ) were made according to Intergroup Rhabdomyosarcoma Study (IRS)-IV Regimen 45 . But the chemotherapy was ineffective and a retoroperitoneal lymphadenectomy (RPLND) was therefore performed. After 3 months following RPLND, the tumor relapsed in a pelvic lymph node involved in right ureter and ileocaecal valve. Resection of the tumor with ileocaecum was performed and then intraoperative radiotherapy (15 Gy) against the tumor bed was performed to ensure the curative effects. After his recovery, he received a total of 6 courses of systemic chemotherapy consisting of vincristin, ifosphamide, etoposide (IRS-IV Regimen 47). The patient was rigorously followed up for 42 months after the final chemotherapy, with no tumor recurrence.", "source": "https://pubmed.ncbi.nlm.nih.gov/19514277/"}
{"doc_id": "83a0b0353d77ad8e33b43deac6ea7ec0", "sentence": "He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission .", "spans": [{"span_id": 0, "text": "rituximab", "start": 42, "end": 51, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cyclophosphamide", "start": 57, "end": 73, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "vincristine", "start": 76, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "doxorubicin", "start": 90, "end": 101, "token_start": 14, "token_end": 15}, {"span_id": 4, "text": "methotrexate/ifosfamide", "start": 104, "end": 127, "token_start": 16, "token_end": 17}, {"span_id": 5, "text": "etoposide", "start": 130, "end": 139, "token_start": 18, "token_end": 19}, {"span_id": 6, "text": "cytarabine", "start": 156, "end": 166, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": false}], "paragraph": "Non-Hodgkin Lymphoma in a Kidney Transplant Patient: A Case Report. Post-transplant lymphoproliferative disorders are a possible complication of kidney transplant due to chronic immunosuppressive therapy, and they can elevate the mortality rate. Furthermore, the type of clinical appearance has a wide range. We describe a case of a 38-year-old male recipient who developed post-transplant lymphoproliferative disorders and received successful treatment. The recipient had received a kidney with 1 HLA-B and 1 HLA-DR match, and the deceased donor allotransplant was performed successfully on December 9, 2012. The cause of kidney failure was membranoproliferative-glomerulonephritis proved by biopsy results. The induction therapy was antithymocyte globulin; the basic immunosuppressive therapy consisted of tacrolimus, steroid, and mycophenolate mofetil. After 2 months the patient had elevated serum creatinine level, and biopsy results revealed cellular rejection (Banff grade I). We applied steroid bolus therapy. After that the graft worked properly for 5 years, and the patient had no symptoms or complaints; then he had right lower abdomen pain. After urgent procedures (laboratory diagnostics, abdominal ultrasonography, computed tomography), we operated on the patient in a short time, and after a few weeks the fluorescence in situ hybridization confirmed the translocation of region C-myc; the diagnosis was diffuse large B-cell lymphoma. With the assistance of hematologists, the patient received adequate therapy. He was asymptomatic half a year after the rituximab with cyclophosphamide , vincristine , doxorubicin , methotrexate/ifosfamide , etoposide , and high-dose cytarabine protocol therapy ; the lymphoma is in remission . Our case is worth presenting because immunosuppressive drugs can modify the clinical picture, complicating the diagnosis and delaying treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/31101215/"}
{"doc_id": "3cd851564f73006f34a5529afd713a77", "sentence": "The RC0.1 and RC1 cells have high cross-resistance to CPT derivatives including SN-38 and topotecan , but are not cross-resistant to the non-top1 inhibitors etoposide , doxorubicin , and vincristine .", "spans": [{"span_id": 0, "text": "topotecan", "start": 90, "end": 99, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "etoposide", "start": 157, "end": 166, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "doxorubicin", "start": 169, "end": 180, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "vincristine", "start": 187, "end": 198, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Characterization of a novel topoisomerase I mutation from a camptothecin-resistant human prostate cancer cell line. In this study, we characterized the structure and function of topoisomerase I (top1) protein in the camptothecin (CPT)-resistant prostate cancer cell lines, DU-145/RC0.1 and DU-145/RC1 (RC0.1 and RC1, respectively). Both of the cell lines were previously selected by continuous exposure to 9-nitro-CPT. The RC0.1 and RC1 cells have high cross-resistance to CPT derivatives including SN-38 and topotecan , but are not cross-resistant to the non-top1 inhibitors etoposide , doxorubicin , and vincristine . Although the top1 protein levels were not decreased in the resistant cells compared with the parental cells, CPT-induced DNA cleavage was markedly reduced in the RC0.1 and RC1 nuclear extracts. The resistant-cell-line nuclear extracts also demonstrated top1 catalytic activity and resistance to CPT, in in vitro assays. Reverse transcription-PCR products from the resistant cell lines were sequenced, and revealed a point mutation resulting in a R364H mutation in the top1 of both RC0.1 and RC1. No wild-type top1 RNA or genomic DNA was detected in the resistant cell lines. Using a purified recombinant R364H top1, we found that the R364H mutant top1 was CPT resistant and fully active. In the published top1 crystal structure, the R364H mutation is close to the catalytic tyrosine and other well-known mutations leading to CPT resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/11280753/"}
{"doc_id": "36a73344b5f63d64d0393e6860b5f08a", "sentence": "To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood .", "spans": [{"span_id": 0, "text": "nifuratel", "start": 20, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "amoxicillin", "start": 32, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "bismuth", "start": 50, "end": 57, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Nifuratel-containing initial anti-Helicobacter pylori triple therapy in children. Proton pump inhibitor-containing triple therapy with amoxicillin and metronidazole is recommended as initial treatment of Helicobacter pylori in childhood. However, eradication rate with this \"classic\" regimen is relatively low in Russia. ### aim To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood . ### Materials And Methods Pediatric outpatients with H. pylori-associated chronic gastritis who underwent endoscopy for dyspeptic symptoms received the combination of bismuth subcitrate (8 mg/kg/day, q.d.s.), nifuratel (30 mg/kg/day, q.d.s.), and amoxicillin (50 mg/kg/day, q.d.s.) for 10 days. H. pylori status was determined before and after the treatment (in 4-6 weeks) by modified Giemsa staining. ### results Seventy-three children (48 boys, 25 girls, age range 9-14) were entered. H. pylori was eradicated in 63 patients (86%; 95% confidence interval: 76.6-93.2; intention-to-treat and per protocol). There were no serious adverse reactions and were no withdrawals due to any side-effects. All of side-effects were self-limiting (dark stools, urine discoloration, blackening of the tongue, and others). ### conclusions The combination of nifuratel, bismuth subcitrate, and amoxicillin was an effective and tolerable regimen for H. pylori eradication.", "source": "https://pubmed.ncbi.nlm.nih.gov/17309749/"}
{"doc_id": "33140a176ef4e6f6be4235f20a0f447d", "sentence": "The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission .", "spans": [{"span_id": 0, "text": "anthracycline", "start": 42, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 58, "end": 67, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "behenoyl cytarabine", "start": 74, "end": 93, "token_start": 13, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2). We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission . At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/15929101/"}
{"doc_id": "200b0264779d54035ddc6c2f1eaaf23e", "sentence": "The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration .", "spans": [{"span_id": 0, "text": "clopidogrel", "start": 46, "end": 57, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "aspirin", "start": 74, "end": 81, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "ASA", "start": 24, "end": 27, "token_start": 4, "token_end": 5}], "rels": [{"class": "NEG", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. We performed a meta-analysis of data from randomized trials to estimate the risk of all-cause mortality and bleeding (and especially gastrointestinal [GI] bleeding) in patients treated with low doses of acetylsalicylic acid (ASA) (75-325 mg/d), alone or in combination with other medications. ### methods We searched 10 electronic databases (until October 2010) and collected data on adverse events in randomized controlled studies that evaluated low doses of ASA, alone (35 trials) or in combination with anticoagulants (18 trials), clopidogrel (5 trials), or proton pump inhibitors (PPIs; 3 trials). We analyzed data using random-effects meta-analysis and meta-regression, applying Peto's odds ratio (OR) for adverse events. ### results Low doses of ASA alone decreased the risk for all-cause mortality (relative risk, 0.93, 95% confidence interval [CI], 0.87-0.99), largely because of effects in secondary prevention populations. The risk of major GI bleeding increased with low doses of ASA alone (OR, 1.55; 95% CI, 1.27-1.90), compared with inert control reagents. The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration . Importantly, PPI use reduced the risk for major GI bleeding in patients given low doses of ASA (OR, 0.34; 95% CI, 0.21-0.57). ### conclusions In a meta-analysis, low doses of ASA increased the risk for GI bleeding; risk increased with accompanying use of clopidogrel and anticoagulant therapies, but decreased in patients who took PPIs.", "source": "https://pubmed.ncbi.nlm.nih.gov/21699808/"}
{"doc_id": "00fed36f9da425f2e99920574f260728", "sentence": "Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug .", "spans": [{"span_id": 0, "text": "Raloxifene", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "letrozole", "start": 190, "end": 199, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combined Raloxifene and Letrozole for Breast Cancer Patients.  Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug . However, the cytotoxic effect of their combination on human breast cancer (MCF-7) and human embryonic kidney (HEK) cell lines is not known. MCF-7 and HEK cell lines were treated with different graded doses of letrozole, raloxifene and their combination, then incubated for 24-48\u00a0h. MTT assay was performed to check the cytotoxicity of the drugs. The study indicates that the combination of letrozole and raloxifene possess additive effect in terms of cytotoxicity of cancer cell lines (MCF-7) and negligible effects in normal cell lines (HEK). Our study indicates that the addition of raloxifene doesn't interfere with anticancer efficacy of letrozole rather the combination acted additively for the treatment of breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/29229198/"}
{"doc_id": "3a94029adb94f341238c07809b06653f", "sentence": "In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate .", "spans": [{"span_id": 0, "text": "flutamide", "start": 60, "end": 69, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "leuprolide acetate", "start": 73, "end": 91, "token_start": 13, "token_end": 15}, {"span_id": 2, "text": "leuprolide acetate", "start": 276, "end": 294, "token_start": 40, "token_end": 42}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate . In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. ### methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. ### results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). flutamide was not associated with enhanced benefit in patients with minimal disease. ### conclusions The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/9761805/"}
{"doc_id": "2840ea50d46d8f2b1fa1546b87a622f3", "sentence": "Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities .", "spans": [{"span_id": 0, "text": "desogestrel", "start": 26, "end": 37, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "levonorgestrel", "start": 41, "end": 55, "token_start": 4, "token_end": 5}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities . We examined the effects of mono and polyphasic oral contraceptives containing desogestrel or levonorgestrel on serum lipoproteins, sex hormone binding globulin and post-heparin plasma lipase activities. ### design The women took either desogestrel or levonorgestrel during the first menstrual cycle on days 15-28. They then received monophasic ethinyloestradiol plus either desogestrel or levonorgestrel for three cycles. After this, the women took sequential pills containing ethinyloestradiol plus either desogestrel or levonorgestrel for the three following cycles. Fasting blood samples were drawn pretreatment and at the end of each treatment. ### patients The study group consisted of 30 apparently healthy women, aged 18-35. They were randomly divided into desogestrel and levonorgestrel groups, each consisting of 15 women. ### measurements Cholesterol, triglyceride and phospholipids were determined in whole serum and in all lipoprotein fractions (following isolation of lipoproteins by ultracentrifugation). Plasma apolipoprotein A-I concentration, post-heparin plasma lipase activities and serum sex hormone binding globulin were also measured. ### results desogestrel (150 micrograms/day) did not change serum total triglyceride concentration, whereas levonorgestrel (150 micrograms/day) decreased it. Except for monophasic ethinyloestradiol plus levonorgestrel, the oestrogen-containing combinations increased serum triglyceride level. Low density lipoprotein (LDL) cholesterol remained stable with all treatments, but the cholesterol/triglyceride ratio of LDL decreased during all combinations with ethinyloestradiol. levonorgestrel reduced total high density lipoprotein (HDL) cholesterol and both progestins reduced HDL2 cholesterol concentration. Addition of ethinyloestradiol reversed this change in the desogestrel but not in the levonorgestrel group. The polyphasic ethinyloestradiol plus levonorgestrel combination did not change total HDL cholesterol. Hepatic lipase was activated with either progestin when administered alone but its activity was suppressed below the baseline level when ethinyloestradiol was added. Conversely, both progestins suppressed sex hormone binding globulin levels, but addition of ethinyloestradiol caused marked increases above baseline. These increases were greater in women taking desogestrel than in those taking levonorgestrel. No treatment affected lipoprotein lipase activity significantly. ### conclusions Monophasic or polyphasic combinations of ethinyloestradiol and desogestrel do not have deleterious effects on serum lipoproteins. If levonorgestrel is used as the progestin component, polyphasic ethinyloestradiol plus levonorgestrel appears more favourable than monophasic ethinyloestradiol plus levonorgestrel.", "source": "https://pubmed.ncbi.nlm.nih.gov/1533186/"}
{"doc_id": "40c71f770fe0068228d83a69ec8659db", "sentence": "Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori , and susceptibility to six antibiotics ( clarithromycin , amoxicillin , gentamicin , furazolidone , metronidazole , and levofloxacin ) was tested from 2012 - 2014 .", "spans": [{"span_id": 0, "text": "clarithromycin", "start": 174, "end": 188, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "amoxicillin", "start": 191, "end": 202, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "gentamicin", "start": 205, "end": 215, "token_start": 29, "token_end": 30}, {"span_id": 3, "text": "furazolidone", "start": 218, "end": 230, "token_start": 31, "token_end": 32}, {"span_id": 4, "text": "metronidazole", "start": 233, "end": 246, "token_start": 33, "token_end": 34}, {"span_id": 5, "text": "levofloxacin", "start": 253, "end": 265, "token_start": 36, "token_end": 37}], "rels": [], "paragraph": "Antibiotics resistance of Helicobacter pylori in children with upper gastrointestinal symptoms in Hangzhou, China. The decreasing eradication rate of Helicobacter pylori is mainly because of the progressive increase in its resistance to antibiotics. Studies on antimicrobial susceptibility of H.\u00a0pylori in children are limited. This study aimed to investigate the resistance rates and patterns of H.\u00a0pylori strains isolated from children. ### Materials And Methods Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori , and susceptibility to six antibiotics ( clarithromycin , amoxicillin , gentamicin , furazolidone , metronidazole , and levofloxacin ) was tested from 2012 - 2014 . ### results A total of 545 H.\u00a0pylori strains were isolated from 1390 children recruited. The total resistance rates of H.\u00a0pylori to clarithromycin, metronidazole, and levofloxacin were 20.6%, 68.8%, and 9.0%, respectively. No resistance to amoxicillin, gentamicin, and furazolidone was detected. 56.1% strains were single resistance, 19.6% were resistant to more than one antibiotic, 16.7% for double resistance, and 2.9% for triple resistance in 413 strains against any antibiotic. And the H.\u00a0pylori resistance rate increased significantly from 2012-2014. There was no significant difference in the resistance rates to clarithromycin, metronidazole, and levofloxacin between different gender, age groups, and patients with peptic ulcer diseases or nonulcer diseases. ### conclusions Antibiotic resistance was indicated in H.\u00a0pylori strains isolated from children in Hangzhou, and it increased significantly during the 3\u00a0years. Our data strongly support current guidelines, which recommend antibiotic susceptibility tests prior to eradication therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/29528162/"}
{"doc_id": "32b6dbf07fe994efe427a84515f594f4", "sentence": "Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively .", "spans": [{"span_id": 0, "text": "guaifenesin", "start": 18, "end": 29, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "diphenhydramine", "start": 32, "end": 47, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "chlorpheniramine", "start": 54, "end": 70, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine. Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively . The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.", "source": "https://pubmed.ncbi.nlm.nih.gov/10414664/"}
{"doc_id": "b0f79f8deba457cab659d10899ce9bf4", "sentence": "The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America .", "spans": [{"span_id": 0, "text": "vincristine", "start": 59, "end": 70, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "actinomycin D", "start": 73, "end": 86, "token_start": 10, "token_end": 12}, {"span_id": 2, "text": "cyclophosphamide", "start": 89, "end": 105, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "doxorubicin", "start": 110, "end": 121, "token_start": 15, "token_end": 16}, {"span_id": 4, "text": "vincristine", "start": 144, "end": 155, "token_start": 22, "token_end": 23}, {"span_id": 5, "text": "doxorubicin", "start": 158, "end": 169, "token_start": 24, "token_end": 25}, {"span_id": 6, "text": "cyclophosphamide", "start": 172, "end": 188, "token_start": 26, "token_end": 27}, {"span_id": 7, "text": "ifosfamide", "start": 191, "end": 201, "token_start": 28, "token_end": 29}, {"span_id": 8, "text": "etoposide", "start": 206, "end": 215, "token_start": 30, "token_end": 31}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [4, 5, 6, 7, 8], "is_context_needed": true}], "paragraph": "[Ewing sarcoma]. Ewing sarcoma is the second most frequent primary bone cancer affecting children or young adults. Advances in molecular biology have revealed common chromosomal translocations such as EWS-FLI 1 among Ewing sarcoma and related diseases such as primitive neuroectodermal tumor (PNET), so these are considered as Ewing sarcoma family tumor (ESFT). Although fewer than 10% of patients with ESFT survived before establishment of modern multiagent chemotherapy, the multimodal therapeutic regimens including combination chemotherapy, radiotherapy, and surgery can cure 60% of patients with localized disease, due to the collaborative research in European-American or the international trials. The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America . Meanwhile, those with metastatic disease have a much worse outcome with an approximately 10-30% 5-year event-free survival rate. New American-European collaborative trials such as EURO-E.W.I.N.G.99 are in progress for further improvement of the cure rate in localized and metastatic ESFT. In Japan, Japan Ewing Sarcoma Study Group (JESS) phase II clinical trial for localized ESFT, and some clinical trials including new drugs are ongoing and waiting for results.", "source": "https://pubmed.ncbi.nlm.nih.gov/17301523/"}
{"doc_id": "c3cb386de34dbea5637e93d5f9c2b7bf", "sentence": "Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies .", "spans": [{"span_id": 0, "text": "Ceftriaxone", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gentamicin", "start": 17, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "ceftriaxone", "start": 31, "end": 42, "token_start": 4, "token_end": 5}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies . This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis.", "source": "https://pubmed.ncbi.nlm.nih.gov/20198402/"}
{"doc_id": "711c51bfb251156a64c6d58f1d2d1839", "sentence": "Combined therapy : what does acamprosate and naltrexone combination tell us ?", "spans": [{"span_id": 0, "text": "acamprosate", "start": 29, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "naltrexone", "start": 45, "end": 55, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combined therapy : what does acamprosate and naltrexone combination tell us ? Relapse prevention treatment with both acamprosate and naltrexone has been shown to be efficacious in the treatment of alcoholism. Whereas both compounds act pharmacologically differently, there is up to now only limited evidence as to whether combined treatment is efficacious and pharmacologically safe. It remains to be answered whether data justify the combination of both drugs in clinical practice. ### methods Review of the three pre-clinical and four clinical studies that have been published to date on either combined tolerability or efficacy. ### results Data available up to now show no occurrence of severe adverse events during combined treatment. Diarrhoea and nausea were shown to be the most significant side-effects. Whereas pre-clinical studies regarding efficacy of combined treatment are not yet conclusive, clinical data show the superiority of combined treatment compared with both placebo and acamprosate monotherapy. The synergistic effect of combined treatment remained after 12 weeks of drug-free follow-up. ### conclusions The combination of acamprosate with naltrexone in a clinical sample seems to be efficacious and safe. Numerous alcohol dependent patients could benefit, particularly those that responded insufficiently on monotherapeutic treatment with either acamprosate or naltrexone.", "source": "https://pubmed.ncbi.nlm.nih.gov/15456690/"}
{"doc_id": "a0c0e90584efb59d8860e1b6f8ecfe7b", "sentence": "Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) .", "spans": [{"span_id": 0, "text": "atovaquone", "start": 83, "end": 93, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "pyrimethamine", "start": 98, "end": 111, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM). Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) . Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.", "source": "https://pubmed.ncbi.nlm.nih.gov/33374980/"}
{"doc_id": "78c18c2e1184f5d132f93846c9e3f49a", "sentence": "TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia .", "spans": [{"span_id": 0, "text": "tenofovir", "start": 36, "end": 45, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "emtricitabine", "start": 48, "end": 61, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "raltegravir", "start": 66, "end": 77, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "TVR", "start": 0, "end": 3, "token_start": 0, "token_end": 1}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-\u03b1 and ribavirin therapy. In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-\u03b1 (PegIFN-\u03b1) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-\u03b1 and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-\u03b12b and RBV for the first 12 weeks, followed by the continuation of PegIFN-\u03b12b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia . Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/24477330/"}
{"doc_id": "9a5d4c5cdf2df42bbc1f3e178e565124", "sentence": "Almost all the isolates were resistant to Ampicillin and Tobramycin ( 99.3 % each ) .", "spans": [{"span_id": 0, "text": "Ampicillin", "start": 42, "end": 52, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Tobramycin", "start": 57, "end": 67, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Bacteriophage typing and antibiotic sensitivity pattern of Staphylococcus aureus from clinical specimen in and around Solapur (South Maharashtra). Two hundred and eighty nine strains of Staphylococcus aureus isolated from pus and wound swabs (149), blood (36), urine (28), sputum (14), stool (12), throat swab (9) and CSF (4) were subjected for bacteriophage typing and antibiotic susceptibility pattern. 113 (39.11%) strains were typable. Among the typable strains, 16 (5.53%) belonged to phage group I, 33 (11.41%) strains belonged to phages group II, 38 (13.14%) belonged to phage group III, 26 (8.99%) strains belonged to the phages which have not been allocated to any group (Miscellaneous group) 176 (60.89%) strains were untypable. Only one (0.34%) strain was sensitive to all the drugs tested. Almost all the isolates were resistant to Ampicillin and Tobramycin ( 99.3 % each ) . 286 (98.96%) strains were found to be resistant to Penicillin and erythromycin followed by kanamycin 272 (94.11%) and gentamicin 263 (91.3%). 113 (39.1%) strains were Methicillin resistant Staphylococcus aureus (MRSA). All MRSA strains were resistant to all drugs tested except vancomycin. Resistance to most of the commonly used antimicrobial agents indicates a need to replace these drugs with other agents and maintenance of surveillance to detect changing patterns of resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/15239300/"}
{"doc_id": "874b4041ed7349e2cad9ebb2f7c2feb5", "sentence": "Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 21, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxycycline", "start": 56, "end": 67, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction:  a comparative clinical and spectroscopic pilot study. Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. ### methods Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. ### results Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal . Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment. ### conclusions The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes.", "source": "https://pubmed.ncbi.nlm.nih.gov/22668581/"}
{"doc_id": "1d48843a67e7504029372f6725caf9ed", "sentence": "Pharmacy costs of cefazolin used as prophylaxis were more than twice the cost for cephapirin .", "spans": [{"span_id": 0, "text": "cefazolin", "start": 18, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "cephapirin", "start": 82, "end": 92, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Use, misuse, and cost of parenteral cephalosporins at a county hospital. We reviewed total usage of parenteral cephalosporins at a county hospital during 1978 with regard to appropriateness, pattern of use, and cost. In addition, we determined the impact of replacing cephalothin with cephapirin in the hospital formulary. During the 12-month study 366 patients received 409 courses of parenteral cephalosporins: 167 received cefazolin, 160 received cephapirin, and 35 received a combination of cefazolin and cephapirin. The surgical service prescribed 87% of the cephapirin and 92% of the cefazolin. Parenteral cephalosporins were used 62% of the time for prophylaxis and 38% of the time for therapy. Usage was judged inappropriate in 47% of all courses based on our criteria; 25% of the therapeutic courses were judged inappropriate, compared to 60% of the prophylactic courses. Pharmacy costs of cefazolin used as prophylaxis were more than twice the cost for cephapirin . Cost of a mean therapeutic course for cefazolin was 43% higher than for cephapirin. Antibiotic audits and continued education combined with judicial substitution of therapeutic equivalents should limit the inappropriate use and expense of parenteral cephalosporins for large as well as small hospitals.", "source": "https://pubmed.ncbi.nlm.nih.gov/7444511/"}
{"doc_id": "b188617afabc590d2a58574c2988de5e", "sentence": "PP-6 isolated from Tibetan Plateau could ferment raffinose , lactose , sorbitol , melibiose and sucrose , and LS-5 could ferment cottonseed sugar , laetrile , rhamnose , lactose , sorbitol , xylose , arabinose , melibiose and sucrose , but the same species of commercial strains could not use these sugars .", "spans": [{"span_id": 0, "text": "lactose", "start": 61, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "lactose", "start": 170, "end": 177, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "xylose", "start": 191, "end": 197, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "[Effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans]. In order to detect the effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans. ### methods We used 3 isolated lactic acid bacteria with better growth at low temperatures of 10 and 15 degrees C at ensiling of Elymus nutans. Subsequently, effects of the selected lactic acid bacteria on fermentation profiles of Elymus nutans silages stored at 15 and 25 degrees C were evaluated by using the same species of commercial inoculants as the control. ### results PP-6 isolated from Tibetan Plateau could ferment raffinose , lactose , sorbitol , melibiose and sucrose , and LS-5 could ferment cottonseed sugar , laetrile , rhamnose , lactose , sorbitol , xylose , arabinose , melibiose and sucrose , but the same species of commercial strains could not use these sugars . Inoculation of these three strains into Elymus nutans at 15 and 25 degrees C ensiled for 50 d, we found that LS-5 significantly reduced silage pH, propionic acid concentration and ratio of ammonia nitrogen/total nitrogen at 15 degrees C (P < 0.05), salvaged more water-soluble carbohydrate and crude protein; Application of LP-2 and PP-6 as a combined inoculant to Elymus nutans significantly improved lactic acid concentration (P < 0.05), resulting in a lower ratio of ammonia nitrogen/total nitrogen, saved more crude protein and significantly reduced neutral detergent fiber content (P < 0.05) as compared with the commercial strains. ### conclusion The three isolated strains can improve silage quality of Elymus nutans growing on the Qinghai-Tibetan Plateau at low temperature, but these strains have no obvious advantages at 25 degrees C in comparison with the commercial inoculants.", "source": "https://pubmed.ncbi.nlm.nih.gov/26939457/"}
{"doc_id": "f7ab75242ec372a88c94d2f9359b2859", "sentence": "Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 31, "end": 40, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxycycline", "start": 43, "end": 54, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Targeting cellular metabolism using rapamycin and/or doxycycline enhances anti-tumour effects in human glioma cells. Glioma is the most common highly aggressive, primary adult brain tumour. Clinical data show that therapeutic approaches cannot reach the expectations in patients, thus gliomas are mainly incurable diseases. Tumour cells can adapt rapidly to alterations during therapeutic treatments related to their metabolic rewiring and profound heterogeneity in tissue environment. Renewed interests aim to develop effective treatments targeting angiogenesis, kinase activity and/or cellular metabolism. mTOR (mammalian target of rapamycin), whose hyper-activation is characteristic for many tumours, promotes metabolic alterations, macromolecule biosynthesis, cellular growth and survival. Unfortunately, mTOR inhibitors with their lower toxicity have not resulted in appreciable survival benefit. Analysing mTOR inhibitor sensitivity, other metabolism targeting treatments and their combinations could help to find potential agents and biomarkers for therapeutic development in glioma patients. ### methods In vitro proliferation assays, protein expression and metabolite concentration analyses were used to study the effects of mTOR inhibitors, other metabolic treatments and their combinations in glioma cell lines. Furthermore, mTOR activity and cellular metabolism related protein expression patterns were also investigated by immunohistochemistry in human biopsies. temozolomide and/or rapamycin treatments altered the expressions of enzymes related to lipid synthesis, glycolysis and mitochondrial functions as consequences of metabolic adaptation; therefore, other anti-metabolic drugs (chloroquine, etomoxir, doxycycline) were combined in vitro. ### results Our results suggest that co-targeting metabolic pathways had tumour cell dependent additive/synergistic effects related to mTOR and metabolic protein expression patterns cell line dependently. Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas . Additionally, our immunohistochemistry results suggest that metabolic and mTOR activity alterations are not related to the recent glioma classification, and these protein expression profiles show individual differences in patients' materials. ### conclusions Based on these, combinations of different new/old drugs targeting cellular metabolism could be promising to inhibit high adaptation capacity of tumour cells depending on their metabolic shifts. Relating to this, such a development of current therapy needs to find special biomarkers to characterise metabolic heterogeneity of gliomas.", "source": "https://pubmed.ncbi.nlm.nih.gov/30574020/"}
{"doc_id": "4ed783b2bf9c376b4f0e615621a6649a", "sentence": "Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful .", "spans": [{"span_id": 0, "text": "prednisolone", "start": 73, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "cyclophosphamide", "start": 130, "end": 146, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "vincristine", "start": 149, "end": 160, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "prednisone", "start": 178, "end": 188, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "methotrexate", "start": 205, "end": 217, "token_start": 31, "token_end": 32}, {"span_id": 5, "text": "psoralen-ultraviolet-A", "start": 22, "end": 44, "token_start": 4, "token_end": 5}, {"span_id": 6, "text": "procarbacine", "start": 163, "end": 175, "token_start": 25, "token_end": 26}, {"span_id": 7, "text": "citrovorum", "start": 230, "end": 240, "token_start": 34, "token_end": 35}], "rels": [{"class": "NEG", "spans": [0, 1, 2, 3, 4, 5, 6, 7], "is_context_needed": false}], "paragraph": "Cutaneous immunoblastic T-cell lymphoma. The case of a 69-year-old male patient with an unusual type of malignant lymphoma is presented. Clinically, it was at first characterized by follicular papules and erythematous patches, later, by the development of cutaneous tumors and enlarged lymph nodes, and by a severe, finally excruciating pruritus. Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful . The patient died of pneumonia 2.5 years after the onset of the first clinical symptoms. An immunoblastic infiltrate was observed histologically and electromicroscopically in the initial lesions of the skin. Therefore, the diagnosis of a cutaneous immunoblastic T-cell lymphoma was tentatively made at the beginning, which was later confirmed in numerous biopsies and laboratory investigations. Immunocytologically and enzymecytochemically, the infiltrating cells were shown to be immature T cells; in the lymph nodes, numerous immunoblasts and large S\u00e9zary cells was observed in the peripheral blood, though there were no very large S\u00e9zary cells or blast cells. In the autopsy, a systemic involvement with an atypical lymphoid infiltration was found in numerous internal organs. The special nature of this case justifies its classification as high-grade malignant lymphoma and its differentiation from normal cases of mycosis fungoides. In contrast, mycosis fungoides generally fulfils criteria typical of low-grade malignant lymphomas.", "source": "https://pubmed.ncbi.nlm.nih.gov/6984639/"}
{"doc_id": "5b2a3850c05cec3894d8fbf760db8885", "sentence": "This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1 , 2004 , through December 31 , 2014 .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 192, "end": 203, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "cetuximab", "start": 207, "end": 216, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer. Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT. ### objective To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC. ### Design Setting And Participants This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1 , 2004 , through December 31 , 2014 . Patients were stratified by tumor origin in the left vs right sides. ### interventions Treatment with SC or SC plus bevacizumab or cetuximab. ### Main Outcomes And Measures Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed. ### results A total of 11\u202f905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P\u2009<\u2009.001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P\u2009<\u2009.001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P\u2009<\u2009.001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n\u2009=\u2009668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P\u2009=\u2009.002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P\u2009<\u2009.001). ### Conclusions And Relevance Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/28975237/"}
{"doc_id": "1754d72a3f257d2ecd67f1aec7bdb7d3", "sentence": "We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population .", "spans": [{"span_id": 0, "text": "Vinorelbine", "start": 41, "end": 52, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "Gemcitabine", "start": 65, "end": 76, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial. High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population . ### methods Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on vinorelbine or gemcitabine according to the patient's preference. ### results A total of 126 cycles of vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on vinorelbine, 5 patients on gemcitabine; 12 patients (26%) had stable disease, 7 patients on vinorelbine, 5 patients on gemcitabine. Of 24 patients with progressive disease on vinorelbine, 3 patients (12.5%) responded to gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. ### conclusion This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/15949597/"}
{"doc_id": "097865bb7793218ba27867eeb0f08c14", "sentence": "Apoptosis in Hep2 cells treated with etoposide and colchicine .", "spans": [{"span_id": 0, "text": "etoposide", "start": 37, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "colchicine", "start": 51, "end": 61, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Apoptosis in Hep2 cells treated with etoposide and colchicine . When malignant cells undergo apoptosis, they exhibit many distinct patterns of behavior, with blebbing being one of the most spectacular and mysterious features. Despite huge advancements in our understanding of cell death, the mechanisms of apoptosis associated blebbing have not been elucidated. In order to verify the putative involvement of actin and tubulin in this process, Hep2 cells were treated with a combination of etoposide (10 microg/ml) and colchicine (0.2 microg/ml) for 24 h. Blebbing was analyzed using immunofluorescence staining of actin and tubulin, and the course of apoptosis was followed by time-lapse videomicroscopy, immunofluorescence detection of caspase-3 and cytokeratin fragment 18. The results indicate that microfilaments (actin) and not microtubules (tubulin) are involved in blebbing of Hep2 cells. Furthermore, despite the different mechanisms by which both chemicals act, their combined effects are not additive, but rather eliminate each other.", "source": "https://pubmed.ncbi.nlm.nih.gov/15225902/"}
{"doc_id": "c9c57db7e9477555da88ff7ea0940e62", "sentence": "The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 82, "end": 93, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "paclitaxel", "start": 105, "end": 115, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II study of carboplatin and weekly paclitaxel combination chemotherapy in advanced non-small cell lung cancer: a Kansai Clinical Oncology Group study.  The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) . Patients received paclitaxel at a dose of 70 mg/m(2) on days 1, 8, 15, and carboplatin with the target dose of area under the curve (AUC) of 6 on day 1 every 28 days. Forty-six patients were enrolled. A median of four cycles (range, 1-13) were administered. Complete response was observed in one patient (2.2%) and partial response in 23 patients (50%), yielding an overall intent-to-treat response rate of 52.2% (95% confidence interval, 37.8-66.6%). The median survival time was 395 days and 1-year survival rate was 51.4%. Toxicities were mild. Twelve patients (26%) had grade 3 and three patients (7%) had grade 4 neutropenia. Grade 3 thrombocytopenia was seen in four patients (8%). Massive hematoemesis due to duodenal ulcer was observed in one patient, but no other patients experienced grade 3 or more non-hematological toxicities. There was no treatment-related death. carboplatin and weekly paclitaxel combination chemotherapy is an efficacious and feasible regimen in patients with advanced NSCLC, and this treatment will be a reasonable alternative to the conventional triweekly regimen of paclitaxel and carboplatin.", "source": "https://pubmed.ncbi.nlm.nih.gov/15140549/"}
{"doc_id": "e12613f5fb6c99cf4926e0c2e73f0ce5", "sentence": "Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) .", "spans": [{"span_id": 0, "text": "vincristine", "start": 44, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cyclophosphamide", "start": 58, "end": 74, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "doxorubicin", "start": 77, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "prednisone", "start": 93, "end": 103, "token_start": 14, "token_end": 15}, {"span_id": 4, "text": "doxorubicin", "start": 114, "end": 125, "token_start": 19, "token_end": 20}, {"span_id": 5, "text": "ranimustine", "start": 128, "end": 139, "token_start": 21, "token_end": 22}, {"span_id": 6, "text": "prednisone", "start": 144, "end": 154, "token_start": 23, "token_end": 24}, {"span_id": 7, "text": "etoposide", "start": 180, "end": 189, "token_start": 30, "token_end": 31}, {"span_id": 8, "text": "carboplatin", "start": 192, "end": 203, "token_start": 32, "token_end": 33}, {"span_id": 9, "text": "prednisone", "start": 208, "end": 218, "token_start": 34, "token_end": 35}, {"span_id": 10, "text": "vindesine", "start": 168, "end": 177, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10], "is_context_needed": true}], "paragraph": "A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) . G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/11380402/"}
{"doc_id": "253ab4e2581ecbfe942bd09e125e9497", "sentence": "Indomethacin , naproxen and dexamethasone had no effect .", "spans": [{"span_id": 0, "text": "naproxen", "start": 15, "end": 23, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "dexamethasone", "start": 28, "end": 41, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Effects of certain antiarthritic agents on the synthesis of type II collagen and glycosaminoglycans in rat chondrosarcoma cultures. Cartilage destruction is a characteristic feature of osteoarthritis. Treatment with certain nonsteroidal anti-inflammatory drugs could exacerbate cartilage destruction by impairing the synthesis of cartilage matrix proteins, type II collagen and proteoglycan. In order to monitor the changes occurring in cartilage collagen synthesis, we developed a type II collagen specific ELISA. The effects of antiarthritic agents on type II collagen and glycosaminoglycan synthesis were examined in rat chondrosarcoma cultures. Drugs were added to the monolayer cultures and 4 days later the total type II collagen, as determined by the type II collagen ELISA, and glycosaminoglycan content, as measured by dimethyl-methylene blue dye binding assay, was measured. All drugs except tiaprofenic acid decreased type II collagen synthesis by at least 40% at 100 micrograms/ml. tiaprofenic acid at 1 microgram/ml increased type II collagen content by 54% of the controls. Glycosaminoglycan synthesis was decreased by acetylsalicylic acid, diclofenac and tiaprofenac acid, at 50 micrograms/ml or above. Indomethacin , naproxen and dexamethasone had no effect . Interestingly, tenidap stimulated the glycosaminoglycan synthesis by 32% at 100 micrograms/ml. We show that the combination of chondrosarcoma cultures, type II collagen specific ELISA and dimethylmethylene blue dye binding assay serves as a useful model for screening the effects of agents capable of modulating type II collagen and glycosaminoglycan synthesis.", "source": "https://pubmed.ncbi.nlm.nih.gov/7942329/"}
{"doc_id": "0570fa2975ebf592e8936069e10116c6", "sentence": "In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 45, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "lapatinib", "start": 61, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts. ### Experimental Design EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal . The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models. ### results lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. ### conclusion Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/20179222/"}
{"doc_id": "ee5d4e0c327fe92e840628a4a703ed85", "sentence": "To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide ( HCTZ ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis , we utilized Xpa-knockout mice , which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice .", "spans": [{"span_id": 0, "text": "voriconazole", "start": 48, "end": 60, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "hydrochlorothiazide", "start": 65, "end": 84, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice. voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide ( HCTZ ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis , we utilized Xpa-knockout mice , which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice . Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle- or HCTZ-administered groups. voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa-knockout mice. Furthermore, the investigation of UVB-induced DNA damage using embryonic fibroblasts of Xpa-knockout mice revealed a significantly higher 8-oxo-7,8-dihydroguanine level in cells treated with voriconazole N-oxide, a voriconazole-metabolite during UV exposure. The data suggest that voriconazole plus UVB-induced inflammatory response may be related to voriconazole-induced skin phototumorigenesis.", "source": "https://pubmed.ncbi.nlm.nih.gov/29968917/"}
{"doc_id": "dcb788b79b119fb6cb54c5eb6c0dae0e", "sentence": "Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising .", "spans": [{"span_id": 0, "text": "Sorafenib", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bevacizumab", "start": 54, "end": 65, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "ixabepilone", "start": 70, "end": 81, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "gemcitabine", "start": 157, "end": 168, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "capecitabine", "start": 176, "end": 188, "token_start": 22, "token_end": 23}, {"span_id": 5, "text": "tamoxifen", "start": 202, "end": 211, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 3], "is_context_needed": false}, {"class": "POS", "spans": [0, 4], "is_context_needed": false}, {"class": "POS", "spans": [0, 5], "is_context_needed": false}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials. To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. ### methods An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms \"sorafenib\" and \"breast cancer\". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. ### results Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising . ### conclusion At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/27579253/"}
{"doc_id": "0b19218cd66509b9ec7b8b74faa776fa", "sentence": "This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 53, "end": 63, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "cisplatin", "start": 78, "end": 87, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "carboplatin", "start": 91, "end": 102, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Current status of taxane and platinum-based chemotherapy in ovarian cancer. Before 1993, the standard of care for the chemotherapeutic management of advanced ovarian cancer was cisplatin or carboplatin combined with a classic alkylating agent (typically cyclophosphamide). Studies in the 1990s have changed this standard to one of the platinum-containing agents combined with a taxane, paclitaxel, or docetaxel. This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet . A separate article discusses the docetaxel-platinum doublet and how that might be considered an appropriate option for first-line therapy in patients with advanced, newly diagnosed ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/12743128/"}
{"doc_id": "84e5e11c5f53a9a86f14e90f0656d9b6", "sentence": "The results indicate that neomycin only inhibits the growth of susceptible bacteria ( E. coli , Staph . aureus ) which , conversely , are poor lactitol fermenters .", "spans": [{"span_id": 0, "text": "neomycin", "start": 26, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "lactitol", "start": 143, "end": 151, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "[Lactitol and neomycin: monotherapy or combined therapy in the prevention and treatment of hepatic encephalopathy?]. The beneficial effect of disaccharides, lactulose and lactitol, in prevention and treatment of hepatic encephalopathy is well established but their use in combination with neomycin is still controversial. We studied in vitro the fecal bacterial growth, acid and gas formation in presence of lactitol (beta-galactoside-sorbitol) and neomycin alone or in combination. The results indicate that neomycin only inhibits the growth of susceptible bacteria ( E. coli , Staph . aureus ) which , conversely , are poor lactitol fermenters . The resistant organisms (Lactobacillus acidophilus, Clostridium perfringens) that are efficient disaccharide fermenters continue to metabolize lactitol still when antibiotic is added. Addition of lactitol 10% increased the inhibitory effect of neomycin on bacterial growth by 25-50% within 60-70 min. These preliminary data suggest that lactitol and neomycin may have additional or synergistic effects in vivo when used together in presence of favourable intestinal microbial environment.", "source": "https://pubmed.ncbi.nlm.nih.gov/2525995/"}
{"doc_id": "d819bb23ae7e300013cb210830b30285", "sentence": "Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) .", "spans": [{"span_id": 0, "text": "cis-platinum", "start": 56, "end": 68, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "carboplatin", "start": 71, "end": 82, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "oxaliplatin", "start": 87, "end": 98, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "Hyperthermia", "start": 0, "end": 12, "token_start": 0, "token_end": 1}], "rels": [{"class": "POS", "spans": [0, 3], "is_context_needed": false}, {"class": "POS", "spans": [1, 3], "is_context_needed": false}, {"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "[Effects of hyperthermia combined platinum-based drugs on ovarian cancer cell lines SKOV3]. To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. ### methods SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 microg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10.0, 20.0, 40 microg/mL) at a temperature of 42 degrees C for hyperthermia or 37 degrees C for normal temperature. Methyl thiazolyl tetrazolium (MTT) method was used to test growth ratios of ovarian cancer cell lines SKOV3. Real-time PCR was adopted to detect the expression level of excision repair cross-complementing group 1 (ERCC1) and Survivin mRNA in SKOV3 cells. ### results DDP, CBP and OXA inhibited the growth of SKOV3 in a dose-dependent manner (P < 0.05). Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) . The half inhibitory concentration (IC50) values of DDP, CBP and OXA were (7.271 +/- 0.096) microg/mL, (37.609 +/- 0.779) microg/mL and (28.328 +/- 0.698) microg/mL respectively. When combined with hyperthermia, the IC50 values of DDP, CBP, and OXA were (2.075 +/- 0.244) microg/mL, (19.591 +/- 0.453) microg/mL, (19.089 +/- 0.424) microg/mL (P < 0.05). The increased sensitivity index was 2.075 +/- 0.244 for cis-platinum, 1.92 +/- 0.044 for carboplatin, 1.484 +/- 0.039 for oxaliplatin. After the treatment of hyperthermia, the expression of ERCC1 and Survivin mRNA showed downward trend. ERCC1 decreased more significantly in the group of hyperthermia combined with carboplatin, and Survivin decreased more significantly in the group of hyperthermia combined with oxaliplatin (P < 0.05). ### conclusion Hyperthermia can enhance the sensitivity of ovarian cancer SKOV3 cells to platinum-based drugs, which may be related to the down regulation of ERCC1 and Survivin expression.", "source": "https://pubmed.ncbi.nlm.nih.gov/25286685/"}
{"doc_id": "ca87164dd56862679e6812be7a454c3f", "sentence": "A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution .", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 130, "end": 144, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "oxaliplatin", "start": 147, "end": 158, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "leucovorin", "start": 165, "end": 175, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Quality of Life Outcomes From a Phase 2 Trial of Short-Course Radiation Therapy Followed by FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer.  A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution . We present here the patient-reported quality of life (QOL) outcomes from this trial. ### Methods And Materials Eighty patients with cT3/T4, any N, any M rectal adenocarcinoma planned for resection were enrolled between 2009 and 2012. The QOL data were obtained prospectively using the Functional Assessment of Cancer Therapy-Colon (FACT-C) questionnaire before RT, before surgery, and 1\u00a0year after surgery. The previously validated minimally importance difference (MID) method was used to measure clinically significant QOL changes in FACT-C scores for each patient across time points. We examined the role of ostomy on QOL. We also compared QOL with disease outcomes and physician-reported toxicity. ### results The FACT-C questionnaire was completed by 97% of patients before RT, 85% immediately before surgery, and 62% 1\u00a0year after surgery. There was no statistically significant change in mean FACT-C scores from before treatment to after treatment. The majority of patients had either no change or an increase in QOL 1\u00a0year after treatment using the MID method. There were significant changes in QOL between patients with ostomy versus no ostomy 1\u00a0year after treatment for functional well-being (FWB) (14.81 vs 20.52, P=.018) and the colorectal cancer subscale (CCS) using the MID method (P=.004). Patients without ostomy reported stable changes in bowel control 1\u00a0year after surgery. There was no statistically significant correlation between QOL and disease recurrence, pathologic complete response, pathologic T stage downstaging, or acute/late toxicity. ### conclusions SC-RT and sequential mFOLFOX6 as preoperative therapy for rectal cancer results in stable patient-reported QOL outcomes 1\u00a0year after treatment. These findings in conjunction with previously reported oncologic outcomes support further evaluation of this regimen in a phase 3 setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/27209506/"}
{"doc_id": "ca50ee6dc69f527347fc782c655a97d4", "sentence": "[ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 62, "end": 73, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "capecitabine", "start": 76, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "Cisplatin", "start": 95, "end": 104, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] . We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23-year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S-1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1.", "source": "https://pubmed.ncbi.nlm.nih.gov/25731506/"}
{"doc_id": "e596e3a511575d9d61a15039a7fb1f62", "sentence": "Sulpiride plus hydroxyzine decrease tinnitus perception .", "spans": [{"span_id": 0, "text": "Sulpiride", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "hydroxyzine", "start": 15, "end": 26, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Sulpiride plus hydroxyzine decrease tinnitus perception . The aim of the study is to confirm the effectiveness of sulpiride and hydroxyzine in tinnitus patients. The administration of sulpiride, a D2 antagonist of dopamine receptors, together with hydroxyzine, a subcortical sedative, covers the areas of tinnitus perception. ### methods A prospective, randomized, single blinded, placebo-control study was done in general otorhinolaryngology consultations for 2002-2004 in Seville and Zaragoza (Spain). One hundred and fifty patients consulted for subjective tinnitus. They were included randomly in three groups of 50. A group took sulpiride (50 mg/8 h) alone, other the same dose of sulpiride plus hydroxyzine (25 mg/12 h), and the third placebo (lactose), for 1 month. One hundred and twenty-two patients completed the study. Clinical history, tonal audiometry, tympanometry, and tinnitometry were done in the beginning and end of the study. Subjective Grading of Tinnitus Perception and visual analogical scale (0-10) were done for result evaluation. ### results Based on the Subjective Grading of Tinnitus Perception, tinnitus perception diminished by 56% in patients treated with sulpiride and by 81% in patients treated with sulpiride plus hydroxyzine. Based on the visual analogical scale, tinnitus perception diminished from 7.8 to 6.3 in the patients treated with sulpiride, and from 7.8 to 5.1 in those treated with sulpiride plus hydroxyzine. ### conclusions sulpiride plus hydroxyzine decreases tinnitus perception. Tinnitus auditolimbic dopaminergic pathway opens wide therapeutical implications.", "source": "https://pubmed.ncbi.nlm.nih.gov/17118597/"}
{"doc_id": "5e2553a4549f2caeca0fb06f63927535", "sentence": "' Arimidex ' ( anastrozole ) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer -- efficacy overview .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 15, "end": 26, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "tamoxifen", "start": 36, "end": 45, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "' Arimidex ' ( anastrozole ) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer -- efficacy overview . ATAC, a randomized, double-blind trial, compared tamoxifen (20 mg) with anastrozole ('Arimidex') (1 mg) alone, and the combination of anastrozole plus tamoxifen (combination), as adjuvant endocrine treatment for postmenopausal patients with early breast cancer. Patients with operable invasive breast cancer following completion of primary therapy, who were candidates to receive adjuvant endocrine therapy, were eligible for this study. Primary endpoints were disease-free survival (DFS) and tolerability. Other endpoints included time to recurrence (TTR: censoring non-breast cancer deaths before recurrence) and the incidence of contralateral breast cancer. A total of 9366 patients were included in this study (N=3125, 3116 and 3125 for anastrozole, tamoxifen and the combination, respectively). Median duration of therapy was 30.7 months and median follow-up was 33.3 months. The total numbers of events were 317, 379 and 383 for anastrozole, tamoxifen and the combination, respectively. DFS was significantly improved in the overall population for anastrozole versus tamoxifen (hazard ratio (HR)=0.81, 95% confidence interval (CI) (0.71-0.96), P=0.013). anastrozole showed improved TTR compared with tamoxifen (HR=0.79, CI (0.67-0.94), P=0.008), which improved even further in the ER+ and/or PR+ subgroup (HR=0.73, CI (0.59-0.90), P=0.003). The incidences of hot flushes, thromboembolic events, ischaemic cerebrovascular events, vaginal bleeding/discharge and endometrial cancer were significantly reduced with anastrozole compared with tamoxifen (P<0.03 for all). Musculoskeletal disorders and fractures were significantly reduced in patients receiving tamoxifen compared with those on anastrozole (P<0.03 for both). No increase in hip fractures was seen for anastrozole versus tamoxifen (11 versus 13, respectively). Combination treatment was equivalent to tamoxifen in terms of both efficacy and tolerability. anastrozole showed superior efficacy to tamoxifen for DFS, TTR and contralateral breast cancer. Early findings show anastrozole to be an effective and well-tolerated endocrine option for the treatment of postmenopausal patients with early breast cancer. For the first time a choice now exists for adjuvant endocrine treatment for postmenopausal women with hormone responsive tumours. Longer follow-up will further define the benefit/risk of anastrozole adjuvant therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/14623537/"}
{"doc_id": "18fa86029153d65989d1c18f32f0b497", "sentence": "We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively .", "spans": [{"span_id": 0, "text": "tissue plasminogen activator", "start": 51, "end": 79, "token_start": 12, "token_end": 15}, {"span_id": 1, "text": "heparin", "start": 100, "end": 107, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "prostaglandin E1", "start": 112, "end": 128, "token_start": 22, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Successful treatment of an infant with veno-occlusive disease developed after allogeneic bone marrow transplantation by tissue plasminogen activator, heparin and prostaglandin E1. A 15-month-old boy with severe aplastic anemia developed veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT), in which the preparative regimen included 50 mg/kg/day cyclophosphamide and anti-lymphocyte globulin for 4 consecutive days. The diagnosis was made based on clinical symptoms and data including, hepatomegaly, right upper quadrant abdominal pain, jaundice, ascites, coagulopathy and thrombocytopenia which was refractory to transfusions of platelet concentrate. We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively . Clinical and biochemical improvement was steady and dramatic. We suggest that tPA following continuous heparin and PGE1 infusion may be useful in the treatment of VOD even in infantile cases.", "source": "https://pubmed.ncbi.nlm.nih.gov/7637394/"}
{"doc_id": "878a3f80aefe1a6b4ea10ef54550325b", "sentence": "Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells .", "spans": [{"span_id": 0, "text": "Roxithromycin", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "clarithromycin", "start": 18, "end": 32, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells . We previously reported antiangiogenic activity of roxithromycin and clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we examined the antitumor effects of roxithromycin and clarithromycin, alone and in combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin and vindesine in vivo. However, neither roxithromycin nor clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell proliferation assay. These results suggest that the antiangiogenic activity of roxithromycin and clarithromycin may provide beneficial effects in combination with cytotoxic therapies against solid tumors.", "source": "https://pubmed.ncbi.nlm.nih.gov/10660084/"}
{"doc_id": "5156321f12ef5608480d7417f89f7022", "sentence": "The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine .", "spans": [{"span_id": 0, "text": "etoposide", "start": 18, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "vinblastine", "start": 30, "end": 41, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "doxorubicin", "start": 44, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 3, "text": "etoposide", "start": 109, "end": 118, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "bleomycin", "start": 125, "end": 134, "token_start": 23, "token_end": 24}, {"span_id": 5, "text": "dacarbazine", "start": 139, "end": 150, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [1, 2, 4, 5], "is_context_needed": true}], "paragraph": "Primary systemic treatment of advanced Hodgkin's disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up. The most commonly used regimen for the treatment of advanced Hodgkin's disease (HD) is ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Two of these components, bleomycin and dacarbazine, have defined toxicities such as pulmonary fibrosis and nausea/vomiting, and also uncertain single-drug activity. The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine . ### Patients And Methods A series of 51 patients with advanced HD without prior systemic therapy were treated. The series included 12 stage II patients with bulky (>10 cm) mediastinal tumors, 10 of whom received complementary radiation therapy. The remaining patients received EVA only. Response, duration of response, survival, toxicity and the efficacy of salvage therapy were evaluated in all patients. The median follow-up time was 111 months and permitted an assessment of the long-term effects of treatment and natural history of a cohort of treated patients. ### results EVA achieved a complete response (or clinical complete response) in 48/51 patients (94%). Of these 48 responders, 16 relapsed in a median of 11 months (range 3-48 months). In follow-up, 32/51 patients had no evidence of relapsed HD, although three died from other causes (two from vascular events and one from large cell lymphoma), resulting in progression-free survival for the entire group of 57% at 111 months. Eight of the 16 were alive and free from disease at follow-up at 111 months. In the entire series, only seven patients (14%) died of HD. 37 patients (73%) continued free from disease. There was no pulmonary toxicity. ### conclusions The EVA regimen appears to have an overall survival (OS) outcome comparable to ABVD, but without the lung toxicity. The high salvage rate of second-line therapy, in most instances at conventional dosage, suggests an absence of cross-resistance to alkylating agents in patients treated with EVA.", "source": "https://pubmed.ncbi.nlm.nih.gov/12562654/"}
{"doc_id": "b8d214801f19a5a385cb42d7e6e2c611", "sentence": "The treatment of advanced non-small-cell lung cancer ( NSCLC is based on the combination of platin and one of the following agents : taxanes , gemcitabine , vinorelbine or irinotecan .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 143, "end": 154, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "vinorelbine", "start": 157, "end": 168, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "irinotecan", "start": 172, "end": 182, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Chemoresistance in non-small cell lung cancer.  The treatment of advanced non-small-cell lung cancer ( NSCLC is based on the combination of platin and one of the following agents : taxanes , gemcitabine , vinorelbine or irinotecan . There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/15720263/"}
{"doc_id": "ea8744d49ad7af4806734b7bb3efc835", "sentence": "Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume .", "spans": [{"span_id": 0, "text": "Carvedilol", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "imatinib", "start": 15, "end": 23, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Carvedilol in glioma treatment alone and with imatinib in vitro. The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 microM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume . carvedilol and imatinib mesylate arrested cells at G0/G1 phase in a time-dependent manner and time-independent manner, respectively. carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/20198329/"}
{"doc_id": "b4f45f2f8481bf448aa604026f442c37", "sentence": "The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 .", "spans": [{"span_id": 0, "text": "cytarabine", "start": 43, "end": 53, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "sorafenib", "start": 80, "end": 89, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. sorafenib is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The National Cancer Institute of Canada (NCIC) Clinical Trials Group initiated a phase I/II study of the combination of sorafenib with cytarabine in older patients with AML or high-risk MDS who were unsuitable for intensive chemotherapy. FLT3 mutational status was determined in all patients. Twenty-one patients were enrolled (four MDS, 17 AML) with a median age of 77 years. The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 . Dose-limiting toxicities were fatigue, sepsis and skin rash. Of 15 evaluable patients treated at the RP2D, two patients responded. The overall response rate for eligible patients was 10%. FLT3 mutations were found in only three patients. We conclude that this combination of sorafenib and cytarabine has limited activity in this unselected cohort of elderly patients with AML/MDS in which FLT3 mutations seemed underrepresented.", "source": "https://pubmed.ncbi.nlm.nih.gov/23061485/"}
{"doc_id": "6a73d9185688e57d42aa5600c5e0d2dd", "sentence": "We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab .", "spans": [{"span_id": 0, "text": "panitumumab", "start": 44, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cetuximab", "start": 146, "end": 155, "token_start": 22, "token_end": 23}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab. cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab . ### Patients And Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. ### results We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. ### conclusions panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/22210091/"}
{"doc_id": "fa64a98ecdeacda0be884781ff6a5743", "sentence": "Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) .", "spans": [{"span_id": 0, "text": "ABT-450", "start": 40, "end": 47, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ritonavir", "start": 77, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "ombitasvir", "start": 109, "end": 119, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "dasabuvir", "start": 147, "end": 156, "token_start": 29, "token_end": 30}, {"span_id": 4, "text": "cyclosporine", "start": 252, "end": 264, "token_start": 49, "token_end": 50}, {"span_id": 5, "text": "tacrolimus", "start": 278, "end": 288, "token_start": 55, "token_end": 56}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}, {"class": "POS", "spans": [0, 1, 2, 3, 5], "is_context_needed": true}], "paragraph": "Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) . In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C\u2082\u2084), and area under the concentration-time curve from time 0 to infinity (AUC(\u221e)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C\u2082\u2084 and AUC(\u221e) were 17-fold and 57-fold, respectively, of either agent alone. cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/25708713/"}
{"doc_id": "25229a6b02806782fe134bb4bcd9e577", "sentence": "In this study a new GC-MS method has been developed for direct analysis of five major steroid estrogens ( estrone , 17beta-estradiol , 17alpha-ethinylestradiol , dienestrol , and diethylstilbestrol ) in river sediments .", "spans": [{"span_id": 0, "text": "estrone", "start": 106, "end": 113, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "diethylstilbestrol", "start": 179, "end": 197, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Novel approaches to the analysis of steroid estrogens in river sediments. A wide range of estrogenic contaminants has been detected in the aquatic environment. Among these, natural and synthetic steroid estrogens, typically present in municipal sewage-treatment plant (STP) effluents, are the most potent. In this study a new GC-MS method has been developed for direct analysis of five major steroid estrogens ( estrone , 17beta-estradiol , 17alpha-ethinylestradiol , dienestrol , and diethylstilbestrol ) in river sediments . Four GC-MS systems used for analysis of underivatized analytes in purified extracts were compared. Relatively low detection limits (1.5-5 ng g(-1) dried sediment) and good repeatability of GC splitless injection (RSD 1-2%) were achieved by use of a system combining low-pressure gas chromatography with a single-quadrupole mass analyzer (LP-GC-MS). Use of orthogonal gas chromatography (GCxGC) hyphenated with high-speed time-of-flight mass spectrometry (HSTOF-MS) enabled not only significantly better resolution of target analytes, and their unequivocal identification, but also further improvement (decrease) of their detection limits. In addition to these outcomes, use of this unique GCxGC-TOF-MS system enabled identification of several other non-target chemicals, including pharmaceutical steroids, present in purified sediment extracts.", "source": "https://pubmed.ncbi.nlm.nih.gov/17219098/"}
{"doc_id": "5754680328c8f57824b1c0bcf7861612", "sentence": "A series of derivatives , like dihydroartemisinin , artesunate , artemether , artether , had the same core chemical structure , and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure .", "spans": [{"span_id": 0, "text": "dihydroartemisinin", "start": 31, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "artesunate", "start": 52, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "artemether", "start": 65, "end": 75, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "[Research progress of effect of artemisinin family drugs on T lymphocytes immunomodulation]. artemisinin was isolated from traditional Chinese herb Artemisia annua for treating malaria. A series of derivatives , like dihydroartemisinin , artesunate , artemether , artether , had the same core chemical structure , and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure . Besides anti-malaria,artemisinin family drugs were found to ameliorate many different diseases,which have attracted wide attention in recent years. Among different diseases,artemisinin family drugs were found to have T lymphocytes immunomodulation effects,including activation,proliferation,differentiation,apoptosis and subsets function. Because T cell immunologic response is the key point of many diseases,and impact the pathogenic process,therapeutic effect and prognosis,the drug studies with it as the target have become hotspots in recent years. Studies of artemisinin family drug on T cell immunomodulation were still at the initial stage and involved in different disease; furthermore,T cell immune process involves complicated molecular mechanism,it is imperative to summarize the advance of current studies for further systematic explanation and exploration of their characteristics and mechanisms. This article will summarize the research progress of artemisinin family drugs for malaria,autoimmune disease,hypersensitivity reaction,tumor,schistosomiasis and AIDS relating to T cell immune modulation,so as to provide basic and professional reference for related research and application.", "source": "https://pubmed.ncbi.nlm.nih.gov/31872610/"}
{"doc_id": "df454d29e767c740e64ec045b436fe31", "sentence": "Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion .", "spans": [{"span_id": 0, "text": "dipyridamole", "start": 26, "end": 38, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "aspirin", "start": 103, "end": 110, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "dipyridamole", "start": 133, "end": 145, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effect of dipyridamole and aspirin on vein graft patency after coronary bypass operations.  Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion . Early (less than or equal to 1 month) and late (1 year) occlusions were reduced both on a per patient and a per distal anastomosis basis. Bleeding complications were not increased. Graft occlusion in high-risk situations (low-flow grafts and endarterectomy) was reduced, but not eliminated, by this antiplatelet regimen. The authors recommend this combination of dipyridamole before surgery, adding aspirin after surgery, to prevent coronary artery bypass graft occlusion.", "source": "https://pubmed.ncbi.nlm.nih.gov/2082487/"}
{"doc_id": "f694219846d032815ad1116286eee7a7", "sentence": "Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 53, "end": 69, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "methotrexate", "start": 72, "end": 84, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "fluorouracil", "start": 89, "end": 101, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil . The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level.", "source": "https://pubmed.ncbi.nlm.nih.gov/2019458/"}
{"doc_id": "fd5eb234c4cfd6cd435a7699e6d13175", "sentence": "All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 50, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "capecitabine", "start": 95, "end": 107, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Lapatinib plus capecitabine for HER2-positive advanced breast cancer: a multicentre study of Anatolian Society of Medical Oncology (ASMO). lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25-82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) . Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10\u00b77 months (range: 1-40 months). An overall response rate (ORR) of 33\u00b74% was achieved including 7 complete responses (CR, 3\u00b74%), 61 partial responses (PR, 30\u00b70%), and 44 stable disease (37\u00b79%). Clinical benefit rate of 71\u00b73% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6-10 months), with a median overall survival (OS) of 15 months (95% CI: 12-18 months). The most common side effects were hand-foot syndrome (46\u00b78%), nausea (42\u00b73%), fatigue (42\u00b72%), anorexia (38\u00b75%), diarrhea (31\u00b75%), and rash (29\u00b76%). Grade 3-4 toxicities were identified as hand foot syndrome (7\u00b79%), diarrhea (6\u00b79%), fatigue (5\u00b79%), and rash (5\u00b74%). There were no symptomatic cardiac events. lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3-4 toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/24112786/"}
{"doc_id": "6e04b97d5214d34a963c8d2d3d179adb", "sentence": "The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine , pyrilamine ( an antagonist of histamine H(1 ) receptors ) , ranitidine ( an antagonist of histamine H(2 ) receptors ) , morphine ( an opioid receptor agonist ) and naloxone ( an opioid receptor antagonist ) in separate and combined treatments .", "spans": [{"span_id": 0, "text": "histamine", "start": 193, "end": 202, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "pyrilamine", "start": 205, "end": 215, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "ranitidine", "start": 265, "end": 275, "token_start": 39, "token_end": 40}, {"span_id": 3, "text": "morphine", "start": 325, "end": 333, "token_start": 50, "token_end": 51}, {"span_id": 4, "text": "naloxone", "start": 369, "end": 377, "token_start": 58, "token_end": 59}], "rels": [], "paragraph": "Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats.  The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine , pyrilamine ( an antagonist of histamine H(1 ) receptors ) , ranitidine ( an antagonist of histamine H(2 ) receptors ) , morphine ( an opioid receptor agonist ) and naloxone ( an opioid receptor antagonist ) in separate and combined treatments . Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 \u03bcl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0-3 min, second phase: 15-33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. naloxone alone non-significantly increased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H(1) and H(2) receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H(1) and H(2) receptors, as well as opioid receptors may be involved in the interaction between histamine and morphine in producing analgesia.", "source": "https://pubmed.ncbi.nlm.nih.gov/21602597/"}
{"doc_id": "fd048d555776da144bf762fba2d83daa", "sentence": "Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore .", "spans": [{"span_id": 0, "text": "curcumin", "start": 10, "end": 18, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "doxorubicin", "start": 58, "end": 69, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells. Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore . ### methods A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, I\u03baB\u03b1 and NF\u03baB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently. ### results Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as I\u03baB\u03b1. Phosphorylated I\u03baB\u03b1 preceded release of NF\u03baB. Phospho-Akt, NF\u03baB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis. ### conclusion Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer..", "source": "https://pubmed.ncbi.nlm.nih.gov/33773562/"}
{"doc_id": "4ce332ca0989680dc6d5e790292fba13", "sentence": "It is well established that several of the older AEDs ( carbamazepine , phenytoin and phenobarbital ) , are strong inducers of the hepatic cytochrome P450 ( CYP ) 3A4 enzyme system , and are associated with increased the risk of contraceptive failure .", "spans": [{"span_id": 0, "text": "carbamazepine", "start": 56, "end": 69, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "phenytoin", "start": 72, "end": 81, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Pharmacokinetic interactions between contraceptives and antiepileptic drugs. The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs ( carbamazepine , phenytoin and phenobarbital ) , are strong inducers of the hepatic cytochrome P450 ( CYP ) 3A4 enzyme system , and are associated with increased the risk of contraceptive failure . In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.", "source": "https://pubmed.ncbi.nlm.nih.gov/18206393/"}
{"doc_id": "fadec01e4bb1d93acce4d2143b9068ec", "sentence": "Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose .", "spans": [{"span_id": 0, "text": "olaparib", "start": 60, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "carboplatin", "start": 102, "end": 113, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "paclitaxel", "start": 118, "end": 128, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.  Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose . ### methods In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m ### results The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent ### conclusions olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. ### Trial Registration Number NCT01650376.", "source": "https://pubmed.ncbi.nlm.nih.gov/30700568/"}
{"doc_id": "f21c5b821b9ba475c2e345f4770ecb35", "sentence": "Abiraterone acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis , CYP17 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency .", "spans": [{"span_id": 0, "text": "Abiraterone", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "pregnenolone", "start": 35, "end": 47, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer.  Abiraterone acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis , CYP17 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency . In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.", "source": "https://pubmed.ncbi.nlm.nih.gov/20465382/"}
{"doc_id": "119edb8f6876404fc0cb6313e179e307", "sentence": "There was no significant correlation between the response to ferrochloroquine and those to mefloquine , halofantrine , primaquine , atovaquone or artesunate .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 91, "end": 101, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "halofantrine", "start": 104, "end": 116, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "primaquine", "start": 119, "end": 129, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "atovaquone", "start": 132, "end": 142, "token_start": 19, "token_end": 20}, {"span_id": 4, "text": "artesunate", "start": 146, "end": 156, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum. The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine , halofantrine , primaquine , atovaquone or artesunate . Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.", "source": "https://pubmed.ncbi.nlm.nih.gov/11481286/"}
{"doc_id": "fdd6c7c9a225a1bd5e1e673f57088495", "sentence": "All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) .", "spans": [{"span_id": 0, "text": "decitabine", "start": 45, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cytarabine", "start": 123, "end": 133, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "aclarubicin", "start": 166, "end": 177, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML. ### Experimental Design All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) . ### results Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged \u226570 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged \u226570 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%. ### conclusion D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (\u226570 years).", "source": "https://pubmed.ncbi.nlm.nih.gov/25749041/"}
{"doc_id": "577dd5441437d2c79fec8349bdb8eb43", "sentence": "In chronic musculoskeletal conditions with assessments over 6 to 12 weeks , topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis , as did topical high-concentration capsaicin in postherpetic neuralgia .", "spans": [{"span_id": 0, "text": "diclofenac", "start": 84, "end": 94, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "ketoprofen", "start": 99, "end": 109, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews. Topical analgesic drugs are used for a variety of painful conditions. Some are acute, typically strains or sprains, tendinopathy, or muscle aches. Others are chronic, typically osteoarthritis of hand or knee, or neuropathic pain. ### objectives To provide an overview of the analgesic efficacy and associated adverse events of topical analgesics (primarily nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate rubefacients, capsaicin, and lidocaine) applied to intact skin for the treatment of acute and chronic pain in adults. ### methods We identified systematic reviews in acute and chronic pain published to February 2017 in the Cochrane Database of Systematic Reviews (the Cochrane Library). The primary outcome was at least 50% pain relief (participant-reported) at an appropriate duration. We extracted the number needed to treat for one additional beneficial outcome (NNT) for efficacy outcomes for each topical analgesic or formulation, and the number needed to treat for one additional harmful outcome (NNH) for adverse events. We also extracted information on withdrawals due to lack of efficacy or adverse events, systemic and local adverse events, and serious adverse events. We required information from at least 200 participants, in at least two studies. We judged that there was potential for publication bias if the addition of four studies of typical size (400 participants) with zero effect increased NNT compared with placebo to 10 (minimal clinical utility). We extracted GRADE assessment in the original papers, and made our own GRADE assessment. ### Main Results Thirteen Cochrane Reviews (206 studies with around 30,700 participants) assessed the efficacy and harms from a range of topical analgesics applied to intact skin in a number of acute and chronic painful conditions. Reviews were overseen by several Review Groups, and concentrated on evidence comparing topical analgesic with topical placebo; comparisons of topical and oral analgesics were rare.For at least 50% pain relief, we considered evidence was moderate or high quality for several therapies, based on the underlying quality of studies and susceptibility to publication bias.In acute musculoskeletal pain (strains and sprains) with assessment at about seven days, therapies were diclofenac Emulgel (78% Emulgel, 20% placebo; 2 studies, 314 participants, NNT 1.8 (95% confidence interval 1.5 to 2.1)), ketoprofen gel (72% ketoprofen, 33% placebo, 5 studies, 348 participants, NNT 2.5 (2.0 to 3.4)), piroxicam gel (70% piroxicam, 47% placebo, 3 studies, 522 participants, NNT 4.4 (3.2 to 6.9)), diclofenac Flector plaster (63% Flector, 41% placebo, 4 studies, 1030 participants, NNT 4.7 (3.7 to 6.5)), and diclofenac other plaster (88% diclofenac plaster, 57% placebo, 3 studies, 474 participants, NNT 3.2 (2.6 to 4.2)).In chronic musculoskeletal pain (mainly hand and knee osteoarthritis) therapies were topical diclofenac preparations for less than six weeks (43% diclofenac, 23% placebo, 5 studies, 732 participants, NNT 5.0 (3.7 to 7.4)), ketoprofen over 6 to 12 weeks (63% ketoprofen, 48% placebo, 4 studies, 2573 participants, NNT 6.9 (5.4 to 9.3)), and topical diclofenac preparations over 6 to 12 weeks (60% diclofenac, 50% placebo, 4 studies, 2343 participants, NNT 9.8 (7.1 to 16)). In postherpetic neuralgia, topical high-concentration capsaicin had moderate-quality evidence of limited efficacy (33% capsaicin, 24% placebo, 2 studies, 571 participants, NNT 11 (6.1 to 62)).We judged evidence of efficacy for other therapies as low or very low quality. Limited evidence of efficacy, potentially subject to publication bias, existed for topical preparations of ibuprofen gels and creams, unspecified diclofenac formulations and diclofenac gel other than Emulgel, indomethacin, and ketoprofen plaster in acute pain conditions, and for salicylate rubefacients for chronic pain conditions. Evidence for other interventions (other topical NSAIDs, topical salicylate in acute pain conditions, low concentration capsaicin, lidocaine, clonidine for neuropathic pain, and herbal remedies for any condition) was very low quality and typically limited to single studies or comparisons with sparse data.We assessed the evidence on withdrawals as moderate or very low quality, because of small numbers of events. In chronic pain conditions lack of efficacy withdrawals were lower with topical diclofenac (6%) than placebo (9%) (11 studies, 3455 participants, number needed to treat to prevent (NNTp) 26, moderate-quality evidence), and topical salicylate (2% vs 7% for placebo) (5 studies, 501 participants, NNTp 21, very low-quality evidence). Adverse event withdrawals were higher with topical capsaicin low-concentration (15%) than placebo (3%) (4 studies, 477 participants, NNH 8, very low-quality evidence), topical salicylate (5% vs 1% for placebo) (7 studies, 735 participants, NNH 26, very low-quality evidence), and topical diclofenac (5% vs 4% for placebo) (12 studies, 3552 participants, NNH 51, very low-quality evidence).In acute pain, systemic or local adverse event rates with topical NSAIDs (4.3%) were no greater than with topical placebo (4.6%) (42 studies, 6740 participants, high quality evidence). In chronic pain local adverse events with topical capsaicin low concentration (63%) were higher than topical placebo (5 studies, 557 participants, number needed to treat for harm (NNH) 2.6), high quality evidence. Moderate-quality evidence indicated more local adverse events than placebo in chronic pain conditions with topical diclofenac (NNH 16) and local pain with topical capsaicin high-concentration (NNH 16). There was moderate-quality evidence of no additional local adverse events with topical ketoprofen over topical placebo in chronic pain. Serious adverse events were rare (very low-quality evidence).GRADE assessments of moderate or low quality in some of the reviews were considered by us to be very low because of small numbers of participants and events. ### Authors Conclusions There is good evidence that some formulations of topical diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains, with low (good) NNT values. There is a strong message that the exact formulation used is critically important in acute conditions, and that might also apply to other pain conditions. In chronic musculoskeletal conditions with assessments over 6 to 12 weeks , topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis , as did topical high-concentration capsaicin in postherpetic neuralgia . Though NNTs were higher, this still indicates that a small proportion of people had good pain relief.Use of GRADE in Cochrane Reviews with small numbers of participants and events requires attention.", "source": "https://pubmed.ncbi.nlm.nih.gov/28497473/"}
{"doc_id": "b2070e475af07a4614d17d8e754452af", "sentence": "Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+ ) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease .", "spans": [{"span_id": 0, "text": "Pertuzumab", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "trastuzumab", "start": 104, "end": 115, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "docetaxel", "start": 120, "end": 129, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Pertuzumab in breast cancer: a systematic review. pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2(+) breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2(-) (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2(+ ) metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease . This approval has been based on data from a phase III Clinical Evaluation of pertuzumab and trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+). Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future.", "source": "https://pubmed.ncbi.nlm.nih.gov/23810292/"}
{"doc_id": "8c541ab8655b0d5cf13cf2688cab9063", "sentence": "Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 23, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "regorafenib", "start": 45, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "lenvatinib", "start": 60, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma . Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. ### methods We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. ### results Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56\u00a0days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. ### conclusions Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/33197087/"}
{"doc_id": "1337e5873ab749cedb2aa9980a3e455a", "sentence": "The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response ( SVR ) in phase III trials .", "spans": [{"span_id": 0, "text": "boceprevir", "start": 19, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "telaprevir", "start": 33, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "peginterferon-alfa", "start": 49, "end": 67, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "ribavirin", "start": 72, "end": 81, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 2, 3], "is_context_needed": true}, {"class": "POS", "spans": [1, 2, 3], "is_context_needed": true}], "paragraph": "Safety and efficacy of protease inhibitor based combination therapy in a single-center \"real-life\" cohort of 110 patients with chronic hepatitis C genotype 1 infection.  The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response ( SVR ) in phase III trials . There is only limited data regarding the safety and efficacy in a \"real-life\" cohort. ### methods We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N\u2009=\u20096) or status post liver transplant (N\u2009=\u20092). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder. ### results SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N\u2009=\u200930) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50\u00a0years, liver cirrhosis, bilirubin >1.1\u00a0mg/dl (P\u2009<\u20090.01, each), platelets <100,000/\u03bcl (P\u2009=\u20090.01), ASAT >100 U/l (P\u2009=\u20090.03) and albumin \u226435\u00a0g/l (P\u2009=\u20090.04) at baseline were associated with occurence of a SAE. ### conclusions The frequency of SVR in a \"real-life\" treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/24884400/"}
{"doc_id": "94639dcf9dbc2232915cc56197ae2ca4", "sentence": "In contrast , the combination of plumbagin with AR antagonists , such as bicalutamide and enzalutamide , showed no improvement over AR antagonists alone .", "spans": [{"span_id": 0, "text": "bicalutamide", "start": 73, "end": 85, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "enzalutamide", "start": 90, "end": 102, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "plumbagin", "start": 33, "end": 42, "token_start": 6, "token_end": 7}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre-clinical study. Plumbagin is a candidate drug for the treatment of prostate cancer. Previous observations indicated that it may improve the efficacy of androgen deprivation therapy (ADT). This study evaluates the effectiveness of treatment with combinations of plumbagin and alternative strategies for ADT in mouse models of prostate cancer to support its clinical use. ### methods Plumbagin was administered per oral in a new sesame oil formulation. Standard toxicology studies were performed in rats. For tumor growth studies, mouse prostate cancer cell spheroids were placed on top of grafted prostate tissue in a dorsal chamber and allowed to form tumors. Mice were separated in various treatment groups and tumor size was measured over time by intra-vital microscopy. Survival studies were done in mice after injection of prostate cancer cells in the prostate of male animals. Androgen receptor (AR) levels were analyzed by Western blot from prostate cancer cells treated with plumbagin. ### results Plumbagin caused a decrease in AR levels in vitro. In mice, plumbagin at 1\u2009mg/kg in sesame oil displayed low toxicity and caused a 50% tumor regression when combined with castration. The combination of plumbagin with various forms of chemical ADT including treatment with a GnRH receptor agonist, a GnRH receptor antagonist, or CYP17A1 inhibitors, outperformed ADT alone, increasing mouse survival compared to the standard regimen of castration alone. In contrast , the combination of plumbagin with AR antagonists , such as bicalutamide and enzalutamide , showed no improvement over AR antagonists alone . Thus, plumbagin is effective in combination with drugs that prevent the synthesis of testosterone or its conversion to dihydrotestosterone, but not with drugs that bind to AR. ### conclusion Plumbagin significantly improves the effect of ADT drugs currently used in the clinic, with few side effects in mice.", "source": "https://pubmed.ncbi.nlm.nih.gov/28971491/"}
{"doc_id": "988d030989c289f7e661a4d25c09a2c2", "sentence": "The B-cell lymphoma 2 ( BCL-2 ) inhibitor venetoclax has an emerging role in acute myeloid leukemia ( AML ) , with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients .", "spans": [{"span_id": 0, "text": "venetoclax", "start": 42, "end": 52, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cytarabine", "start": 195, "end": 205, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy.  The B-cell lymphoma 2 ( BCL-2 ) inhibitor venetoclax has an emerging role in acute myeloid leukemia ( AML ) , with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients . The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. ### Patients And Methods Patients with AML who were \u2265 65 years (\u2265 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days -6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m ### results Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade \u2265 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (\u2265 50%) were noted in ### conclusion venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).", "source": "https://pubmed.ncbi.nlm.nih.gov/32687450/"}
{"doc_id": "72cb047193f8acd0c8cbdc92c42cd17b", "sentence": "Combination chemotherapy with vincristine , bleomycin , and methotrexate for advanced head and neck cancers .", "spans": [{"span_id": 0, "text": "vincristine", "start": 30, "end": 41, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bleomycin", "start": 44, "end": 53, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "methotrexate", "start": 60, "end": 72, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Combination chemotherapy with vincristine , bleomycin , and methotrexate for advanced head and neck cancers . Thirty-three patients with a histologically confirmed diagnosis of advanced squamous cell carcinoma of the head and neck were treated with a combination of vincristine, methotrexate, and bleomycin. The regimen was as follows: Day 1, vincristine (2 mg iv) and methotrexate (200 mg/m2 iv over 24 hours); Day 2, bleomycin (15 mg/day by iv infusion for 48 hours). Folinic acid rescue began 36 hours after the start of methotrexate. The regimen was repeated at intervals of 3 weeks. Toxicity was minimal but the overall response rate was only 24% (three complete responses and five partial responses) and the median duration of remission was only 16 weeks overall. The combination of vincristine, methotrexate, and bleomycin in this dosage schedule has a response rate lower than that reported with single-agent treatment of advanced head and neck cancers.", "source": "https://pubmed.ncbi.nlm.nih.gov/93514/"}
{"doc_id": "78463449815401119d838bb799893921", "sentence": "Combination therapy with labetalol ( 400 mg/day ) and prazosin ( 6 mg/day ) was unsatisfactory , and the addition of long-acting nifedipine ( 40 mg/day ) produced a marked decrease in blood pressure .", "spans": [{"span_id": 0, "text": "labetalol", "start": 25, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "prazosin", "start": 54, "end": 62, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "nifedipine", "start": 129, "end": 139, "token_start": 22, "token_end": 23}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Effectiveness of long-acting nifedipine in pheochromocytoma. In the present study, we report a case of pheochromocytoma whose high blood pressure was well controlled by single-agent therapy with long-acting nifedipine, in spite of the failure of the combination of labetalol and prazosin in lowering blood pressure satisfactorily. A 48 year old female was first noted to have hypertension (160/100 mmHg) at 45 years of age. Hypertension was not controlled by conventional antihypertensive drugs. She was admitted to Fukui Prefectural Hospital in September, 1985. Her blood pressure on admission was 210/110 mmHg. Extraction of the left adrenal gland containing a pheochromocytoma (30 x 37 x 10 mm) was performed in November, 1985. Her hypertension and abnormally high plasma noradrenaline (NA) concentration (1,760 pg/ml, normal value 40-350 pg/ml) were sustained even after operation. Combination therapy with labetalol ( 400 mg/day ) and prazosin ( 6 mg/day ) was unsatisfactory , and the addition of long-acting nifedipine ( 40 mg/day ) produced a marked decrease in blood pressure . Furthermore, single therapy with long-acting nifedipine was effective. No reduction of urinary NA excretion was observed in our patient during long-acting nifedipine therapy, suggesting that the decrease in blood pressure was not caused by suppression of NA release from pheochromocytoma tissue.", "source": "https://pubmed.ncbi.nlm.nih.gov/2614935/"}
{"doc_id": "416a6d9375f6c9b30592a8c095d439f3", "sentence": "The monoclonal antibodies Ipilimumab , Pembrolizumab and Nivolumab , designed to interfere with T-cell inhibitory signals to activate immune responses against tumours , were originally approved as monotherapy .", "spans": [{"span_id": 0, "text": "Ipilimumab", "start": 26, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "Pembrolizumab", "start": 39, "end": 52, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "Nivolumab", "start": 57, "end": 66, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Combined anti-PD-1\u00a0and anti-CTLA-4 checkpoint blockade: treatment of melanoma and immune mechanisms of action. Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies Ipilimumab , Pembrolizumab and Nivolumab , designed to interfere with T-cell inhibitory signals to activate immune responses against tumours , were originally approved as monotherapy . Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune related adverse events. In this review we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use. This article is protected by copyright. All rights reserved.", "source": "https://pubmed.ncbi.nlm.nih.gov/33450785/"}
{"doc_id": "1d2dab74d65b4ba99e22aac2286ee71c", "sentence": "Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 41, "end": 52, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "tamoxifen", "start": 82, "end": 91, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI . This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole. ### Patients And Methods Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed. ### results Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study. ### conclusion The suppressed levels of plasma estradiol and estrone sulfate in postmenopausal women with early ER-positive breast cancer treated with the AIs anastrozole and letrozole are related to BMI.", "source": "https://pubmed.ncbi.nlm.nih.gov/22802308/"}
{"doc_id": "e412b8e2c69930c30c2634235d41b7fe", "sentence": "It was identified as C. lunata ( Wakker ) Boedijn var . aeria ( Batista , Lima and Vasconcelos ) Ellis ( IMI 253204 ) and its growth was better at 28 degrees C than at 37 degrees C. In vitro , the fungus was most sensitive to amphotericin B followed by miconazole nitrate , clotrimazole and triphenyltin isoselenocyanate 4-picoline which had the same activity .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 226, "end": 238, "token_start": 48, "token_end": 49}, {"span_id": 1, "text": "miconazole", "start": 253, "end": 263, "token_start": 52, "token_end": 53}, {"span_id": 2, "text": "clotrimazole", "start": 274, "end": 286, "token_start": 55, "token_end": 56}, {"span_id": 3, "text": "triphenyltin isoselenocyanate 4-picoline", "start": 291, "end": 331, "token_start": 57, "token_end": 60}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Clinical and experimental keratitis due to Curvularia lunata (Wakker) Boedijn var. aeria (Batista, Lima and Vasconcelos) Ellis. A case of mycotic keratitis due to Curvularia lunata var. aeria is reported for the first time from India. Direct microscopic examination of the corneal scrapings in KOH (50 g1(-1)), stained with lactophenol cotton blue, revealed brown septate hyphae and the cultures were found positive for fungus. It was identified as C. lunata ( Wakker ) Boedijn var . aeria ( Batista , Lima and Vasconcelos ) Ellis ( IMI 253204 ) and its growth was better at 28 degrees C than at 37 degrees C. In vitro , the fungus was most sensitive to amphotericin B followed by miconazole nitrate , clotrimazole and triphenyltin isoselenocyanate 4-picoline which had the same activity . Lactones were least active and tolciclate and arnebins and inactive. The fungus produced experimental keratomycosis in the rabbit cornea and the infection severity as well as histopathological changes were more pronounced in rabbits that received penicillin, streptomycin and cortisone.", "source": "https://pubmed.ncbi.nlm.nih.gov/6890237/"}
{"doc_id": "25386eeed3d1ac4d4c3dcdcc1f1a7528", "sentence": "Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC .", "spans": [{"span_id": 0, "text": "Everolimus", "start": 12, "end": 22, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "bevacizumab", "start": 40, "end": 51, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "mFOLFOX-6", "start": 28, "end": 37, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first-line treatment of metastatic colorectal cancer. Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6\u2009+\u2009bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3\u2009+\u20093 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6\u00a0months (PFS-6\u00a0m). Results The everolimus MTD was 10\u00a0mg daily with mFOLFOX6\u2009+\u2009bevacizumab based on safety from phase I (n\u2009=\u200922). Twenty-five patients were treated in the phase II at 10\u00a0mg everolimus daily. Frequent grade 3-4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10\u00a0mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6\u00a0m was 96% (95% CI 89-99.9%) at the MTD (n\u00a0=\u200935). The everolimus recommended phase II dose of this regimen is 7.5\u00a0mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC . Further studies are warranted in PTEN deficiency.", "source": "https://pubmed.ncbi.nlm.nih.gov/30302599/"}
{"doc_id": "fe47fe1a70f1d97f8051d2f8e7e98202", "sentence": "Physician Utilization Patterns for VEGF-Inhibitor Drugs in the 2012 United States Medicare Population : Bevacizumab , Ranibizumab , and Aflibercept .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 104, "end": 115, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "Ranibizumab", "start": 118, "end": 129, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "Aflibercept", "start": 136, "end": 147, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Physician Utilization Patterns for VEGF-Inhibitor Drugs in the 2012 United States Medicare Population : Bevacizumab , Ranibizumab , and Aflibercept . To evaluate variation in physician use of vascular endothelial growth factor (VEGF) inhibitors. ### Patients And Methods Population-based analysis of comprehensive, publicly available 2012 Medicare claims, aggregated by physician specialty and service type - including intravitreal injections of bevacizumab (Avastin; Genentech, South San Francisco, CA), ranibizumab (Lucentis; Genetech, South San Francisco, CA), and aflibercept (Eylea; Regeneron, Tarrytown, NY). Physicians were characterized by total patients treated, proportion treated with each drug, total intravitreal injection payments, and proportion of total payments for each drug. ### results The authors identified 2,869 ophthalmologists. On average, each treated 203 patients with VEGF-inhibitors, 75.9% of which were treated with bevacizumab. Using all three agents was the most common practice (1,121 physicians), closely followed by using bevacizumab only (1,061 physicians). ranibizumab accounted for most payments, but bevacizumab was the largest payment source for a sizeable proportion of physicians who used only/mostly bevacizumab. ### conclusion Most ophthalmologists use multiple VEGF inhibitors, but vary in their relative use. A subset of ophthalmologists predominantly use ranibizumab, but ophthalmologists overall use more bevacizumab despite financial incentives favoring ranibizumab. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:555-562.].", "source": "https://pubmed.ncbi.nlm.nih.gov/27327285/"}
{"doc_id": "a1de37ff2e4c46ad4bbbd914ca5be3dd", "sentence": "Antimicrobials that can be used with confidence to treat NG infection currently in China include ceftriaxone and spectinomycin , but not penicillin , tetracycline , ciprofloxacin , and cefixime .", "spans": [{"span_id": 0, "text": "ceftriaxone", "start": 97, "end": 108, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "spectinomycin", "start": 113, "end": 126, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "penicillin", "start": 137, "end": 147, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "tetracycline", "start": 150, "end": 162, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "ciprofloxacin", "start": 165, "end": 178, "token_start": 25, "token_end": 26}, {"span_id": 5, "text": "cefixime", "start": 185, "end": 193, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Antimicrobial Susceptibility Evaluation and Multiple-Locus Variable Number Tandem Repeat Analysis of Neisseria gonorrhoeae Isolates in China in 2012. This study aimed to gain information on the antimicrobial susceptibility and molecular epidemiological typing of Neisseria gonorrhoeae (NG) isolates in China in 2012. ### methods A total of 244 NG isolates were consecutively recovered from patients with uncomplicated gonorrhea attending sexually transmitted disease clinics in 3 Chinese cities-Guangzhou, Nanjing, and Tianjin-in 2012. Neisseria gonorrhoeae susceptibilities to penicillin and tetracycline were examined by detecting penicillinase-producing NG (PPNG) and high-level tetracycline-resistant NG, and NG susceptibilities to ciprofloxacin, spectinomycin, ceftriaxone, and cefixime were determined using an agar dilution method. Neisseria gonorrhoeae isolates were typed by multiple-locus variable number tandem repeat analysis. We conducted a \u03c7 analysis to compare clusters with Bonferroni correction and Kruskal-Wallis test. ### results Neisseria gonorrhoeae isolates gathered from the 3 cities differed significantly in the prevalence of tetracycline-resistant NG (P < 0.001) and NG treated with ceftriaxone with a minimum inhibitory concentration of 0.125 mg/L or higher (P < 0.001). The analysis of the combination of the 7 variable number of tandem repeats loci for all of the 244 isolates yielded 110 multiple-locus variable number tandem repeat analysis types falling into 5 clusters. Cluster III was associated with PPNG, whereas cluster II was associated with non-PPNG (P < 0.05) and NG treated with ceftriaxone with a minimum inhibitory concentration of 0.125 mg/L or higher (P < 0.05). ### conclusions Antimicrobials that can be used with confidence to treat NG infection currently in China include ceftriaxone and spectinomycin , but not penicillin , tetracycline , ciprofloxacin , and cefixime . Moreover, some of the resulting clusters were associated with PPNG and NG with decreased ceftriaxone susceptibility.", "source": "https://pubmed.ncbi.nlm.nih.gov/28282644/"}
{"doc_id": "e32aef4112b7d8f12296ed7e7c257710", "sentence": "A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise , with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 196, "end": 205, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "everolimus", "start": 228, "end": 238, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise , with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET .", "source": "https://pubmed.ncbi.nlm.nih.gov/21672194/"}
{"doc_id": "354bb4d160b5a92cbae23b489a5a84a4", "sentence": "We conducted a prospective phase II study to determine the response rate , toxicity , and survival rate of concurrent weekly paclitaxel , carboplatin , and hyperfractionated radiation therapy ( paclitaxel/carboplatin/HFX RT ) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 125, "end": 135, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "carboplatin", "start": 138, "end": 149, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "paclitaxel", "start": 250, "end": 260, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "carboplatin", "start": 265, "end": 276, "token_start": 40, "token_end": 41}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study).  We conducted a prospective phase II study to determine the response rate , toxicity , and survival rate of concurrent weekly paclitaxel , carboplatin , and hyperfractionated radiation therapy ( paclitaxel/carboplatin/HFX RT ) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer ( NSCLC ) . The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. ### Methods And Materials Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). ### results Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. ### conclusions Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study.", "source": "https://pubmed.ncbi.nlm.nih.gov/10863062/"}
{"doc_id": "f2d6a8abff8a039a68a209d7406b262c", "sentence": "A phase Ib study of pertuzumab , a recombinant humanised antibody to HER2 , and docetaxel in patients with advanced solid tumours .", "spans": [{"span_id": 0, "text": "pertuzumab", "start": 20, "end": 30, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "docetaxel", "start": 80, "end": 89, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase Ib study of pertuzumab , a recombinant humanised antibody to HER2 , and docetaxel in patients with advanced solid tumours . pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.", "source": "https://pubmed.ncbi.nlm.nih.gov/18000498/"}
{"doc_id": "22da74305c60249c0d19f42ca0802851", "sentence": "These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells .", "spans": [{"span_id": 0, "text": "vorinostat", "start": 24, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxorubicin", "start": 39, "end": 50, "token_start": 6, "token_end": 7}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors. Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear. ### methods We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T-lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects. ### results vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase. ### conclusion These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells . L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/27504186/"}
{"doc_id": "b1f01aa95f676b3db6a8efa07177bf39", "sentence": "Based on encouraging results of previous combination regimens , we used a combination of VM26 , ifosfamide , methyl GAG , mitoxantrone ( or adriamycin ) , high-dose ( HD ) methotrexate and HD Ara C to treat 18 patients with relapsed or refractory NHL .", "spans": [{"span_id": 0, "text": "VM26", "start": 89, "end": 93, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "ifosfamide", "start": 96, "end": 106, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "methyl GAG ,", "start": 109, "end": 121, "token_start": 18, "token_end": 21}, {"span_id": 3, "text": "mitoxantrone", "start": 122, "end": 134, "token_start": 21, "token_end": 22}, {"span_id": 4, "text": "adriamycin", "start": 140, "end": 150, "token_start": 24, "token_end": 25}, {"span_id": 5, "text": "methotrexate", "start": 172, "end": 184, "token_start": 31, "token_end": 32}, {"span_id": 6, "text": "Ara C", "start": 192, "end": 197, "token_start": 34, "token_end": 36}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 5, 6], "is_context_needed": true}, {"class": "POS", "spans": [0, 1, 2, 4, 5, 6], "is_context_needed": true}], "paragraph": "VIM3-ARA C: an effective salvage regimen in refractory or recurrent aggressive non Hodgkin's lymphoma. A report on 18 cases.  Based on encouraging results of previous combination regimens , we used a combination of VM26 , ifosfamide , methyl GAG , mitoxantrone ( or adriamycin ) , high-dose ( HD ) methotrexate and HD Ara C to treat 18 patients with relapsed or refractory NHL . Front-line therapy had been in most of them a reinforced CHOP regimen. Twelve patients (67 per cent) responded: there were nine (50 per cent) partial responses (PR) and three (17 per cent) complete remissions (CR). Nine of these 12 responders were grafted (eight autologous, one allogeneic transplants), one relapsed before autograft could be performed and the two remaining patients were excluded from autograft because of positive bone marrow. Five of nine patients remained free of disease after 11+ to 27+ months. Response rate was higher in patients who relapsed 'off' therapy (2/3), but CR was also obtained in two refractory NHL and persisted for 11+ and 26+ months, suggesting that VIM3-ARA C was, at least partially, non-cross-resistant with front-line adriamycin-containing regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/1743628/"}
{"doc_id": "a64fa34c261376602b678d6653cbfc87", "sentence": "We treated this patient with six cycles of CHOEP ( Cyclophosphamide , Doxorubicin , Vincristine , Etoposide , and Prednisone ) chemotherapy .", "spans": [{"span_id": 0, "text": "Cyclophosphamide", "start": 51, "end": 67, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "Doxorubicin", "start": 70, "end": 81, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "Vincristine", "start": 84, "end": 95, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "Etoposide", "start": 98, "end": 107, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "Prednisone", "start": 114, "end": 124, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "ALK-positive anaplastic large cell lymphoma presenting multiple lymphomatous polyposis: A case report and literature review. Anaplastic large cell lymphoma (ALCL) is a type of T-cell lymphoma that can be divided into two categories: anaplastic lymphoma kinase-positive (ALK+) and ALK-negative. Gastrointestinal ALK+ ALCL is rare. Multiple lymphomatous polyposis (MLP) is thought to be a representative form of gastrointestinal lesion in mantle cell lymphoma, and T-cell lymphomas seldom show this feature. Here, we report the first known case of ALK+ ALCL with gastroduodenal involvement to present with MLP. ### Case Summary The patient was a 43-year-old man who was complained of a mass in the left inguinal area and was performed open biopsy. ALK+ ALCL was diagnosed pathologically. Computed tomography scan demonstrated multiple lymph node lesions in the abdomen - pelvis/inguinal region, and scattered nodular lesions in both lung fields. He did not complain of gastrointestinal symptoms. While, esophagogastroduodenoscopy identified MLP lesions from the antrum of the stomach to the descending portion of the duodenum and mild thickened folds on the corpus of the stomach, and biopsy showed invasion of ALK+ ALCL. We treated this patient with six cycles of CHOEP ( Cyclophosphamide , Doxorubicin , Vincristine , Etoposide , and Prednisone ) chemotherapy . At the conclusion of treatment, there was complete remission. Numerous white scars were found on the stomach, endoscopically consistent with a remission image of lymphoma. The endoscopic features of this case were thought to be similar to those of MCL. ### conclusion The macroscopic/endoscopic features of gastrointestinal ALK+ ALCL may be more similar to those of B-cell lymphomas rather than T-cell lymphomas.", "source": "https://pubmed.ncbi.nlm.nih.gov/31423437/"}
{"doc_id": "d0b9720d23cd33576ee3ef84353999bb", "sentence": "One study evaluated gemcitabine with gemcitabine and pertuzumab .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 20, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "gemcitabine", "start": 37, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "pertuzumab", "start": 53, "end": 63, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Gemcitabine for recurrent ovarian cancer - a systematic review and meta-analysis. More than 80 % of women with advanced ovarian cancer relapse either during or after adjuvant therapy. Platinum-sensitive women are rechallenged with a platinum-combination therapy and platinum-resistant women are challenged with non-platinum drugs. gemcitabine is one of many treatments that can be used both as single-agent or as combination therapy for the treatment of recurrent ovarian cancer. ### methods We included all randomised controlled trials investigating patients treated with gemcitabine for recurrent ovarian cancer and reporting data on overall survival, progression-free survival and toxicity. CENTRAL, EMBASE and MEDLINE were searched on the 31 ### results We included six randomised controlled trials that evaluated gemcitabine either alone or as combination therapy. Two studies compared gemcitabine to pegylated liposomal doxorubicin in women with platinum-resistant recurrent ovarian cancer. Difference in overall and progression-free survival was non-significant. gemcitabine treatment was associated with significantly more neutropenia, whereas pegylated liposomal doxorubicin was associated with significantly more hand-foot syndrome. One study evaluated carboplatin and gemcitabine to carboplatin. Difference in overall survival was non-significant, but progression-free survival was longer with gemcitabine and carboplatin (HR: 0.72, 95% CI 0.58-0.9). One study evaluated gemcitabine with gemcitabine and pertuzumab . Overall survival and progression-free survival was similar between the two arms. One study compared gemcitabine and carboplatin to gemcitabine, carboplatin and bevacizumab. Overall survival was similar in the two arms. Progression-free survival was significantly better in the bevacizumab arm (HR 0.48 95% CI 0.39-0.61). One study compared etoposide and gemcitabine to etoposide. The study showed similar overall survival and progression-free survival. ### discussion The results show that gemcitabine is an active and safe agent in the treatment of both platinum-sensitive and resistant recurrent ovarian cancer but might highlight the need of new randomised studies in heavily pre-treated patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/31604664/"}
{"doc_id": "d202522f84cf3c5b0747be8be67b851e", "sentence": "Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein ( MRP ) .", "spans": [{"span_id": 0, "text": "verapamil", "start": 105, "end": 114, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "reserpine", "start": 119, "end": 128, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Contribution of mdr1b-type P-glycoprotein to okadaic acid resistance in rat pituitary GH3 cells. Okadaic acid as well as other, structurally different, inhibitors of serine/threonine phosphatases 1 and 2A induce apoptosis in pituitary GH3 cells. Incubation with stepwise raised concentrations of okadaic acid resulted in the isolation of cells that were increasingly less sensitive to the cytotoxic effect of this agent. After about 18 months cells were selected that survived at 300 nM okadaic acid, which is about 30 times the initially lethal concentration. This study revealed that a major pharmacokinetic mechanism underlying cell survival was the development of a P-glycoprotein-mediated multidrug resistance (MDR) phenotype. The increase in mRNA levels of the mdr1b P-glycoprotein isoform correlated with the extent of drug resistance. Functional assays revealed that increasing drug resistance was paralleled by a decreased accumulation of rhodamine 123, a fluorescent dye which is a substrate of mdr1-mediated efflux activity. Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein ( MRP ) . Okadaic acid resistance included cross-resistance to other cytotoxic agents that are substrates of mdr1-type P-glycoproteins, like doxorubicin and actinomycin D, but not to non-substrates of mdr1, e.g. cytosine arabinoside. Thus, functional as well as biochemical features support the conclusion that okadaic acid is a substrate of the mdr1-mediated efflux activity in rat pituitary GH3 cells. Maintenance of resistance after withdrawal of okadaic acid as well as metaphase spreads of 100 nM okadaic acid-resistant cells suggested a stable MDR genotype without indications for the occurrence of extrachromosomal amplifications, e.g. double minute chromosomes.", "source": "https://pubmed.ncbi.nlm.nih.gov/10494879/"}
{"doc_id": "922f735090a2604374e6743893bd2a15", "sentence": "We conclude that the combination of thiotepa , 5FU , and leucovorin had significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer .", "spans": [{"span_id": 0, "text": "thiotepa", "start": 36, "end": 44, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "5FU", "start": 47, "end": 50, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "leucovorin", "start": 57, "end": 67, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Phase II trial of 5-fluorouracil, folinic acid, and N,N1,N11-triethylenethiophosphoramide (thiotepa) in patients with advanced breast cancer. A total of 35 women with advanced, metastatic breast cancer were treated with combination chemotherapy consisting of folinic acid 500 mg/m2 over 2 hours administered with 600 mg/m2 of 5FU at the midpoint of the folinic acid infusion weekly for 6 weeks, plus 60 mg/m2 of thiotepa on day 1 and day 28. The cycle was repeated every 8 weeks. Patients were evaluated for toxicity weekly. Response was evaluated at the end of each 8-week cycle. The median age was 55 years (range: 34-67). Prior to this study 30 patients had received chemotherapy; 13 had 1 regimen; 17 had 2 or more regimens; 8 had 5FU treatment. The overall response rate was 40% (1 complete and 13 partial); median duration of response was 4 months. Four of 8 patients with prior 5FU responded. Hematologic toxicity was significant; nadir WBC count: < 1,000/mm3 (10 patients); 1,000-1,999/mm (13 patients); nadir platelet count: < 20,000/mm3 (8 patients): 20,000-49,000/mm3 (8 patients); 50,000-99,000/mm3 (10 patients). We conclude that the combination of thiotepa , 5FU , and leucovorin had significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer .", "source": "https://pubmed.ncbi.nlm.nih.gov/7572752/"}
{"doc_id": "362de315475f7a6a9eb10761b7406f1f", "sentence": "Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin ( 20 mg/m2/d continuous infusion [ CI ] ) , fluorouracil ( 800 mg/m2/d CI ) , and leucovorin ( 500 mg/m2/d CI ; PFL ) for 4 days followed by concurrent therapy with cisplatin ( 100 mg/m2/d on days 1 and 22 ) and approximately 70 Gy of external-beam radiotherapy .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 135, "end": 144, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "fluorouracil", "start": 189, "end": 201, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "leucovorin", "start": 227, "end": 237, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "cisplatin", "start": 310, "end": 319, "token_start": 54, "token_end": 55}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Cisplatin, fluorouracil, and leucovorin induction chemotherapy followed by concurrent cisplatin chemoradiotherapy for organ preservation and cure in patients with advanced head and neck cancer: long-term follow-up. The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. ### Patients And Methods Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin ( 20 mg/m2/d continuous infusion [ CI ] ) , fluorouracil ( 800 mg/m2/d CI ) , and leucovorin ( 500 mg/m2/d CI ; PFL ) for 4 days followed by concurrent therapy with cisplatin ( 100 mg/m2/d on days 1 and 22 ) and approximately 70 Gy of external-beam radiotherapy . ### results Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. ### conclusion Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.", "source": "https://pubmed.ncbi.nlm.nih.gov/15284256/"}
{"doc_id": "9c5365a40b4985db2716f6a1bcce365b", "sentence": "The saliva is shown to inhibit human platelet aggregation induced by thrombin , collagen , adenosine diphosphate ( ADP ) , epinephrine , platelet activating factor ( 1-O-alkyl-2-acetyl-sn-3-glycerophophoryl choline [ PAF ] ) , and arachidonic acid .", "spans": [{"span_id": 0, "text": "epinephrine", "start": 123, "end": 134, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "platelet activating factor", "start": 137, "end": 163, "token_start": 23, "token_end": 26}], "rels": [], "paragraph": "Platelet aggregation and coagulation inhibitors in leech saliva and their roles in leech therapy. Prolonged bleeding by the host after the leech ceases to feed and several reports that the use of leeches restores blood flow in the microcirculation after plastic surgery led us to search for inhibitors of platelet aggregation in Hirudo medicinalis saliva. Dilute leech saliva was collected by phagostimulating starved leeches with a solution of arginine in saline. The saliva is shown to inhibit human platelet aggregation induced by thrombin , collagen , adenosine diphosphate ( ADP ) , epinephrine , platelet activating factor ( 1-O-alkyl-2-acetyl-sn-3-glycerophophoryl choline [ PAF ] ) , and arachidonic acid . We have isolated the PAF inhibitor and found it to be an amphipathic phosphoglyceride. We have also purified apyrase adenosine triphosphate ([ATP] diphosphohydrolase), which inhibits ADP-induced platelet aggregation, and have described collagenase. Besides well-known hirudin, Hirudo saliva contains a potent inhibitor of coagulation factor Xa. We also report antiaggregant and anticoagulant activities in the crop content of the closely related Nile leech, Limnatis nilotica. Anticoagulants of hematophagous species are surveyed. We have used medicinal leeches in plastic surgery for decompression of skin flaps and in patients with postphlebitic syndrome and peripheral arterial occlusions. Preliminary results indicate certain beneficial effects of leech therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/8836013/"}
{"doc_id": "4fe6d3a7529d53292ae55a225e485bef", "sentence": "This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 45, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "vinorelbine", "start": 60, "end": 71, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Randomized phase II clinical trial and biomarker analysis of paclitaxel plus epirubicin versus vinorelbine plus epirubicin as neoadjuvant chemotherapy in locally advanced HER2-negative breast cancer with TEKT4 variations. Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy . ### methods In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group. ### results 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P\u2009=\u20090.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P\u2009=\u20090.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P\u2009=\u20090.011). ### conclusions Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.", "source": "https://pubmed.ncbi.nlm.nih.gov/32975708/"}
{"doc_id": "16f4c299a62155543b6089073a1917bc", "sentence": "Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight ?", "spans": [{"span_id": 0, "text": "l-leucine", "start": 22, "end": 31, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "metformin", "start": 46, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "sildenafil", "start": 60, "end": 70, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial. This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. ### Study Question Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight ? ### Study Design We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18-65 years of age without diabetes and with the body mass index (BMI) of 30-45 kg/m2. ### Measures And Outcomes The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. ### results Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were -1.99%, -1.69%, and -1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin \u226512mU/L (3.5%). ### conclusions Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30-39.9 kg/m2, especially participants with hyperinsulinemia.", "source": "https://pubmed.ncbi.nlm.nih.gov/33369909/"}
{"doc_id": "4e1fd1d1db4d8bba13b1e7ac24a90361", "sentence": "Combinatory activity of linezolid and levofloxacin with antituberculosis drugs in Mycobacterium tuberculosis .", "spans": [{"span_id": 0, "text": "linezolid", "start": 24, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "levofloxacin", "start": 38, "end": 50, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combinatory activity of linezolid and levofloxacin with antituberculosis drugs in Mycobacterium tuberculosis . The increase of multidrug and extensively drug resistant Mycobacterium tuberculosis strains turns the search for new tuberculosis (TB) treatment options of paramount importance. ### objective In this sense, the present study evaluates the in vitro activity of isoniazid (INH)/rifampicin (RIF)/levofloxacin (LVX) and INH/RIF/linezolid (LNZ) combinations in resistant M. tuberculosis. ### design The activities of the combinations were evaluated with M. tuberculosis H ### results MIC ranged from 0.03 - 6.25\u202f\u03bcg/mL for INH, 0.008-100\u202f\u03bcg/mL for RIF, 0.12-0.25\u202f\u03bcg/mL for LVX and 0.25-0.5\u202f\u03bcg/mL for LNZ in the H ### conclusion The present study calls attention for the potential use of INH/RIF/LVX and INH/RIF/LNZ combinations in the treatment of resistant TB.", "source": "https://pubmed.ncbi.nlm.nih.gov/30029913/"}
{"doc_id": "636111941b260acfe7cf2c70fa38a62c", "sentence": "Canadian clinical guidelines recommend the use of the combination of tamsulosin and dutasteride for men with moderate/severe symptoms associated with BPH and enlarged prostate volume .", "spans": [{"span_id": 0, "text": "tamsulosin", "start": 69, "end": 79, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dutasteride", "start": 84, "end": 95, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Cost analysis of fixed-dose combination of dutasteride and tamsulosin compared with concomitant dutasteride and tamsulosin monotherapy in patients with benign prostatic hyperplasia in Canada. We estimate the lifetime cost of treatment for moderate/severe symptoms associated with benign prostatic hyperplasia (BPH) in a cohort of Canadian men aged 50 to 59, and we evaluate the costs of 2 daily bioequivalent treatment options: fixed-dose combination (FDC) of dutasteride (0.5 mg) and tamsulosin (0.4 mg), or concomitant administration of dutasteride (0.5 mg) and tamsulosin (0.4 mg) monotherapies. ### methods The expected lifetime costs were estimated by modelling the incidence of acute urinary retention (AUR), BPH-related surgery and clinical progression over a patient's lifetime (up to 25 years). A model was developed to simulate clinical events over time, based on a discrete Markov process with 6 mutually exclusive health states and annual cycle length. ### results The estimated lifetime budget cost for the cohort of 374 110 men aged 50 to 59 in Canada is between $6.35 billion and $7.60 billion, equivalent to between $16 979 and $20 315 per patient with moderate/severe symptoms associated with BPH. Costs are lower for FDC treatment, with the net difference in lifetime budget impact between the 2 treatment regimens at $1.25 billion. In this analysis, the true costs of BPH in Canada are underestimated for 2 main reasons: (1) to make the analysis tractable, it is restricted to a cohort aged 50 to 59, whereas BPH can affect all men; and (2) a closed cohort approach does not include the costs of new (incident) cases. ### conclusion Canadian clinical guidelines recommend the use of the combination of tamsulosin and dutasteride for men with moderate/severe symptoms associated with BPH and enlarged prostate volume . This analysis, using a representational patient group, suggests that the FDC is a more cost-effective treatment option for BPH.", "source": "https://pubmed.ncbi.nlm.nih.gov/24454593/"}
{"doc_id": "1e2154eeedba947f07269a6b40e09f81", "sentence": "The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor ( perindopril ) and of the diuretic indapamide in spontaneously hypertensive rats ( SHR ) .", "spans": [{"span_id": 0, "text": "perindopril", "start": 144, "end": 155, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "indapamide", "start": 178, "end": 188, "token_start": 29, "token_end": 30}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects.  The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor ( perindopril ) and of the diuretic indapamide in spontaneously hypertensive rats ( SHR ) . ### methods Adult SHR were treated with placebo or increasing doses of the combination of the drugs (0.3, 1 and 3 mg/kg per day; ratio of doses 0.32). In a separate set of experiments, the effects of the drugs combined (1 mg/kg per day) was compared with those induced by each drug alone. ### results The drug combination dose-dependently decreased systolic blood pressure and its hypotensive effect was more marked than those induced by each treatment administered alone (untreated 208 +/- 5 mmHg, indapamide 185 +/- 5 mmHg, perindopril 150 +/- 3 and the combination 123 +/- 7 mmHg). A 12-week treatment with the drug combination (1 mg/kg per day) was not accompanied by any change in diuresis or urinary excretion of Na or K. The same treatment decreased cardiac hypertrophy and collagen. At the vascular level, the drug combination decreased aortic, carotid and femoral media cross-sectional areas, as well as aortic and carotid collagen density. This latter effect was accompanied by a significant increase in carotid artery compliance assessed in vivo at constant pressure. Finally, in isolated aortae, chronic combined drug treatment was associated with an increased basal release of nitric oxide and a decrease in the hypertension-induced endothelium-dependent contractions in response to acetylcholine. ### conclusion These experiments suggest that chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor and a diuretic such as indapamide may be of value in the treatment of hypertension.", "source": "https://pubmed.ncbi.nlm.nih.gov/8986928/"}
{"doc_id": "2197c51f733605c3f8260a584aed73ec", "sentence": "A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia .", "spans": [{"span_id": 0, "text": "azacitidine", "start": 19, "end": 30, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "fludarabine", "start": 55, "end": 66, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "cytarabine", "start": 71, "end": 81, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": true}], "paragraph": "A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia . Options to treat elderly patients (\u226565 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA). ### methods Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was \u22650.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. ### results The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). ### conclusions FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/33626197/"}
{"doc_id": "f933973c4ea22c3f3c27201921adcf04", "sentence": "Five other treatments closely followed ( dabrafenib [ HR PFS : 0.30 ] , nivolumab plus ipilimumab [ HR PFS : 0.34 ] , vemurafenib [ HR PFS : 0.38 ] , nivolumab [ HR PFS : 0.42 ] and pembrolizumab [ HR PFS : 0.46 ] ) .", "spans": [{"span_id": 0, "text": "dabrafenib", "start": 41, "end": 51, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "nivolumab", "start": 72, "end": 81, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "ipilimumab", "start": 87, "end": 97, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "vemurafenib", "start": 118, "end": 129, "token_start": 24, "token_end": 25}, {"span_id": 4, "text": "nivolumab", "start": 150, "end": 159, "token_start": 32, "token_end": 33}, {"span_id": 5, "text": "pembrolizumab", "start": 182, "end": 195, "token_start": 40, "token_end": 41}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma. Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. ### methods A systematic literature review (SLR) was conducted in Embase, MEDLINE\u00a0and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS)\u00a0and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel\u00a0and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. ### results The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen\u00a0treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed ( dabrafenib [ HR PFS : 0.30 ] , nivolumab plus ipilimumab [ HR PFS : 0.34 ] , vemurafenib [ HR PFS : 0.38 ] , nivolumab [ HR PFS : 0.42 ] and pembrolizumab [ HR PFS : 0.46 ] ) . In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46)\u00a0and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). ### conclusions Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.", "source": "https://pubmed.ncbi.nlm.nih.gov/31670077/"}
{"doc_id": "94f63b0823dca4159b120ef7a33e61d3", "sentence": "IGROV-1/APL resistant cell line shows the typical MDR phenotype : ( 1 ) increased expression of membrane-associated P-glycoprotein , ( 2 ) cross-resistance to drugs like etoposide , doxorubicin , vinblastine , vincristine , taxol , colchicin and the novel anticancer drug Yondelis ( ET-743 ) .", "spans": [{"span_id": 0, "text": "etoposide", "start": 170, "end": 179, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "doxorubicin", "start": 182, "end": 193, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "vinblastine", "start": 196, "end": 207, "token_start": 30, "token_end": 31}, {"span_id": 3, "text": "vincristine", "start": 210, "end": 221, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression. Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype : ( 1 ) increased expression of membrane-associated P-glycoprotein , ( 2 ) cross-resistance to drugs like etoposide , doxorubicin , vinblastine , vincristine , taxol , colchicin and the novel anticancer drug Yondelis ( ET-743 ) . The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin by increasing the drug intracellular concentration. The resistance to Aplidin was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells over-expressing Pgp are resistant to Aplidin was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin compared to the CEM parental cell line.", "source": "https://pubmed.ncbi.nlm.nih.gov/16258264/"}
{"doc_id": "0ad86118b39b724723eb97299cbb1378", "sentence": "Patients with newly diagnosed , locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin ( area under the curve , 1.5 ) and paclitaxel ( 45 mg/m(2 ) ) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks ( every day for 18 days , twice a day for 12 days ) ( grading determined according to the TNM staging system ) .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 98, "end": 109, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "paclitaxel", "start": 145, "end": 155, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer. A randomized phase 2 study was performed to investigate the efficacy/toxicity of combining concomitant boost radiation and weekly carboplatin/paclitaxel with or without amifostine in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). ### methods Patients with newly diagnosed , locally advanced stage III or IV SCCHN received 4 weekly doses of carboplatin ( area under the curve , 1.5 ) and paclitaxel ( 45 mg/m(2 ) ) concurrently with concomitant boost radiation consisting of 72 grays in 42 fractions over 6 weeks ( every day for 18 days , twice a day for 12 days ) ( grading determined according to the TNM staging system ) . All patients were randomized to subcutaneous daily amifostine at a dose of 500 mg (Arm A) or no amifostine (Arm B). Toxicity data were collected weekly, and saliva collection was performed with and without citric acid stimulation. To evaluate the correlation between serum cytokine levels and the severity of oral mucositis, we evaluated a subset (13 patients in Arm A and 11 patients in Arm B) of subjects at baseline and then on alternate weeks. ### results Fifty-eight patients were enrolled, 29 in each arm. The majority of patients were men (90%), had stage IV disease (82%), and had the oropharynx as the primary tumor site (60%). Major toxicities encountered were similar in both arms and included grade 3 (as determined by Common Terminology Criteria for Adverse Events, version 3.0) mucositis (75% in Arm A and 70% in Arm B) and grade 2 xerostomia (41% in both arms). The median number of amifostine doses delivered was 28, with skin toxicity (grade 3 in 11 patients) as the limiting factor. Saliva production showed no difference between the arms. The median follow-up was 34 months, and only 5 failures had been encountered (2 local and 3 distant) at the time of last follow-up, with an overall survival rate of 89%. Neck dissection was performed in 25 patients; 5 patients demonstrated persistent disease and 4 patients were alive without disease recurrence at the time of last follow-up. The median time to percutaneous endoscopic gastrostomy removal was 9.6 months in Arm A and 10.4 months in Arm B. Only 1 patient remained percutaneous endoscopic gastrostomy-dependent at the time of last follow-up. A correlation was noted between levels of selected cytokines and mucositis severity, in which higher levels of proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-1, and IL-6) and lower levels of anti-inflammatory cytokines (IL-13) were noted. No changes in C-reactive protein levels were noted. ### conclusions Four weekly doses of carboplatin/paclitaxel with concomitant boost radiation was found to be a highly effective regimen in this patient population with advanced SCCHN. The overall survival rate was 89%. The time to percutaneous endoscopic gastrostomy removal was prolonged. amifostine given subcutaneously did not improve the rates of xerostomia and mucositis with this fairly intensive chemoradiotherapy regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/19634161/"}
{"doc_id": "20e450bb899c2d7d5613cd92168ae214", "sentence": "Phase 1b trial of docetaxel , prednisone , and pazopanib in men with metastatic castration-resistant prostate cancer .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 18, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "prednisone", "start": 30, "end": 40, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "pazopanib", "start": 47, "end": 56, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase 1b trial of docetaxel , prednisone , and pazopanib in men with metastatic castration-resistant prostate cancer . docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. ### methods This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. ### results Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75\u2009mg/m ### conclusions The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/31497882/"}
{"doc_id": "c48cfa5bbedd29f4434e9586b60ec7ce", "sentence": "Growth inhibition of cloned promastigotes showed that the films have enough releasing capacity and in vivo system , the films containing paromomycin and gentamicin was able to reduce the lesion size and induced complete cure in 80 % of the mice but relapse was seen in 60 % of the cured mice and overall 50 % cure rate was seen during 20 weeks period of the study .", "spans": [{"span_id": 0, "text": "paromomycin", "start": 137, "end": 148, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "gentamicin", "start": 153, "end": 163, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Leishmanicidal Activity of Films Containing Paromomycin and Gentamicin Sulfate both In Vitro and In Vivo. Based on the efficacy of paromomycin ointment and recent ongoing clinical trials of combination of paromomycin and gentamicin, a new physical form of films of the paromomycin and gentamicin was prepared and anti-Leishmania activities of the prepared films were assessed in vitro and in vivo. ### methods paromomycin 15% and gentamicin 0.5% was incorporated in a film using ethyl cellulose and HPMC (Hydroxyl Propyl Methyl Cellulose). In order to assess the drug release and anti-Leishmania activities of the preparation, a clone L. major parasite was established using a set of modified NNN medium without overlay liquid layer. Therapeutic effects of the films were evaluated using Balb/c mice model. The mice were inoculated with 2\u00d710(6)L. major promastigotes (MRHO/IR/75/ER) and then when the lesions developed the mice were randomly divided in 3 groups, 10 mice per group, and treated with either perpetrated films or placebo for 28 days or left untreated. ### results Growth inhibition of cloned promastigotes showed that the films have enough releasing capacity and in vivo system , the films containing paromomycin and gentamicin was able to reduce the lesion size and induced complete cure in 80 % of the mice but relapse was seen in 60 % of the cured mice and overall 50 % cure rate was seen during 20 weeks period of the study . ### conclusion It seems that the prepared films might be further used in human clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/22347298/"}
{"doc_id": "084c0fc7d39df4df24e947ba414c6e06", "sentence": "Management and outcome : The patient was initially treated with bortezomib and dexamethasone for the myeloma .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 64, "end": 74, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dexamethasone", "start": 79, "end": 92, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Synchronous detection of multiple myeloma and acute myeloid leukemia: A diagnostic and therapeutic challenge. Synchronous detection of multiple myeloma and acute myeloid leukemia in a single patient is a rare coincidence. Treatment of these patients is still unclear, mostly based on acute myeloid leukemia strategies combined with bortezomib. ### Case Report A 72-year-old male with no medical history was investigated for pancytopenia. On medical examination, he was complicated with a wide and severe skin infection on arm. On examination of bone marrow aspirate, 25% myeloblasts infiltration and additional 10% plasma cells were seen. Acute myeloid leukemia was diagnosed and plasma cell proliferation was attributed to reactive plasmacytosis due to skin infection. However, flowcytometric studies and immunohistochemical examination revealed two different cell populations with 30-40% atypical plasma cells and >20% myeloblasts. Serum M-protein detected by serum electrophoresis test and immunofixation test revealed a monoclonal IgG lambda band. He was diagnosed with concurrent acute myeloid leukemia and multiple myeloma without history of chemotherapy. Management and outcome : The patient was initially treated with bortezomib and dexamethasone for the myeloma . Subsequently, azacitidine was administered subcutaneously for the acute myeloid leukemia treatment. The tru-cut biopsy of the lesion on his arm revealed suppurative inflammatory findings and no malign cells detected. Antibiotherapy was started according to susceptibility. He expired after three\u2009months of survival. ### discussion The synchronous occurrence of these two different clonal hematological malignancies is rare in hematology practice. Patient-based prospective studies and case series are needed to guide diagnosis and treatment strategies. Furthermore, this report highlights the importance of ruling out reactive plasmacytosis in patients with hematological malignancy who developed severe infections.", "source": "https://pubmed.ncbi.nlm.nih.gov/33620259/"}
{"doc_id": "a8dd8920926a20064069044a6f415a1c", "sentence": "Majority of the interventions were to stop the antimicrobial therapy ( 30.3 % ) , and the most common audited antimicrobials was Piperacillin/Tazobactam ( 25.5 % ) , followed by Meropenem ( 11.82 % ) , Amoxicillin/Clavulanate and Vancomycin ( 8.18 % ) respectively .", "spans": [{"span_id": 0, "text": "Meropenem", "start": 178, "end": 187, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "Vancomycin", "start": 230, "end": 240, "token_start": 38, "token_end": 39}], "rels": [], "paragraph": "Antimicrobial stewardship program in a Malaysian district hospital: First year experience. Antimicrobial resistance is an alarming public health threat that requires urgent global solution. Implementation of antimicrobial stewardship program (ASP) is an essential practice element for healthcare institutions in gate-keeping judicious antimicrobial use. This study highlighted the development, first year experience, and result of the implementation of ASP utilizing persuasive and restrictive approaches in a Malaysian district hospital. ### methods An observational study was conducted between January 2015 to December 2015 on implementation of ASP among hospitalized inpatients age 12 years old and above. ### results Recommendations were provided for 60% of cases (110 patients) with the average acceptance rate of 83.33%. Majority of the interventions were to stop the antimicrobial therapy ( 30.3 % ) , and the most common audited antimicrobials was Piperacillin/Tazobactam ( 25.5 % ) , followed by Meropenem ( 11.82 % ) , Amoxicillin/Clavulanate and Vancomycin ( 8.18 % ) respectively . The concordance rate towards authorization policy was increased in 2015 (71.59% of cases) as compared before the implementation of ASP in 2014 (60.6% of cases). Restrictive enforcement under ASP had been shown to improve significantly adherence rate towards antimicrobials authorization policy (p-value: 0.004). ### conclusion ASP was successfully implemented in a district hospital. Future studies on its clinical outcomes are important to evaluate its effectiveness as well as focus on the improvement to the pre-existing strategies and measures.", "source": "https://pubmed.ncbi.nlm.nih.gov/27648056/"}
{"doc_id": "5e8cfd3f800bb3e3855a1c5a47bfbd12", "sentence": "Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer .", "spans": [{"span_id": 0, "text": "Ribociclib", "start": 46, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "Abemaciclib", "start": 61, "end": 72, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer . Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field.", "source": "https://pubmed.ncbi.nlm.nih.gov/27493615/"}
{"doc_id": "42a09be85103a5958ec546ff014eb697", "sentence": "We retrospectively evaluated 52 metastatic renal cell carcinoma patients who were treated with nivolumab plus ipilimumab between August 2015 and January 2020 .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 95, "end": 104, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "ipilimumab", "start": 110, "end": 120, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. To investigate the efficacy and safety of first-line nivolumab plus ipilimumab for patients treated with metastatic renal cell carcinoma. ### methods We retrospectively evaluated 52 metastatic renal cell carcinoma patients who were treated with nivolumab plus ipilimumab between August 2015 and January 2020 . Data on patient characteristics, treatment parameters and adverse events were obtained. Oncological outcomes were assessed according to the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model. Furthermore, differences in treatment parameters between patients with objective response (responders) and non-responders were compared. ### results The median age and follow-up periods were 69\u00a0years and 8.2\u00a0months, respectively. The 1-year progression-free survival and overall survival rates were 55% and 75%, respectively. The objective response rate was 39%, and it was significantly different between the International Metastatic Renal Cell Carcinoma Database Consortium intermediate- and poor-risk groups (52% vs 24%). We observed 36 (69%) any immune-related adverse events, and 19 (37%) severe immune-related adverse events (grades\u00a0III-V). The International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and higher value of initial C-reactive protein (\u22651.0\u00a0mg/dL) were significantly associated with non-responders. Patients with two factors (the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group plus C-reactive protein \u22651.0\u00a0mg/dL) had a significantly poor overall survival than those with none or a single factor. ### conclusions In our experience, treatment response to nivolumab plus ipilimumab is comparable with that of the CheckMate 214 clinical trial, but the incidence of treatment-related adverse events is lower. The International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and initial C-reactive protein value might have a prognostic value for poor survival.", "source": "https://pubmed.ncbi.nlm.nih.gov/32893401/"}
{"doc_id": "5059821f165b54b741fff5d949937c46", "sentence": "Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat , thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier ( BBB ) in vivo .", "spans": [{"span_id": 0, "text": "cyclosporin", "start": 99, "end": 110, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "escitalopram", "start": 151, "end": 163, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "escitalopram", "start": 188, "end": 200, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "escitalopram", "start": 257, "end": 269, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents. Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat , thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier ( BBB ) in vivo . The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.", "source": "https://pubmed.ncbi.nlm.nih.gov/23670590/"}
{"doc_id": "43e5febf8c327a283f09cb768dda4713", "sentence": "The combination of mezlocillin and an aminoglycoside produced synergy more often than did carbenicillin plus an aminoglycoside .", "spans": [{"span_id": 0, "text": "mezlocillin", "start": 19, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "carbenicillin", "start": 90, "end": 103, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "aminoglycoside", "start": 38, "end": 52, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "aminoglycoside", "start": 112, "end": 126, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "COMB", "spans": [1, 3], "is_context_needed": true}], "paragraph": "Synergy of azlocillin and mezlocillin combined with aminoglycoside antibiotics and cephalosporins. Synergistic activity between both azlocillin and mezlocillin and aminoglycosides or cefazolin could be demonstrated by checkerboard dilution, isobologram, and killing curve techniques. azlocillin and mezlocillin combined with gentamicin, netilmicin, or amikacin were synergistic against Escherichia coli, Klebsiella, Citrobacter, Enterobacter, Serratia, and indole-positive Proteus. Synergy was observed with isolates that were susceptible or resistant to azlocillin or mezlocillin. Synergy was seen most often when azlocillin or mezlocillin were combined with amikacin, gentamicin, or netilmicin against Pseudomonas aeruginosa. The combination of mezlocillin and an aminoglycoside produced synergy more often than did carbenicillin plus an aminoglycoside . No antagonism was seen when aminoglycoside antibiotics were combined with azlocillin or mezlocillin. cefazolin was synergistic against Pseudomonas, Providencia, P. mirabilis, indole-positive Proteus, Citrobacter, Klebsiella, and Escherichia coli, when combined with azlocillin or mezlocillin. However, the combination of either agent with cefazolin was antagonistic when tested against selected indole-positive Proteus and Enterobacter isolates.", "source": "https://pubmed.ncbi.nlm.nih.gov/666302/"}
{"doc_id": "6d09f2725d4b0e2d4cf4b2c255f6dec9", "sentence": "Eligible patients ( n = 17 ) were divided into 2 groups receiving a combined chemotherapy of intravenous cisplatinum ( 70 mg/m2 ) and cyclophosphamide ( 700 mg/m2 ) with or without the addition of Lenograstim .", "spans": [{"span_id": 0, "text": "cisplatinum", "start": 105, "end": 116, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "cyclophosphamide", "start": 134, "end": 150, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "Lenograstim", "start": 197, "end": 208, "token_start": 35, "token_end": 36}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The use of lenograstim (Granocyte) in chemotherapy for ovarian cancer. We have conducted an open, controlled study on the febrile neutropenia effects by lenograstim (Granocyte) therapy following cytotoxic chemotherapy of cisplatinum and cyclophosphamide in patients with primary advanced epithelial ovarian cancer. Eligible patients ( n = 17 ) were divided into 2 groups receiving a combined chemotherapy of intravenous cisplatinum ( 70 mg/m2 ) and cyclophosphamide ( 700 mg/m2 ) with or without the addition of Lenograstim . Subcutaneous administration of lenograstim (100 micrograms/day) for 7 consecutive days was given from day 8 to day 14 of the 3rd to the 5th cycle of chemotherapy in lenograstim treated patients. After 3 cycles of treatment, lenograstim treated patients (group 1, n = 10) showed a significant improvement in white blood cell (WBC) count as compared with group 2 (control) of 7 patients (p = 0.00002). Group 1 patients also showed an increased C-reactive protein, though of no significance. There were no significant differences among the 2 groups regarding ESR, hematocrit, platelet counts and blood chemistry profiles. This preliminary data encourages more study of the benefits of lenograstim in the treatment of ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/9681128/"}
{"doc_id": "b3163af31193b27f97a8a16973bd30c2", "sentence": "In particular , caspofungin for invasive candidiasis and voriconazole for invasive aspergillosis seem at least equivalent to amphotericin B. A clear advantage is the advent of lipid formulations of amphotericin B.", "spans": [{"span_id": 0, "text": "caspofungin", "start": 16, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "voriconazole", "start": 57, "end": 69, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "amphotericin", "start": 125, "end": 137, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "amphotericin", "start": 198, "end": 210, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "[Therapy of severe fungal infections]. Severe fungal infections increase in numbers in the Western world. This is due to more intensive therapies against cancers leading to severe and prolonged immunosuppression. For many years treatment of severe fungal infections had to be done solely with amphothericin B desoxycholate and 5-fluorocytosine. With the advent of triazoles such as fluconazole, lipid formulations of amphotericin B and the development of echinocandines such as caspofungin also severe candidiasis and invasive aspergillosis has become treatable. In particular , caspofungin for invasive candidiasis and voriconazole for invasive aspergillosis seem at least equivalent to amphotericin B. A clear advantage is the advent of lipid formulations of amphotericin B. This regards especially side effects which are reduced with these newer formulations, i.e. nephrotoxicity. Due to the fact that prospective trials are difficult to conduct because patient populations may vary considerably (especially the underlying disease) many comparisons were not yet performed. Nevertheless, promising results indicate that certain combinations of antifungals may enhance prognosis of refractory fungal infections with a so far very serious prognosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/14689198/"}
{"doc_id": "9d63911361295300c7b4ea4df9aa7984", "sentence": "Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days , and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1 .", "spans": [{"span_id": 0, "text": "Ifosfamide", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 92, "end": 103, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for recurrent or refractory osteosarcoma patients in China: a retrospective study. The aim of this retrospective study was to evaluate the feasibility and efficacy of response to continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for patients with recurrent or refractory osteosarcoma. ### Materials And Methods Eighteen recurrent or refractory osteosarcoma patients who were treated with continuous-infusion ifosfamide and doxorubicin combination between May 1999 and April 2011 were included in the analysis. Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days , and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1 . The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. ### results The patients (ages 7-53 years) received a total of 42 cycles of chemotherapy (median: 2 courses; range: 2-5 courses). The overall response rate was 0% and the disease control rate was 22.3%, with four patients having stable disease. The median time to progression and overall survival time were 2 months (range: 2-5 months) and 9 months (range: 3-29 months), respectively. Major severe toxicities were leucopenia 7 (38.9%), nausea and vomiting 3 (16.7%) and alopecia 9 (50%). There were no treatment-related deaths. ### conclusions In our experience, continuous-infusion ifosfamide and doxorubicin combination therapy at this dosage and schedule was found to be well tolerated and moderate effective, which could be considered as salvage therapy for patients with recurrent or refractory osteosarcoma. Further assessment is necessary to confirm the safety and efficacy of this treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/25824770/"}
{"doc_id": "269cf8a7f7d3ae688bf0187afe5819b6", "sentence": "A Randomized , Double-blind , Placebo-controlled Trial of Celecoxib Augmentation of Sertraline in Treatment of Drug-naive Depressed Women : A Pilot Study .", "spans": [{"span_id": 0, "text": "Celecoxib", "start": 58, "end": 67, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "Sertraline", "start": 84, "end": 94, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Randomized , Double-blind , Placebo-controlled Trial of Celecoxib Augmentation of Sertraline in Treatment of Drug-naive Depressed Women : A Pilot Study . This study was designed to examine the antidepressant effect of celecoxib (200 mg/day) augmentation of sertraline in the treatment of female patients with first episode of major depression over 8 weeks of therapy. Thirty female outpatients diagnosed with first episode of major depression, were recruited for this study. Participants were randomly assigned into two equal groups receiving either sertraline plus celecoxib 100 mg twice daily or sertraline plus placebo twice daily. Patients were assessed by Hamilton Depression and Anxiety Rating Scale at baseline, week 4 and week 8 of treatment. Both treatment groups showed notable improvement in their symptoms from baseline; however, celecoxib group showed greater decrease in Hamilton Depression Scores compared to the placebo group after four weeks of treatment. Response rates were also found to be significantly higher in the celecoxib group compared to the placebo group over 4 weeks. Nevertheless, the mentioned differences between two groups were not significant at the end of week 8. Also, remission rate was remarkably higher in celecoxib group in comparison with placebo at the end point. The results suggested that celecoxib may hasten the onset of therapeutic action of sertraline and increase response and remission rate in depressive disorders.", "source": "https://pubmed.ncbi.nlm.nih.gov/26330878/"}
{"doc_id": "33ceaf2ec6a03465860d3825e935bddb", "sentence": "The aim of this retrospective study was to investigate susceptibility rates of Mycobacterium tuberculosis complex ( MTBC ) isolates against streptomycin , rifampicin , isoniazid , and ethambutol between January 1998 and December 2000 in the Turkish Army .", "spans": [{"span_id": 0, "text": "streptomycin", "start": 140, "end": 152, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "isoniazid", "start": 168, "end": 177, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "ethambutol", "start": 184, "end": 194, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Resistance patterns of Mycobacterium tuberculosis complex isolates in the Turkish Army from 1998 to 2000.  The aim of this retrospective study was to investigate susceptibility rates of Mycobacterium tuberculosis complex ( MTBC ) isolates against streptomycin , rifampicin , isoniazid , and ethambutol between January 1998 and December 2000 in the Turkish Army . Specimens collected from patients were cultured both conventionally and radiometrically. Differentiation of MTBC bacteria from Mycobacteria other than tuberculosis bacilli was made by the BACTEC p-nitro-alpha-acetyl-amino-beta-hydroxypropiophenone test. Susceptibility testing of MTBC isolates was performed using the BACTEC radiometric susceptibility assay for mycobacteria. Most of the specimens originated from respiratory system. A total of 98 isolates in 1998, 123 isolates in 1999, and 84 isolates in 2000 were obtained and identified as MTBC using the radiometric BACTEC TB460 system. Initial resistance was most frequent to isoniazid followed by ethambutol, streptomycin , and rifampicin in this study period. The differences between resistance rates were not statistically significant on an annual basis. None of these isolates was resistant to all four antimycobacterial agents. Although resistance rates of our isolates were not as high as previously reported by some authors from Turkey and there was no significant difference between the annual susceptibility rates, routine screening of antituberculosis drug susceptibility should be continued to control the resistance development and its spread.", "source": "https://pubmed.ncbi.nlm.nih.gov/12546241/"}
{"doc_id": "f3511ea384b9ad10337cbf06d03a2514", "sentence": "JAK2 ATP competitive inhibitors ( ruxolitinib , lestaurtinib , SAR302503 , SB1518 and CYT387 ) or drugs that indirectly inhibit the JAK-STAT pathway ( everolimus ) have documented major effects on splenomegaly and its constitutional symptoms .", "spans": [{"span_id": 0, "text": "ruxolitinib", "start": 34, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "lestaurtinib", "start": 48, "end": 60, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "everolimus", "start": 151, "end": 161, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Emerging targeted therapies in myelofibrosis. Conventional drugs for myelofibrosis are driven by clinical needs, primarily anemia and splenomegaly. With these therapies, stem cell transplantation remains the only potentially curative approach. The discovery that mutations affecting JAK2 or MPL lead to activation of the intracellular JAK-STAT signaling pathway, and that other mutations (TET2, EZH2, ASXL1, IDH1 and IDH2) interfere with the normal machinery of epigenetics, has prompted to the development of therapies targeted at controling the major disease mechanisms. JAK2 ATP competitive inhibitors ( ruxolitinib , lestaurtinib , SAR302503 , SB1518 and CYT387 ) or drugs that indirectly inhibit the JAK-STAT pathway ( everolimus ) have documented major effects on splenomegaly and its constitutional symptoms . Epigenetic drugs (demethylating agents and histone deacetylase inhibitors) have displayed only minor effects on the disease symptoms. Relenting disease progression remains an unmet clinical need.", "source": "https://pubmed.ncbi.nlm.nih.gov/22780211/"}
{"doc_id": "dfc119d182b2ca831617594789da1242", "sentence": "We therefore tested second-generation inhibitors of the 20S proteasome ( delanzomib , carfilzomib and ixazomib ) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination ( b-AP15 , MLN4924 ) for their effectiveness and mechanism of action in GIST .", "spans": [{"span_id": 0, "text": "delanzomib", "start": 73, "end": 83, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "carfilzomib", "start": 86, "end": 97, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "ixazomib", "start": 102, "end": 110, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells. The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome ( delanzomib , carfilzomib and ixazomib ) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination ( b-AP15 , MLN4924 ) for their effectiveness and mechanism of action in GIST . All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.", "source": "https://pubmed.ncbi.nlm.nih.gov/32198455/"}
{"doc_id": "9991b6203110cd7b2d728fcfd1b25a75", "sentence": "In seven patients with type B insulin resistance , standardized treatment with rituximab , cyclophosphamide , and pulse steroids results in remission of the disease .", "spans": [{"span_id": 0, "text": "rituximab", "start": 79, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "cyclophosphamide", "start": 91, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "steroids", "start": 120, "end": 128, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies. Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success. ### methods We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment. ### results All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events. ### conclusions In seven patients with type B insulin resistance , standardized treatment with rituximab , cyclophosphamide , and pulse steroids results in remission of the disease . Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.", "source": "https://pubmed.ncbi.nlm.nih.gov/20484479/"}
{"doc_id": "44a992639d1a8ab6152baa1f9da60aed", "sentence": "The purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen ( regular and escalated ) ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisone ) as compared to the ABVD regimen ( doxorubicin , vinblastine , dacarbazine , bleomycin ) in Hodgkin lymphoma patients under the age of 40 at the time of treatment .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 143, "end": 152, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "etoposide", "start": 155, "end": 164, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "doxorubicin", "start": 167, "end": 178, "token_start": 29, "token_end": 30}, {"span_id": 3, "text": "cyclophosphamide", "start": 181, "end": 197, "token_start": 31, "token_end": 32}, {"span_id": 4, "text": "vincristine", "start": 200, "end": 211, "token_start": 33, "token_end": 34}, {"span_id": 5, "text": "procarbazine", "start": 214, "end": 226, "token_start": 35, "token_end": 36}, {"span_id": 6, "text": "prednisone", "start": 229, "end": 239, "token_start": 37, "token_end": 38}, {"span_id": 7, "text": "doxorubicin", "start": 276, "end": 287, "token_start": 46, "token_end": 47}, {"span_id": 8, "text": "vinblastine", "start": 290, "end": 301, "token_start": 48, "token_end": 49}, {"span_id": 9, "text": "dacarbazine", "start": 304, "end": 315, "token_start": 50, "token_end": 51}, {"span_id": 10, "text": "bleomycin", "start": 318, "end": 327, "token_start": 52, "token_end": 53}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": true}, {"class": "POS", "spans": [8, 9, 10, 7], "is_context_needed": true}], "paragraph": "Fertility in young patients following treatment for Hodgkin's lymphoma: a single center survey.  The purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen ( regular and escalated ) ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , prednisone ) as compared to the ABVD regimen ( doxorubicin , vinblastine , dacarbazine , bleomycin ) in Hodgkin lymphoma patients under the age of 40 at the time of treatment . ### methods A questionnaire was sent to 180 Hodgkin lymphoma (HL) patients. The questionnaire was composed of questions concerning reproduction and also menopausal and aging symptoms in females and males. The analyses were made using data collected from 123 patients (76 females and 47 males) who returned the questionnaire. All of the patients were treated between 1999 and 2012. ### results In comparing the ABVD and BEACOPP groups of female patients, the frequency of the therapy-induced amenorrhea and the restored menses following treatment were found to be significantly different statistically (p = 0.002 and p = 0.012, respectively). The secondary amenorrhea statistically appeared more often in the BEACOPP group (p = 0.003) while the cases of achieving pregnancy and having children after chemotherapy were not significantly different (p = 0.630, p = 0.070, respectively). In comparing the ABVD and BEACOPP treatments in male patients, the only significant difference was in the number of artificially inseminated or in vitro pregnancies achieved in the BEACOPP and escalated BEACOPP group, p = 0.008 and p = 0.002, respectively. In total, 45.2% of patients in the ABVD female group, 34.6% in the BEACOPP female group, 52.6% in the ABVD male group, and 33.3% in the male BEACOPP group, respectively, of patients attempting conception post-therapy, had children after chemotherapy. ### conclusions Based on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/26678493/"}
{"doc_id": "91b767ae52b2ae4a4f7e75bd7b793361", "sentence": "The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol , CGRP(8 - 37 ) , or combined propranolol+CGRP(8 - 37 ) .", "spans": [{"span_id": 0, "text": "DPDPE", "start": 27, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "propranolol", "start": 74, "end": 85, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "CGRP(8", "start": 88, "end": 94, "token_start": 13, "token_end": 14}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Delta-opioid augments cardiac contraction through \u03b2-adrenergic and CGRP-receptor co-signaling. Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing \u03b4-opioid receptors (DOR). We hypothesized that \u03b4-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist dpdpe (100 \u03bcg/kg) with or without 10-min pretreatment with either \u03b2-adrenergic receptor (\u03b2-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP(8-37) (300 \u03bcg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after dpdpe infusion. At 5-min dpdpe induced a 36 \u00b1 18% (p<0.001) increase of the LVFS, which continues to increase to 51 \u00b1 24% (p<0.0001) by 10 min, and 68 \u00b1 19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9\u00b15% (p<0.01) by 5 min and 11 \u00b1 6% (p<0.001) by 15 min post dpdpe infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17 \u00b1 8% (p<0.05) and 28\u00b15% (p<0.001) by 5- and 20-min post dpdpe administration, respectively. There was a modest (9 \u00b1 9%, p=0.03) decrease in SBP that was not apparent until 20 min post dpdpe infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol , CGRP(8 - 37 ) , or combined propranolol+CGRP(8 - 37 ) . Furthermore, in whole animal and cardiomyocyte cell culture preparations, dpdpe induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP(8-37). DOR agonists augment myocardial contraction through enhanced \u03b2-AR and CGRPR co-signaling.", "source": "https://pubmed.ncbi.nlm.nih.gov/22108711/"}
{"doc_id": "4e423fff47565b3915ebb416a65e38ed", "sentence": "A case of Scedosporium apiospermum infection after BMT , treated initially with amphotericin B ( total dose of 2.5 g ) and then with itraconazole ( for 25 days ) , is reported here .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 80, "end": 92, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "itraconazole", "start": 133, "end": 145, "token_start": 24, "token_end": 25}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Scedosporium apiospermum pneumonia after autologous bone marrow transplantation. Although opportunistic infections after bone marrow transplantation (BMT) are very common, only five cases of Pseudallescheria boydii infection have been reported in the literature, two of which were autopsy findings. A case of Scedosporium apiospermum infection after BMT , treated initially with amphotericin B ( total dose of 2.5 g ) and then with itraconazole ( for 25 days ) , is reported here . When the patient failed to improve, Scedosporium apiospermum pneumonia was diagnosed and therapy was changed. The patient was treated successfully with miconazole (600 mg/8h for 32 days) and ketoconazole (200 mg/8h for 7 days) plus surgery.", "source": "https://pubmed.ncbi.nlm.nih.gov/8874080/"}
{"doc_id": "a61f2a1bdd946f81943993a86ee40960", "sentence": "Thymidine Phosphorylase/\u03b2-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 136, "end": 148, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "paclitaxel", "start": 154, "end": 164, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Thymidine Phosphorylase/\u03b2-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel . To assess the role of Thymidine Phosphorylase and \u03b2-tubulin III in clinical outcome of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. ### methods The clinical data and tumor biopsies prior treatment from 33 advanced gastric cancer patients receiving capecitabine plus paclitaxel (cohort 1, experimental group) and 18 patients receiving capecitabine plus cisplatin (cohort 2, control group) in Beijing Cancer Hospital from July 2003 to December 2008 were retrospectively collected and analyzed for Thymidine Phosphorylase and \u03b2-tubulin III expressions by immunohistochemistry. The relationships between expressions of biomarkers and response or survival were determined by statistical analysis. ### results The median age of 51 patients was 57 years (range, 27-75) with male 34 and female 17, and the response rate, median progression-free survival and overall survival were 43.1%, 120d and 265d. Among cohort 1, the response rate, median progression-free survival and overall survival in \u03b2-tubulin III positive (n = 22) and negative patients (n = 11) were 36.4%/72.7% (positive vs negative, P = 0.049), 86d/237d (P = 0.046) and 201d/388d (P = 0.029), respectively; the response rate (87.5% vs 14.3%, P = 0.01) and median progression-free survival (251d vs 84d, P = 0.003) in Thymidine Phosphorylase positive & \u03b2-tubulin III negative patients (n = 8) were also significantly higher than those in Thymidine Phosphorylase negative & \u03b2-tubulin III positive patients (n = 7). There was no correlation between \u03b2-tubulin III expression and response or survival among cohort 2 (n = 18). ### conclusions In Chinese advanced gastric cancer, Thymidine Phosphorylase positive & \u03b2-tubulin III negative might predict response and prognosis to capecitabine plus paclitaxel chemotherapy. Further prospective evaluation in large samples should be performed to confirm these preliminary findings.", "source": "https://pubmed.ncbi.nlm.nih.gov/21586171/"}
{"doc_id": "ab09d23f3137b7dee2757d07895c695b", "sentence": "An equihypotensive dose of the calcium antagonist nifedipine had no significant effect ; however , EMD 52692 produced the same reduction in infarct size as had nicorandil .", "spans": [{"span_id": 0, "text": "nifedipine", "start": 50, "end": 60, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "nicorandil", "start": 160, "end": 170, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "Cardioprotective effects of nicorandil. The effects of nicorandil, a nicotinamide nitrate with K(+)-channel-opening activity, was investigated in several models of ischemia-reperfusion injury in conscious and anesthetized dogs or isolated buffer-perfused rat hearts. In several models of reversible ischemic injury (stunned myocardium) in dogs, nicorandil resulted in an enhanced recovery of regional systolic shortening during reperfusion after a single episode of coronary artery occlusion (10-15 min). These beneficial actions of nicorandil were not shared by the nitrovasodilator sodium nitroprusside but were mimicked by the selective K(+)-channel opener EMD 52692. In a model of irreversible ischemia-reperfusion injury (i.e., 2 h of coronary occlusion followed by reperfusion) in anesthetized dogs, nicorandil produced a marked reduction of myocardial infarct size. An equihypotensive dose of the calcium antagonist nifedipine had no significant effect ; however , EMD 52692 produced the same reduction in infarct size as had nicorandil . In isolated, perfused rat hearts subjected to 20 min of low-flow (1.0 ml/min) global ischemia followed by 30 min of reperfusion, nicorandil (7 microM) resulted in a significant improvement in the recovery of isovolumic left ventricular minute work during reperfusion compared with untreated hearts. Finally, the results of in vitro experiments indicated that nicorandil (10(-6) to 10(-3) M) produced a concentration-dependent inhibition of superoxide anion free radical production by human and canine neutrophils. The K(+)-channel opener EMD 52692 also inhibited superoxide production in canine neutrophils. These results indicate that nicorandil is a highly efficacious myocardial protective agent in several animal models of reversible or irreversible ischemia-reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/1282172/"}
{"doc_id": "f92a7d9296c1377c90cc43814c1eb6b0", "sentence": "Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 13, "end": 23, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "doxorubicin", "start": 72, "end": 83, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Epirubicin: a review of its intravesical use in superficial bladder cancer. The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80 mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-alpha-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification. Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in many trials of intravesical epirubicin, and when reported generally occurred in < or =5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial . The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG. ### conclusions Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/10582777/"}
{"doc_id": "49c8d4c6aa6ad992443539db2ba18d2c", "sentence": "Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects .", "spans": [{"span_id": 0, "text": "irbesartan", "start": 68, "end": 78, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "hydrochlorothiazide", "start": 83, "end": 102, "token_start": 8, "token_end": 9}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Modeling of the pharmacokinetic/pharmacodynamic interaction between irbesartan and hydrochlorothiazide in normotensive subjects . To investigate the pharmacokinetic/pharmacodynamic (PK/PD) interaction between irbesartan (IRB) and hydrochlorothiazide (HCT) in normotensive subjects. ### methods A three-way crossover study was used. Serial drug concentrations and drug effects, including systolic and diastolic blood pressure and heart rate were monitored after administration of irbesartan and hydrochlorothiazide alone and in combination. The data were fitted to a PK/PD model and the parameters for irbesartan and hydrochlorothiazide when administered alone and in combination were compared. ### results The plasma profiles for irbesartan and hydrochlorothiazide followed the two-compartment model after a single dose. The PK parameters of irbesartan were not affected by hydrochlorothiazide; however irbesartan decreased the hydrochlorothiazide AUC by 25% and increased its clearance by 25%. There were no significant changes in heart rate after each drug alone or in combination. irbesartan plus hydrochlorothiazide had a greater blood pressure lowering effect compared with irbesartan alone, despite the unchanged irbesartan PK. The relationship between irbesartan plasma concentration and its effects plotted in chronological order showed anticlockwise hysteresis. The PD parameter estimates for the effect of irbesartan on systolic blood pressure, when administered with hydrochlorothiazide were significantly different from those when irbesartan was administered alone. This was manifested by a 25% increase in Emax , and a 40% decrease in EC50 , suggesting a synergistic blood pressure lowering effect for the combination. While parameter estimates for the effect of irbesartan on diastolic blood pressure were changed by hydrochlorothiazide, the differences were only significant for EC50 . ### conclusion A limited potential for clinically significant interactions between irbesartan and hydrochlorothiazide at the given doses were observed; therefore, no dosage adjustments were recommended for either drug when used together. (ClinicalTrials.gov Identifier NCT01858610)", "source": "https://pubmed.ncbi.nlm.nih.gov/25545238/"}
{"doc_id": "4f83a84ae42010b73e8bd3862738df14", "sentence": "We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine ( F-ara-A ) and hydroxyurea ( HU ) enhanced ara-CTP levels in two human myeloid ( HL-60 , CMK ) and two lymphoblastic leukemia cell lines ( MOLT-4 , BLIN-1 ) and also in blasts from 28 children with acute leukemia ( AML : 14 , ALL : 14 ) .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 84, "end": 95, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "hydroxyurea", "start": 112, "end": 123, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Modulation of ara-CTP levels by fludarabine and hydroxyurea in leukemic cells. The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine ( F-ara-A ) and hydroxyurea ( HU ) enhanced ara-CTP levels in two human myeloid ( HL-60 , CMK ) and two lymphoblastic leukemia cell lines ( MOLT-4 , BLIN-1 ) and also in blasts from 28 children with acute leukemia ( AML : 14 , ALL : 14 ) . Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.", "source": "https://pubmed.ncbi.nlm.nih.gov/11243402/"}
{"doc_id": "078b4247228f2bac344b5add11ee697a", "sentence": "In Group IV , the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine .", "spans": [{"span_id": 0, "text": "olprinone", "start": 41, "end": 50, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "nicardipine", "start": 111, "end": 122, "token_start": 20, "token_end": 21}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The effect of olprinone compared with milrinone on diaphragmatic muscle function in dogs. We compared the effect of olprinone with milrinone on the contractility of fatigued diaphragms in dogs. Animals were divided into four groups of 10 each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. After producing fatigue, Group I received only maintenance fluids; Group II was given a bolus injection (50 microg/kg) followed by continuous infusion (0.5 microg x kg(-1) x min(-1)) of milrinone; Group III was infused with olprinone (10 microg/kg initial dose plus 0.3 microg x kg(-1) x min(-1) maintenance dose); Group IV was infused with nicardipine (5 microg x kg(-1) x min(-1)) during olprinone administration. After the fatigue-producing period in each group, transdiaphragmatic pressure (Pdi) at low-frequency (20 Hz) stimulation decreased from the prefatigued values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups II and III, during study drug infusion, Pdi at both stimuli increased from fatigued values (P < 0.05). The increase in Pdi was larger in Group III than in Group II (P < 0.05). In Group IV , the augmentation of Pdi by olprinone was abolished in the fatigued diaphragm with an infusion of nicardipine . We conclude that olprinone is more effective than milrinone for the improvement of contractility in he fatigued diaphragm and that the potentiating mechanism of olprinone may be closely related to the transmembrane calcium movement. ### implications Diaphragmatic fatigue may contribute to the development of respiratory failure. Compared with milrinone, olprinone improves the contractility in fatigued diaphragm in dogs.", "source": "https://pubmed.ncbi.nlm.nih.gov/10475325/"}
{"doc_id": "d37eb6b8bb8d8d15526161f2cfe27698", "sentence": "Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan .", "spans": [{"span_id": 0, "text": "Telmisartan", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "candesartan", "start": 67, "end": 78, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells. Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. ### methods 12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. ### results telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan . telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. ### conclusions The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation.", "source": "https://pubmed.ncbi.nlm.nih.gov/23451083/"}
{"doc_id": "c1417edecd6a1bb79585910ff15c392b", "sentence": "A single 1-g dose of oral azithromycin is as effective as a seven-day course of oral doxycycline , 100 mg twice a day , for the treatment of chlamydial infection .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 26, "end": 38, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "doxycycline", "start": 85, "end": 96, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Drug treatment of common STDs: Part II. Vaginal infections, pelvic inflammatory disease and genital warts. The Centers for Disease Control and Prevention (CDC) released new guidelines for the treatment of sexually transmitted diseases (STDs) in 1998. Several treatment advances have been made since the previous guidelines were published. Part II of this two-part series on STDs describes recommendations for the treatment of diseases characterized by vaginal discharge, pelvic inflammatory disease, epididymitis, human papillomavirus infection, proctitis, proctocolitis, enteritis and ectoparasitic diseases. Single-dose therapies are recommended for the treatment of several of these diseases. A single 1-g dose of oral azithromycin is as effective as a seven-day course of oral doxycycline , 100 mg twice a day , for the treatment of chlamydial infection . erythromycin and ofloxacin are alternative agents. Four single-dose therapies are now recommended for the management of uncomplicated gonococcal infections, including 400 mg of cefixime, 500 mg of ciprofloxacin, 125 mg of ceftriaxone or 400 mg of ofloxacin. Advances in the treatment of bacterial vaginosis also have been made. A seven-day course of oral metronidazole is still recommended for the treatment of bacterial vaginosis in pregnant women, but intravaginal clindamycin cream and metronidazole gel are now recommended in nonpregnant women. Single-dose therapy with 150 mg of oral fluconazole is a recommended treatment for vulvovaginal candidiasis. Two new topical treatments, podofilox and imiquimod, are available for patient self-administration to treat human papillomavirus infection. Permethrin cream is now the preferred agent for the treatment of pediculosis pubis and scabies.", "source": "https://pubmed.ncbi.nlm.nih.gov/10537386/"}
{"doc_id": "089f35f8fbaac65263cd437b70b772de", "sentence": "The side-effects of halofantrine and mefloquine were comparable and transient .", "spans": [{"span_id": 0, "text": "halofantrine", "start": 20, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "mefloquine", "start": 37, "end": 47, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Clinical trials with halofantrine in acute uncomplicated falciparum malaria in Thailand. The antimalarial efficacy of halofantrine was compared with mefloquine in an open-label, randomized comparative trial in adult male patients with acute uncomplicated falciparum malaria. Twenty-eight patients received halofantrine and 27 received mefloquine. halofantrine was administered in 3 doses of 500 mg at 6 hour intervals and mefloquine was administered in divided doses of 1,250 mg or 1,500 mg depending on whether the patients weighed less than or more than 60 kg. The patients were followed for 42 days and observed for drug tolerance and evidence of recrudescence. Response to treatment was favorable with both drugs, but three patients (two treated with halofantrine and one with mefloquine) did not completely eliminate malaria parasites from peripheral blood films in seven days. The parasite and fever clearance times were 75.6 and 55.7 hours, and 80.1 and 61.3 hours, respectively for halofantrine and mefloquine. However, 12 patients recrudesced during the 42 day follow-up period. Nine of these had been treated with halofantrine and three with mefloquine. The 42-day cure rate for the two drugs was 56% and 84%, respectively. The side-effects of halofantrine and mefloquine were comparable and transient . These are diarrhea, dizziness, orthostatic hypotension and black out. However, vomiting was found to be more common in mefloquine group (41% vs 22%).", "source": "https://pubmed.ncbi.nlm.nih.gov/8362305/"}
{"doc_id": "fe77c57a1fc49e8755ef2c89b0c3538b", "sentence": "Significantly , green tea polyphenols , as well as several flavonoids such as genistein , curcumin and resveratrol , have also been shown to have chemo-sensitizing properties in prostate , breast , hepatic , and lung tumors .", "spans": [{"span_id": 0, "text": "genistein", "start": 78, "end": 87, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "curcumin", "start": 90, "end": 98, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "resveratrol", "start": 103, "end": 114, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "The proteasome as a potential target for novel anticancer drugs and chemosensitizers. A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly , green tea polyphenols , as well as several flavonoids such as genistein , curcumin and resveratrol , have also been shown to have chemo-sensitizing properties in prostate , breast , hepatic , and lung tumors . Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.", "source": "https://pubmed.ncbi.nlm.nih.gov/17197231/"}
{"doc_id": "c40e8bcd51fa9cf5c9ba39f9135e357b", "sentence": "In a 71 years-old patient , a severe therapy-resistant depressive episode without psychotic symptoms was successfully treated by a combination of paroxetine and risperidone .", "spans": [{"span_id": 0, "text": "paroxetine", "start": 146, "end": 156, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "risperidone", "start": 161, "end": 172, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[Paroxetine augmentation with risperidone in therapy-resistant depression].  In a 71 years-old patient , a severe therapy-resistant depressive episode without psychotic symptoms was successfully treated by a combination of paroxetine and risperidone . Previously, several different antidepressants were not effective in ameliorating the depressive symptoms which occurred repeatedly over a period of more than ten years.", "source": "https://pubmed.ncbi.nlm.nih.gov/11721229/"}
{"doc_id": "2d78b663f4a80912c2ae2082c42ba522", "sentence": "While there is no standard of care for PBL , current recommendations include dose-adjusted EPOCH ( etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) , with or without bortezomib .", "spans": [{"span_id": 0, "text": "etoposide", "start": 99, "end": 108, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "vincristine", "start": 111, "end": 122, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "doxorubicin", "start": 125, "end": 136, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "cyclophosphamide", "start": 139, "end": 155, "token_start": 22, "token_end": 23}, {"span_id": 4, "text": "prednisone", "start": 162, "end": 172, "token_start": 25, "token_end": 26}, {"span_id": 5, "text": "bortezomib", "start": 193, "end": 203, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": false}, {"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": false}], "paragraph": "A Rare Presentation of HIV-Negative Plasmablastic Lymphoma: A Diagnostic Dilemma. Plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM) have many overlapping characteristics. Clinical correlation can help make the distinction between the two entities. Human immunodeficiency virus- (HIV-) negative PBL is a rare disease, making the diagnosis more challenging. While there is no standard of care for PBL , current recommendations include dose-adjusted EPOCH ( etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) , with or without bortezomib . We report an aggressive case of HIV-negative plasmablastic lymphoma and discuss the challenge in establishing a diagnosis. We review the literature regarding this disease and current recommendations for treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/30906602/"}
{"doc_id": "89bbfb63ec14dde2805f31218f1ea77b", "sentence": "Our report of a patient with severe tardive dyskinesia ( TD ) who has been exposed to both typical antipsychotic and clozapine , olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD .", "spans": [{"span_id": 0, "text": "clozapine", "start": 117, "end": 126, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "olanzapine", "start": 129, "end": 139, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "quetiapine", "start": 144, "end": 154, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report.  Our report of a patient with severe tardive dyskinesia ( TD ) who has been exposed to both typical antipsychotic and clozapine , olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD . Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.", "source": "https://pubmed.ncbi.nlm.nih.gov/14571157/"}
{"doc_id": "9f7e34d9f7937382363be90a76a98bd1", "sentence": "Paclitaxel plus bevacizumab in patients with chemosensitive relapsed small cell lung cancer : a safety , feasibility , and efficacy study from the Hoosier Oncology Group .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bevacizumab", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Paclitaxel plus bevacizumab in patients with chemosensitive relapsed small cell lung cancer : a safety , feasibility , and efficacy study from the Hoosier Oncology Group . bevacizumab when combined with carboplatin and paclitaxel improves response rates (RRs) and overall survival in patients with advanced non-small cell lung cancer. paclitaxel has single-agent activity in relapsed small cell lung cancer (SCLC). Angiogenesis seems to play an important role in the pathogenesis of SCLC. This study evaluated the safety and efficacy of paclitaxel plus bevacizumab in patients with chemosensitive relapsed SCLC. ### methods Patients with relapsed chemosensitive SCLC with an Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. They received paclitaxel 90 mg/m intravenously on days 1, 8, and 15. bevacizumab was administered at 10 mg/kg intravenously on days 1 and 15. Cycles were every 28 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included RRs, toxicity, and overall survival. Correlative studies evaluated vascular endothelial growth factor polymorphisms. ### results Thirty-four patients were enrolled in the study. Median age was 66.5 (range, 38-88) years, male:female: 61.8%:38.2%, Eastern Cooperative Oncology Group performance status 0:1 47.1%:52.9%. Median progression-free survival was 14.7 weeks (equivalent to historical controls). Median survival time was 30 weeks. The overall RR was 18.1%. Stable disease rate was 39.3%, and 45.4% of patients had progressive disease. No unexpected toxicities were noted, and grade 3/4 toxicities were limited to neutropenia, fatigue, and dyspnea. None of the vascular endothelial growth factor polymorphisms evaluated were significantly associated with response. ### conclusions The addition of bevacizumab to paclitaxel does not improve outcomes in relapsed chemosensitive SCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/21102263/"}
{"doc_id": "0be07de2b909239dfdf4b4f903db6ef2", "sentence": "On day ten of admission , HIT panel was positive , and Dabigatran was changed to Lepirudin .", "spans": [{"span_id": 0, "text": "Dabigatran", "start": 55, "end": 65, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "Lepirudin", "start": 81, "end": 90, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Heparin-Induced Thrombocytopenia in a Patient with Essential Thrombocythemia: A Case Based Update. Vascular thrombosis is a common clinical feature of both essential thrombocythemia (ET) and heparin-induced thrombocytopenia (HIT). The development of HIT in a patient with ET is rare and underrecognized. We report the case of a 77-year-old woman with preexisting ET, who was admitted with acute coronary syndrome, and IV heparin was started. She was exposed to unfractionated heparin (UFH) 5 days prior to this admission. Decrease in platelet count was noted, and HIT panel was sent. heparin was discontinued. Patient developed atrial fibrillation, and dabigatran was started. On day three, patient also developed multiple tiny cerebral infarctions and acute right popliteal DVT. On day ten of admission , HIT panel was positive , and Dabigatran was changed to Lepirudin . Two days later, lepirudin was also discontinued because patient developed pseudoaneurysm on the right common femoral artery at the site of cardiac catheterization access. A progressive increase in the platelet count was noted after discontinuing heparin. Physicians should be aware of the coexistence of HIT and ET, accompanied challenges of the prompt diagnosis, and initiation of appropriate treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/26579318/"}
{"doc_id": "87a5b7601669048d416f0bda0058f733", "sentence": "If in vivo testing confirms the in vitro effectiveness of azithromycin , it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women , who should not take doxycycline , and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 58, "end": 70, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "doxycycline", "start": 198, "end": 209, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "In vitro effectiveness of azithromycin against doxycycline-resistant and -susceptible strains of Rickettsia tsutsugamushi, etiologic agent of scrub typhus. In an effort to find a potential alternative treatment for scrub typhus, we evaluated the effectiveness of the standard drug doxycycline and the new macrolide azithromycin against a doxycycline-susceptible strain (Karp) and a doxycycline-resistant strain (AFSC-4) of Rickettsia tsutsugamushi. The antibiotics were tested in an in vitro assay system in which infected mouse fibroblast cells (L929) were incubated for 3 days in various concentrations of the drugs. Rickettsial growth was evaluated by direct visual counts of rickettsiae in Giemsastained cells or by flow cytometry. Initial tests were conducted at the concentration of each antibiotic considered to be the upper breakpoint for susceptibility (16 micrograms/ml for doxycycline and 8 micrograms/ml for azithromycin). Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics, as measured by visual counts, although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60% as great as the percentage of cells infected with Karp in the presence of azithromycin. Flow cytometry confirmed that rickettsial growth occurred in the absence of antibiotics, but it failed to detect it in the presence of high concentrations of either drug. Visual counts of rickettsial growth at lower concentrations of the antibiotics (0.25 to 0.0078 microgram/ml) showed that the Karp strain was 16 times more susceptible that the AFSC-4 strain to doxycycline. azithromycin was much more effective than doxycycline against AFSC-4, inhibiting rickettsial growth at 0.0156 microgram/ml to levels below that achieved by 0.25 microgram of doxycycline per ml. azithromycin was also more effective than doxycycline against the Karp strain, causing greater reductions in the number of rickettsiae per cell at lower concentrations. If in vivo testing confirms the in vitro effectiveness of azithromycin , it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women , who should not take doxycycline , and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found . When tested in an in vitro assay system, azithromycin was more effective than doxycycline against doxycycline-susceptible and -resistant strains of R. tsutsugamushi.", "source": "https://pubmed.ncbi.nlm.nih.gov/8585717/"}
{"doc_id": "febbf2b27d4e13039a1618260b55b41a", "sentence": "Significantly , genes regulated by both formoterol and budesonide were overrepresented in the genome ; moreover , budesonide-plus-formoterol induced and repressed 609 and 577 mRNAs , respectively , of which ~1/3 failed the cut-off criterion for either treatment alone .", "spans": [{"span_id": 0, "text": "formoterol", "start": 40, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "budesonide", "start": 55, "end": 65, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Transcriptome-level interactions between budesonide and formoterol provide insight into the mechanism of action of ICS/LABA combination therapy in asthma. In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting \u03b22-adrenoceptor agonist (LABA) combination therapy should be a first-in-line treatment option for asthma. Although clinically superior to ICS, mechanisms underlying the efficacy of this combination therapy remain unclear. We hypothesised the existence of transcriptomic interactions, an effect that was tested in BEAS-2B and primary human bronchial epithelial cells (pHBECs) using formoterol and budesonide as representative LABA and ICS, respectively. In BEAS-2B cells, formoterol produced 267 (212 induced; 55 repressed) gene expression changes (>=2/<=0.5-fold) that were dominated by rapidly (1-2h) upregulated transcripts. Conversely, budesonide induced 370 and repressed 413 mRNAs, which occurred predominantly at 6-18h and were preceded by transcripts enriched in transcriptional regulators. Significantly , genes regulated by both formoterol and budesonide were overrepresented in the genome ; moreover , budesonide-plus-formoterol induced and repressed 609 and 577 mRNAs , respectively , of which ~1/3 failed the cut-off criterion for either treatment alone . While induction of many mRNAs by budesonide-plus-formoterol was supra-additive, the dominant (and potentially beneficial) effect of budesonide on formoterol-induced transcripts, including those encoding many pro-inflammatory proteins, was repression. Gene ontology analysis of the budesonide-modulated transcriptome returned enriched terms for transcription, apoptosis, proliferation, differentiation, development and migration. This \"functional\" ICS signature was augmented in presence of formoterol. Thus, LABAs modulate glucocorticoid action and comparable transcriptome-wide interactions in pHBECs imply that such effects may be extrapolated to asthmatics taking combination therapy. While repression of formoterol-induced pro-inflammatory mRNAs should be beneficial, the pathophysiological consequences of other interactions require investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/33376135/"}
{"doc_id": "09edda12a9b4dd6af65d9697d8404aae", "sentence": "This study aimed to investigate the therapeutic responses of lung cancer mice models with adenocarcinoma HCC827 ( gefitinib sensitive ) and HCC827R ( gefitinib resistant ) to the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib alone and in combination with the anti-angiogenesis agent bevacizumab using dynamic contrast enhanced ( DCE ) and diffusion-weighted MRI .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 114, "end": 123, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "gefitinib", "start": 150, "end": 159, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "erlotinib", "start": 238, "end": 247, "token_start": 34, "token_end": 35}, {"span_id": 3, "text": "bevacizumab", "start": 306, "end": 317, "token_start": 43, "token_end": 44}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "POS", "spans": [0, 2, 3], "is_context_needed": true}], "paragraph": "Functional evaluation of therapeutic response of HCC827 lung cancer to bevacizumab and erlotinib targeted therapy using dynamic contrast-enhanced and diffusion-weighted MRI.  This study aimed to investigate the therapeutic responses of lung cancer mice models with adenocarcinoma HCC827 ( gefitinib sensitive ) and HCC827R ( gefitinib resistant ) to the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib alone and in combination with the anti-angiogenesis agent bevacizumab using dynamic contrast enhanced ( DCE ) and diffusion-weighted MRI . In the HCC827 model, temporal changes in DCE-MRI derived parameters (Ktrans, kep, and iAUC90) and apparent diffusion coefficient (ADC) were significantly correlated with tumor size. Ktrans and iAUC90 significantly decreased at week 2 in the groups receiving erlotinib alone and in combination with bevacizumab, whereas kep decreased at week 1 and 2 in both treatment groups. In addition, there was a significant difference in iAUC90 between the treatment groups at week 1. Compared to the control group of HCC827, there was a significant reduction in microvessel density and increased tumor apoptosis in the two treatment group. ADC value increased in the erlotinib alone group at week 1 and week 2, and in the erlotinib combined with bevacizumab group at week 2. Enlarged areas of central tumor necrosis were associated with a higher ADC value. However, progressive enlargement of the tumors but no significant differences in DCE parameters or ADC were noted in the HCC827R model. These results showed that both erlotinib alone and in combination with bevacizumab could effectively inhibit tumor growth in the gefitinib-sensitive lung cancer mice model, and that this was associated with decreased vascular perfusion, increased ADC percentage, decreased microvessel density, and increased tumor apoptosis with a two-week treatment cycle.", "source": "https://pubmed.ncbi.nlm.nih.gov/29121075/"}
{"doc_id": "2581d924556a6f63227c9ff8e08e605a", "sentence": ", olmesartan medoxomil + amlodipine + HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies , irrespective of hypertension severity , age , sex , race or diabetes mellitus status .", "spans": [{"span_id": 0, "text": "olmesartan medoxomil", "start": 2, "end": 22, "token_start": 1, "token_end": 3}, {"span_id": 1, "text": "amlodipine", "start": 25, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "HCTZ", "start": 38, "end": 42, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Olmesartan medoxomil/amlodipine/hydrochlorothiazide: fixed-dose combination in hypertension. The antihypertensive agents olmesartan medoxomil, amlodipine and hydrochlorothiazide (HCTZ) are now available as a fixed-dose combination tablet (olmesartan medoxomil/amlodipine/HCTZ). In a 12-week, randomized, double-blind, multicentre trial (TRINITY) in adults with moderate to severe hypertension, olmesartan medoxomil\u2009+\u2009amlodipine\u2009+\u2009HCTZ triple combination therapy produced significantly greater least squares mean reductions from baseline in seated diastolic blood pressure (BP) [primary endpoint] and seated systolic BP than olmesartan medoxomil/amlodipine, olmesartan medoxomil/HCTZ or amlodipine\u2009+\u2009HCTZ. Furthermore, significantly more patients achieved BP goals and targets with the triple combination regimen than with any of the dual combination regimens at week 12, with olmesartan medoxomil\u2009+\u2009amlodipine\u2009+\u2009HCTZ also demonstrating benefit over the dual regimens in terms of ambulatory BP control. According to subgroup analyses of the TRINITY trial , olmesartan medoxomil + amlodipine + HCTZ was more effective in reducing BP and achieving BP goals than each of the dual therapies , irrespective of hypertension severity , age , sex , race or diabetes mellitus status . Data from a number of smaller clinical studies indicated that olmesartan medoxomil\u2009+\u2009amlodipine\u2009+\u2009HCTZ triple combination therapy provides antihypertensive efficacy in patients whose BP is not adequately controlled with olmesartan medoxomil\u2009+\u2009amlodipine. olmesartan medoxomil\u2009+\u2009amlodipine\u2009+\u2009HCTZ was generally well tolerated in the TRINITY study, with adverse events usually being mild or moderate in severity.", "source": "https://pubmed.ncbi.nlm.nih.gov/21275446/"}
{"doc_id": "a59d85a5e7f76dbd749b45c864dfdb7c", "sentence": "Multiple-dose pharmacokinetics of telmisartan and of hydrochlorothiazide following concurrent administration in healthy subjects .", "spans": [{"span_id": 0, "text": "telmisartan", "start": 34, "end": 45, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "hydrochlorothiazide", "start": 53, "end": 72, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Multiple-dose pharmacokinetics of telmisartan and of hydrochlorothiazide following concurrent administration in healthy subjects . This open-label, crossover study had two objectives: to compare the steady-state pharmacokinetics of high-dose telmisartan with and without coadministered high-dose hydrochlorothiazide and to compare the steady-state pharmacokinetics of hydrochlorothiazide with and without coadministered telmisartan. A total of 13 healthy males and females of nonchildbearing potential received the following oral, once-daily medications, each for 7 days: telmisartan 160 mg, hydrochlorothiazide 25 mg, and telmisartan 160 mg plus hydrochlorothiazide 25 mg. Between medication periods, there was a 14-day washout. Blood was collected at intervals over 48 and 84 hours, respectively, at the end of the 7-day dosing period for the determination of plasma telmisartan and hydrochlorothiazide concentrations by high-performance liquid chromatography. Predose blood samples were also collected on days 1, 6, and 7. Tolerability of single-agent and combination medication was monitored. For hydrochlorothiazide and telmisartan, given alone or in combination, there were no appreciable differences in trough plasma concentrations between days 6, 7, and 8; thus, at day 7, both agents had achieved steady state. Mean values of the primary end points (Cmax and AUC0-24) and secondary end points (Cmin and t1/2) for both telmisartan and hyrochlorothiazide were unaffected when administered simultaneously. Moreover, concurrent telmisartan had no effect on urinary excretion of hydrochlorothiazide. Transient lightheadedness, associated with postural hypotension, was the most common adverse event. The absence of any significant effects on the pharmacokinetics of either hydrochlorothiazide or telmisartan shows that no dose adjustment is required if the two agents are given concurrently for the management of hypertension.", "source": "https://pubmed.ncbi.nlm.nih.gov/11185630/"}
{"doc_id": "415bbe9c2f11592ae2af241a79743f8f", "sentence": "The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 91, "end": 100, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "temsirolimus", "start": 111, "end": 123, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "sorafenib", "start": 127, "end": 136, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results . ### methods In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. ### results The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. ### conclusions sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. \u00a9 2017 American Cancer Society.", "source": "https://pubmed.ncbi.nlm.nih.gov/28662274/"}
{"doc_id": "64f63b536073641af3534f1feda74dcd", "sentence": "The authors report the case of a 4-year-old boy with a diagnosis of stage IV neuroblastoma ( NB ) , who had been treated with 6 cycles of cyclophosphamide , doxorubicin , cisplatin , and etoposide for 12 months .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 138, "end": 154, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "doxorubicin", "start": 157, "end": 168, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "cisplatin", "start": 171, "end": 180, "token_start": 32, "token_end": 33}, {"span_id": 3, "text": "etoposide", "start": 187, "end": 196, "token_start": 35, "token_end": 36}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Simultaneous occurrence of advanced neuroblastoma and acute myeloid leukemia.  The authors report the case of a 4-year-old boy with a diagnosis of stage IV neuroblastoma ( NB ) , who had been treated with 6 cycles of cyclophosphamide , doxorubicin , cisplatin , and etoposide for 12 months . The patient reached partial remission and presented a diagnosis of acute myelomonocytic leukemia (M4 AML), confirmed by immunophenotyping. After 2 months of therapy for leukemia, the child died with both malignancies in activity. A necropsy histologically confirmed the simultaneity of the two diseases. The authors review the possibilities of this association. The review leads to the conclusion that AML can occur as a secondary malignancy after the onset of the neuroblastoma, or be suggested by a misdiagnosis. The simultaneous occurrence of both as described here is not, however, found in the literature, to the best of the authors' knowledge.", "source": "https://pubmed.ncbi.nlm.nih.gov/11255731/"}
{"doc_id": "81f6f0d6eaf34525aa979c4077fde7b5", "sentence": "Days of utilization , adherence ( proportion of days covered \u22650.8 ) , and discontinuation ( non-use for \u226530 days immediately prior to BP measurement ) of three statins ( atorvastatin , pravastatin , and simvastatin ) over a period of up to 2 years was monitored retrospectively from electronic databases .", "spans": [{"span_id": 0, "text": "atorvastatin", "start": 170, "end": 182, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "pravastatin", "start": 185, "end": 196, "token_start": 32, "token_end": 33}, {"span_id": 2, "text": "simvastatin", "start": 203, "end": 214, "token_start": 35, "token_end": 36}], "rels": [], "paragraph": "Statin utilisation in a real-world setting: a retrospective analysis in relation to arterial and cardiovascular autonomic function. Randomized trials suggest that statin treatment may lower blood pressure and influence cardiovascular autonomic function (CVAF), but the impact of duration of usage, discontinuation, and adherence to this therapy is unknown. We examined these issues with regard to blood pressure (BP)-related variables in a large, population-based study. Participants were 4942 adults (58% male; aged 50-84\u00a0years): 2179 on statin treatment and 2763 untreated. Days of utilization , adherence ( proportion of days covered \u22650.8 ) , and discontinuation ( non-use for \u226530 days immediately prior to BP measurement ) of three statins ( atorvastatin , pravastatin , and simvastatin ) over a period of up to 2 years was monitored retrospectively from electronic databases . Systolic BP (SBP), diastolic BP (DBP), augmentation index, excess pressure, reservoir pressure, and CVAF (pulse rate and BP variability) parameters were calculated from aortic pressure waveforms derived from suprasystolic brachial measurement. Days of statin treatment had inverse relationships with pulse rate variability parameters in cardiac arrhythmic participants (20-25% lower than in statin non-users) and with most arterial function parameters in everyone. For example, compared to untreated participants, those treated for \u2265659\u00a0days had 3.0\u00a0mmHg lower aortic SBP (", "source": "https://pubmed.ncbi.nlm.nih.gov/28097009/"}
{"doc_id": "0b38299d34d4d410042ee85945da2432", "sentence": "Due to dose-limiting toxicity ( DLT ) in both patients ( elevated transaminases and thrombocytopenia ) , an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2 .", "spans": [{"span_id": 0, "text": "trabectedin", "start": 169, "end": 180, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "gemcitabine", "start": 196, "end": 207, "token_start": 32, "token_end": 33}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG). Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. trabectedin's introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. ### methods We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. ### results Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m2 on day 1 and gemcitabine 700 mg/m2 on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity ( DLT ) in both patients ( elevated transaminases and thrombocytopenia ) , an additional three patients were treated on dose level -1 with trabectedin 0.7 mg/m2 plus gemcitabine 700 mg/m2 . Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. ### conclusion The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/25591040/"}
{"doc_id": "1e94c488f0f6c6510be68295b36d7a0a", "sentence": "Compared with alemtuzumab , bendamustine was considered to be a dominant treatment providing greater benefit ( 6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs ) at lower cost ( $ 78,776 versus $ 121,441 ) .", "spans": [{"span_id": 0, "text": "alemtuzumab", "start": 14, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "bendamustine", "start": 28, "end": 40, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Economic implications of using bendamustine, alemtuzumab, or chlorambucil as a first-line therapy for chronic lymphocytic leukemia in the US: a cost-effectiveness analysis. The objective of this analysis was to evaluate the cost-effectiveness of using bendamustine versus alemtuzumab or bendamustine versus chlorambucil as a first-line therapy in patients with Binet stage B or C chronic lymphocytic leukemia (CLL) in the US. ### methods A discrete event simulation of the disease course of CLL was developed to evaluate the economic implications of single-agent treatment with bendamustine, alemtuzumab, or chlorambucil, which are indicated for a treatment-na\u00efve patient population with Binet stage B or C CLL. Data from clinical trials were used to create a simulated patient population, risk equations for progression-free survival and survival post disease progression, response rates, and rates of adverse events. Costs from a US health care payer perspective in 2012 US dollars, survival (life years), and quality-adjusted life years (QALYs) were estimated over a patient's lifetime; all were discounted at 3% per year. ### results Compared with alemtuzumab , bendamustine was considered to be a dominant treatment providing greater benefit ( 6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs ) at lower cost ( $ 78,776 versus $ 121,441 ) . Compared with chlorambucil, bendamustine was associated with higher costs ($78,776 versus $42,337) but with improved health outcomes (6.10 versus 5.21 life years and 4.02 versus 3.30 QALYs), resulting in incremental cost-effectiveness ratios of $40,971 per life year gained and $50,619 per QALY gained. ### conclusion bendamustine is expected to provide cost savings and greater health benefit than alemtuzumab in treatment-na\u00efve patients with CLL. Furthermore, it can be considered as a cost-effective treatment providing health benefits at an acceptable cost versus chlorambucil in the US.", "source": "https://pubmed.ncbi.nlm.nih.gov/24729719/"}
{"doc_id": "3a30e0b4d614f6d5d5f93bc0236ded4c", "sentence": "He accepted surgical resection with followed multi-agent chemotherapy , containing vincristine , doxorubicin , ifosfamide and etoposide .", "spans": [{"span_id": 0, "text": "vincristine", "start": 83, "end": 94, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "doxorubicin", "start": 97, "end": 108, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "ifosfamide", "start": 111, "end": 121, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "etoposide", "start": 126, "end": 135, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Primary desmoplastic small round cell tumor of the tibia: PET/CT and MRI presentation of a rare case and review of the literature. Desmoplastic small round cell tumor (DSRCT) was a soft tissue sarcoma of mesenchymal cell origin that typically exhibited a multi-phenotypic pattern of immunohistochemical staining. DSRCT mainly presented in the abdomen sites and primary occurrence in bone was exceptional. In this study, we reported a new case of primary DSRCT of the tibia in a 33-year-old man who had intermittent pain in the left tibia. Radiographs showed transparent lesions in the left upper tibial. MRI revealed a lobular, lytic and ill-identified lesion with adjacent soft tissues swelling of the upper left tibia. CT confirmed notable destruction and wormlike osteolysis of the bone cortex. PET/CT showed a mass of high uptakes, indicating the malignance. He accepted surgical resection with followed multi-agent chemotherapy , containing vincristine , doxorubicin , ifosfamide and etoposide . Clinically and radiologically, the patient did not show any evidence of recurrence or metastasis at 30 months after surgical treatment. Primary osteogenic DSRCT was extremely rare and should be considered in differential diagnosis of bone tumors.", "source": "https://pubmed.ncbi.nlm.nih.gov/31871884/"}
{"doc_id": "042530ad82d750063f600c5c6c9b69f9", "sentence": "The gemcitabine and mitoxantrone regimen was feasible to administer even in heavily pre-treated patients .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 4, "end": 15, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "mitoxantrone", "start": 20, "end": 32, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Mitoxantrone and prolonged infusion gemcitabine as salvage therapy in patients with acute myelogenous leukemia. In a recent phase I study, a combination of gemcitabine at 10 mg/(m(2)min) for 12 h and mitoxantrone 12 mg/m(2) daily for 3 days, achieved a complete remission (CR) in 3 of 12 (25%) patients with refractory leukemia. A pilot assessment of this regimen was conducted to determine its tolerability in patients with refractory acute myeloid leukemia (AML). In a cohort of 18 patients with very refractory disease (6 primary refractory, 12 relapsed, mean initial CR duration 3.5 months), one patient achieved a CR, a second CR with incomplete platelet recovery (CRp). Sepsis and mucositis were significant extramedullary toxicities. The gemcitabine and mitoxantrone regimen was feasible to administer even in heavily pre-treated patients . It was not active in patients who had failed a prior salvage regimen. It may warrant further study in patients with primary resistant AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/12531220/"}
{"doc_id": "3abf5b8dae64e23003a5ae9522e0ead1", "sentence": "The aim of this study was to evaluate four phytocompounds ( cinnamaldehyde , citral , eugenol and geraniol ) for their in vitro inhibitory activity against pre-formed biofilms of Candida albicans alone or in combination with fluconazole and amphotericin B. These compounds were also tested at subinhibitory concentrations for their ability to inhibit biofilm formation .", "spans": [{"span_id": 0, "text": "cinnamaldehyde", "start": 60, "end": 74, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "citral", "start": 77, "end": 83, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "eugenol", "start": 86, "end": 93, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "geraniol", "start": 98, "end": 106, "token_start": 17, "token_end": 18}, {"span_id": 4, "text": "fluconazole", "start": 225, "end": 236, "token_start": 36, "token_end": 37}, {"span_id": 5, "text": "amphotericin", "start": 241, "end": 253, "token_start": 38, "token_end": 39}], "rels": [{"class": "POS", "spans": [0, 4], "is_context_needed": true}], "paragraph": "Antibiofilm activity of certain phytocompounds and their synergy with fluconazole against Candida albicans biofilms.  The aim of this study was to evaluate four phytocompounds ( cinnamaldehyde , citral , eugenol and geraniol ) for their in vitro inhibitory activity against pre-formed biofilms of Candida albicans alone or in combination with fluconazole and amphotericin B. These compounds were also tested at subinhibitory concentrations for their ability to inhibit biofilm formation . ### methods The XTT reduction assay, light microscopy and scanning electron microscopy (SEM) were employed to determine the inhibitory effect of the test compounds on biofilms. A chequerboard method was used for combination studies. ### results Both clinical and reference strains of C. albicans (C. albicans 04 and C. albicans SC5314, respectively) displayed formation of strong biofilms. Pre-formed Candida biofilms showed \u22651024\u00d7 increased resistance to antifungal drugs and 2\u00d7 increased resistance to cinnamaldehyde and geraniol, but no increased tolerance of eugenol. The test compounds were more active against pre-formed biofilms than amphotericin B and fluconazole. At 0.5\u00d7 MIC, eugenol and cinnamaldehyde were the most inhibitory compounds against biofilm formation. Light and electron microscopic studies revealed the deformity of three-dimensional structures of biofilms formed in the presence of sub-MICs of eugenol and cinnamaldehyde. The cell membrane appeared to be the target site of compounds in both planktonic and sessile C. albicans cells, as observed by SEM. Combination studies showed that synergy was highest between eugenol and fluconazole (fractional inhibitory concentration index = 0.14) against pre-formed biofilms of C. albicans SC5314. ### conclusions Promising antibiofilm activity was displayed by eugenol and cinnamaldehyde, which also showed synergy with fluconazole in vitro. Further evaluation in in vivo systems is required to determine whether these findings can be exploited in treating biofilm-associated candidiasis.", "source": "https://pubmed.ncbi.nlm.nih.gov/22167241/"}
{"doc_id": "b1e132fb73f96e11922acfd78c2ac03d", "sentence": "Neoadjuvant trastuzumab , pertuzumab , and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer ( KRISTINE ): a randomised , open-label , multicentre , phase 3 trial .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 12, "end": 23, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "pertuzumab", "start": 26, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "trastuzumab emtansine", "start": 63, "end": 84, "token_start": 8, "token_end": 10}, {"span_id": 3, "text": "pertuzumab", "start": 90, "end": 100, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Neoadjuvant trastuzumab , pertuzumab , and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer ( KRISTINE ): a randomised , open-label , multicentre , phase 3 trial . HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. ### methods We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3\u00b76 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m ### findings Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44\u00b74%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55\u00b77%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11\u00b73 percentage points, 95% CI -20\u00b75 to -2\u00b70; p=0\u00b7016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment. ### interpretation Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. ### funding F Hoffmann-La Roche and Genentech.", "source": "https://pubmed.ncbi.nlm.nih.gov/29175149/"}
{"doc_id": "8fc577a14f80c50cfbb664588f852a56", "sentence": "\u2265 3 adverse events ( AE ) than cetuximab and conatumumab , neutropenia than conatumumab , and fatigue than cetuximab .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 31, "end": 40, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "conatumumab", "start": 45, "end": 56, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "conatumumab", "start": 76, "end": 87, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "cetuximab", "start": 107, "end": 116, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Efficacy and Safety of Regorafenib in Combination with Chemotherapy as Second-Line Treatment in Patients with Metastatic Colorectal Cancer: A Network Meta-Analysis and Systematic Literature Review. Although various therapies are available for the treatment of metastatic colorectal cancer (mCRC), there is lack of head-to-head evidence. Recent studies have demonstrated the efficacy of chemotherapy in combination with different biological agents including regorafenib in second-line therapy in patients with mCRC. We conducted a network meta-analysis (NMA) to estimate the relative efficacy and safety of regorafenib in combination with chemotherapy compared to other biological agents with chemotherapy combinations. ### methods A literature search was conducted in PubMed, Embase, and Cochrane databases to identify all randomized controlled trials (RCTs) evaluating the efficacy and safety of bevacizumab, regorafenib, panitumumab, cetuximab, ramucirumab, conatumumab, ganitumab, and aflibercept in combination with chemotherapy against chemotherapy alone as second-line setting from inception to 7\u00a0February 2019 in patients with mCRC. The survival outcomes were analyzed by the frequentist statistical approach (R software, netmeta package) while the level of individual treatment arms was assessed using the Bayesian method (R software, gemtc package). ### results We identified 12 articles involving eight RCTs studies analyzing 6805 patients. The studies compared bevacizumab (3), regorafenib (1), panitumumab (2), cetuximab (3), ramucirumab (1), conatumumab (1), ganitumab (1), and aflibercept (1) against chemotherapy alone as comparator. The progression-free survival (PFS) revealed that regorafenib performed better than aflibercept (HR 0.9631, 95% CI 0.6785-1.367), ganitumab (HR 0.7228, 95% CI 0.3985-1.3109), panitumumab (HR 0.9653, 95% CI 0.6781-1.3742), and ramucirumab (HR 0.9206, 95% CI 0.6504-1.303). regorafenib performed better than bevacizumab (OR 0.797, 95% CI 0.328-1.88) in terms of tumor response. Safety analysis showed that regorafenib performed better in reducing grade \u2265 3 adverse events ( AE ) than cetuximab and conatumumab , neutropenia than conatumumab , and fatigue than cetuximab . ### conclusions regorafenib combined with chemotherapy might be a potential alternative to conventional therapeutic options in second-line treatment of patients with metastatic colorectal cancer and could be considered as the best option for treating patients with KRAS and BRAF mutated mCRC. However future RCTs are needed to confirm these results.", "source": "https://pubmed.ncbi.nlm.nih.gov/32770529/"}
{"doc_id": "dbd1477b1210b870d5f317aa732a145d", "sentence": "Ultimately , the patient was successfully treated with combination therapy of Liposomal amphotericin B and Miltefosine without any relapse .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 88, "end": 100, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "Miltefosine", "start": 107, "end": 118, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A rare case of Visceral leishmaniasis with multiple relapse and multi-drug unresponsive: successfully treated with combination therapy. We report a 32-year old relapse case of Visceral leishmaniasis, treated with paromomycin who belonged from a endemic zone of Bihar state, India. After confirmation, he was treated with amphotericin B, followed by Liposomal amphotericin B in full course and even in higher dose. But after each therapy, the patient either did not responded or relapsed after treatment. Ultimately , the patient was successfully treated with combination therapy of Liposomal amphotericin B and Miltefosine without any relapse . ### conclusion The multi-drug unresponsive Visceral leishmaniasis cases could pose a major threat to treatment strategy in the elimination program. In such situation, combination therapy seems to be a better approach that needs to be explored.", "source": "https://pubmed.ncbi.nlm.nih.gov/21833710/"}
{"doc_id": "4644446d0aa8617bcb774da8032011f6", "sentence": "However , verapamil significantly increased the sensitivity to etoposide , doxorubicin and vincristine in cells highly expressing MRP gene .", "spans": [{"span_id": 0, "text": "verapamil", "start": 10, "end": 19, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "etoposide", "start": 63, "end": 72, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "doxorubicin", "start": 75, "end": 86, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "vincristine", "start": 91, "end": 102, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 3], "is_context_needed": false}], "paragraph": "The multidrug resistance-associated protein gene confers drug resistance in human gastric and colon cancers. To determine the expression of multidrug resistance-associated protein (MRP) gene and its role in gastric and colon cancers, we analyzed 10 gastric and 10 colon non-drug-selected cell lines and a similar number of tissue samples of these cancers. We compared the expression of MRP and mdrl mRNA in cell lines and tissues using reverse-transcriptase polymerase chain reaction. In mdrl-negative cells, the relationship between the level of MRP gene expression and sensitivity to anticancer drugs was examined. The effect of verapamil, an MRP-modulating agent, was also examined in these cells. The expression of MRP gene in gastric cancer cell lines varied from a low to a high level, but mdrl was not detected in any of these cell lines. Colon cancer cell lines expressed low to intermediate levels of MRP gene, and half of the cells co-expressed low to high levels of mdrl. In tissue samples, the expression pattern of the two multidrug resistance (MDR) genes was broadly similar to that described for the cell lines, except that most of the gastric cancer tissue samples did express low levels of mdrl. No significant correlation was observed between the level of MRP gene expression and sensitivity to anticancer drugs in gastric and colon cell lines. However , verapamil significantly increased the sensitivity to etoposide , doxorubicin and vincristine in cells highly expressing MRP gene . Our results indicate that MRP gene may be important in conferring MDR in gastric and colon cancer cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/9045962/"}
{"doc_id": "6fd826d6cc886ea9bdc4d4f22b40c1f0", "sentence": "Based on available phase III randomized trials , anti-VEGF agents such as sunitinib , sorafenib , bevacizumab-based therapy , and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 74, "end": 83, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "sorafenib", "start": 86, "end": 95, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "temsirolimus", "start": 159, "end": 171, "token_start": 24, "token_end": 25}, {"span_id": 3, "text": "everolimus", "start": 176, "end": 186, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials , anti-VEGF agents such as sunitinib , sorafenib , bevacizumab-based therapy , and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease . Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.", "source": "https://pubmed.ncbi.nlm.nih.gov/21789125/"}
{"doc_id": "5e0548f00dcd95ab82e9f43765a7ea76", "sentence": "Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib .", "spans": [{"span_id": 0, "text": "trametinib", "start": 93, "end": 103, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "palbociclib", "start": 108, "end": 119, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6. The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. ### Experimental Design Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration. ### results Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib . Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model. ### conclusions Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/26369631/"}
{"doc_id": "c7b449ddcf06a1a101b77f14c026b7f1", "sentence": "Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine .", "spans": [{"span_id": 0, "text": "sulfisoxazole", "start": 55, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "sulfamethoxazole", "start": 73, "end": 89, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine . A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsulfamethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivyt limit of 2 microgram/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.", "source": "https://pubmed.ncbi.nlm.nih.gov/512885/"}
{"doc_id": "80278bd2e6c19140fe092fa4726b25da", "sentence": "Background Epidemiological evidence is insufficient to draw conclusions on the impact of low-dose aspirin use on breast cancer risk , and the potential impact of other antiplatelet drugs such as clopidogrel needs to be explored .", "spans": [{"span_id": 0, "text": "aspirin", "start": 98, "end": 105, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "clopidogrel", "start": 195, "end": 206, "token_start": 30, "token_end": 31}], "rels": [], "paragraph": "Antiplatelet drug use and breast cancer risk in a prospective cohort of postmenopausal women.  Background Epidemiological evidence is insufficient to draw conclusions on the impact of low-dose aspirin use on breast cancer risk , and the potential impact of other antiplatelet drugs such as clopidogrel needs to be explored . Methods We investigated the association between breast cancer risk and low-dose aspirin or clopidogrel use in the E3N cohort, which includes 98,995 women, with information on breast cancer risk factors collected from biennial questionnaires matched with drug reimbursement data available from 2004. Women with at least two reimbursements of the drug of interest in any previous three-month period were considered \"ever\" exposed. Exposure was considered as time-varying and multivariable Cox regression models were used to estimate hazard ratios (HRs) of breast cancer. Results Among 62,512 postmenopausal women followed during nine years on average, 2,864 breast cancer cases were identified. Compared with never use, a transient higher breast cancer risk was observed during the 3rd year of low-dose aspirin use [HR2-{less than or equal to}3 years of use= 1.49 (1.08-2.07)], followed by a lower risk [HR4+ years of use= 0.72 (0.52-0.99)]. clopidogrel ever use was associated with a higher breast cancer risk [HR= 1.30 (1.02-1.68)], restricted to estrogen receptor negative (ER-) tumors [HRER+= 1.14 (0.83-1.57), HRER-= 3.07 (1.64-5.76), Phomogeneity= 0.01]. Conclusions Low-dose aspirin was associated with a lower breast cancer risk only after several years of use, while ever use of clopidogrel was associated with a higher ER- breast cancer risk. Impact Antiplatelet drugs are not good pharmacological candidates for breast cancer prevention.", "source": "https://pubmed.ncbi.nlm.nih.gov/33531438/"}
{"doc_id": "6217aaf92cbd6304f2ccffe4ac3e0acb", "sentence": "Using a FOLFOXIRI ( 5-fluorouracil [ 5-FU ] , irinotecan , and oxaliplatin ) combination regimen , patients with metastatic colorectal cancer now have the possibility of longer survival , but disappointingly , with increased toxicities .", "spans": [{"span_id": 0, "text": "FOLFOXIRI", "start": 8, "end": 17, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "5-fluorouracil", "start": 20, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "5-FU", "start": 37, "end": 41, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "irinotecan", "start": 46, "end": 56, "token_start": 9, "token_end": 10}, {"span_id": 4, "text": "oxaliplatin", "start": 63, "end": 74, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [2, 3, 4], "is_context_needed": false}], "paragraph": "Triplet chemotherapy in patients with metastatic colorectal cancer: toward the best way to safely administer a highly active regimen in clinical practice. A major problem concerning the addition of more drugs in a chemotherapy combination is designing a proper schedule assuring the balance between dose intensity of each drug, efficacy of the combination, and tolerability lessening the burden of drug toxicity. We evaluated triplet chemotherapy-based intensive regimens proposed as first-line treatment in patients with metastatic colorectal cancer. Using a FOLFOXIRI ( 5-fluorouracil [ 5-FU ] , irinotecan , and oxaliplatin ) combination regimen , patients with metastatic colorectal cancer now have the possibility of longer survival , but disappointingly , with increased toxicities . Triplet chemotherapy regimen according to 5-fluorouracil, irinotecan /5-fluorouracil, oxaliplatin, characterized by timed flat-infusion 5-FU administration, without leucovorin, obtained efficacy equivalent to other reported similar combination regimens (5-FU, irinotecan, and oxaliplatin), with increased received 5-FU dose intensity and lower grade 3 to 4 neutropenia. To guarantee the proper balance between dose intensities, efficacy, and toxicity, triplet chemotherapy schedules could be further improved by abrogation of folinic acid and bolus 5-FU, a new and easy modality of 5-FU administration, such as timed flat-infusion 5-FU, associated with alternating irinotecan and oxaliplatin; this could favor diffusion of this intensive treatment in clinical practice.", "source": "https://pubmed.ncbi.nlm.nih.gov/22694897/"}
{"doc_id": "4510363c81a8ffc6245472b6466c935e", "sentence": "Combinations of antibodies with targeted drugs like ibrutinib , idelalisib , or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future .", "spans": [{"span_id": 0, "text": "antibodies", "start": 16, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "ibrutinib", "start": 52, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "idelalisib", "start": 64, "end": 74, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "lenalidomide", "start": 80, "end": 92, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 3], "is_context_needed": false}], "paragraph": "Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia. The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib , idelalisib , or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future . However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL.", "source": "https://pubmed.ncbi.nlm.nih.gov/27040707/"}
{"doc_id": "55a6025065dfb1ee3c4e2b620a95e55a", "sentence": "The responses to quinine and mefloquine or halofantrine showed no correlation with each other .", "spans": [{"span_id": 0, "text": "quinine", "start": 17, "end": 24, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "mefloquine", "start": 29, "end": 39, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "halofantrine", "start": 43, "end": 55, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "In vitro activity of halofantrine and its relationship to other standard antimalarial drugs against African isolates and clones of Plasmodium falciparum. The in vitro activity of halofantrine was studied in chloroquine-susceptible and chloroquine-resistant African clones of Plasmodium falciparum over a period of six months. The susceptibility level remained stable in both clones. The chloroquine-susceptible clone (50% inhibitory concentration [IC50] 6.88 nM) was less susceptible to halofantrine than the chloroquine-resistant clone (IC50 2.98 nM). Using an isotopic semimicro drug susceptibility test, the in vitro activity of halofantrine was compared with the activities of chloroquine, quinine, and mefloquine to study the cross-resistance patterns against 76 African isolates of P. falciparum isolated from cases of malaria imported into France. chloroquine-resistant isolates (n = 47) were significantly less susceptible to quinine (IC50 234 nM), but were more susceptible to both mefloquine (IC50 3.20 nM) and halofantrine (IC50 1.14 nM) compared with the chloroquine-susceptible isolates (n = 29; IC50 147 nM for quinine, 7.16 nM for mefloquine, and 2.62 nM for halofantrine). A significant positive correlation was found between the activities of chloroquine and quinine and between those of mefloquine and halofantrine, indicating cross-resistance between these drugs, while a negative correlation was observed between chloroquine and mefloquine or halofantrine. The responses to quinine and mefloquine or halofantrine showed no correlation with each other . These results reinforce the importance of a cautious use of antimalarial drugs in Africa.", "source": "https://pubmed.ncbi.nlm.nih.gov/1443351/"}
{"doc_id": "796d6cd33fac087057506e5a6e1727e7", "sentence": "In a phase II study , we treated 26 consecutive patients with refractory advanced sarcoma with ifosfamide and etoposide combination chemotherapy .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 95, "end": 105, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "etoposide", "start": 110, "end": 119, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Treatment of advanced refractory sarcomas with ifosfamide and etoposide combination chemotherapy. Chemotherapy options for resistant advanced-stage sarcomas are limited and in most cases disappointing. In a phase II study , we treated 26 consecutive patients with refractory advanced sarcoma with ifosfamide and etoposide combination chemotherapy . All patients had received prior doxorubicin- and/or cyclophosphamide-based chemotherapies. Seventeen patients were male and 9 were female. The patients' median age was 35 years (range: 19-67 years). A total of 24 patients were eligible for evaluation of responses. Seven patients had a complete response (CR) (29.1%), 3 had a partial response (PR) (12.5%), 3 had stable disease (SD) (12.5%), and 11 had progressive disease (PD) (45.9%). An overall 41.6% objective response was achieved. Median time to treatment failure was 13.3 months. A total of 108 cycles of therapy were evaluable for evaluation of toxicity. Myelosuppression, observed in 55.5% of the treatment courses, was the major dose-limiting toxicity. Nausea and vomiting, seen in 64% of the courses, were the most important nonhematological side effects. Alopecia was almost universal. Hemorrhagic cystitis was observed in only 1 patient. We have concluded that the combination of ifosfamide, mesna, and etoposide is effective in advanced refractory sarcomas, and has acceptable toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/9627675/"}
{"doc_id": "aff9e9e3cfdf825cee175d0da197c451", "sentence": "A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy .", "spans": [{"span_id": 0, "text": "goserelin acetate", "start": 88, "end": 105, "token_start": 14, "token_end": 16}, {"span_id": 1, "text": "tamoxifen", "start": 110, "end": 119, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy . In September 2000, a 32-year-old woman presented to our hospital with a right breast mass. In September 2000, she underwent pectoral muscle-preserving mastectomy for the treatment of right breast cancer. Pathologyy results revealed a mucinous carcinoma 27 \u00d7 20 \u00d7 18 mm in size accompanied by an extensive intraductal component. The tumor was staged as T2 N1M0 stage IIB and found to be estrogen receptor-positive, and 6 cycles of postoperative adjuvant chemotherapy consisting of 5-fluorouracil, epirubicin, and cyclophosphamide were carried out. goserelin acetate plus tamoxifen was prescribed from April 2001 to March 2005. Since the patient received tamoxifen from April 2005 and eumenorrhea started in June 2006, goserelin acetate plus tamoxifen was started in August 2006. The patient was determined to be 25 weeks pregnant by abdominal ultrasonography in February 2007. This meant that she had been taking goserelin acetate plus tamoxifen for 6 months without realizing she was pregnant. She gave birth to a girl by cesarean section in May 2007. No abnormalities, including anomaly of the genitalia, were seen, and the subsequent growth of the infant was also satisfactory. We here report this case and a brief review of the literature.", "source": "https://pubmed.ncbi.nlm.nih.gov/23636905/"}
{"doc_id": "bd09951c809d28a0d257abf828fd1b19", "sentence": "Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 107, "end": 116, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "fluorouracil", "start": 119, "end": 131, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "hydroxyurea", "start": 138, "end": 149, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "docetaxel", "start": 242, "end": 251, "token_start": 42, "token_end": 43}, {"span_id": 4, "text": "cisplatin", "start": 275, "end": 284, "token_start": 50, "token_end": 51}, {"span_id": 5, "text": "fluorouracil", "start": 312, "end": 324, "token_start": 59, "token_end": 60}], "rels": [{"class": "NEG", "spans": [3, 4, 5], "is_context_needed": true}, {"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. ### Patients And Methods Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). ### results A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P = .002). With a minimum follow-up of 30 months, there were no statistically significant differences in OS (hazard ratio, 0.91; 95% CI, 0.59 to 1.41), RFS, or DF-free survival. ### conclusion IC did not translate into improved OS compared with CRT alone. However, the study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms. IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.", "source": "https://pubmed.ncbi.nlm.nih.gov/25049329/"}
{"doc_id": "fe55806bbc6429c1b87f7ee28230d11a", "sentence": "A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry ( LC-MS/MS ) of five tyrosine kinase inhibitors ( afatinib , crizotinib , osimertinib , erlotinib and nintedanib ) used in the treatment of non-small cell lung cancer ( NSCLC ) was developed and validated in human plasma .", "spans": [{"span_id": 0, "text": "afatinib", "start": 143, "end": 151, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "crizotinib", "start": 154, "end": 164, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "osimertinib", "start": 167, "end": 178, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "erlotinib", "start": 181, "end": 190, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "nintedanib", "start": 195, "end": 205, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the EGFR inhibitors afatinib, erlotinib and osimertinib, the ALK inhibitor crizotinib and the VEGFR inhibitor nintedanib in human plasma from non-small cell lung cancer patients.  A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry ( LC-MS/MS ) of five tyrosine kinase inhibitors ( afatinib , crizotinib , osimertinib , erlotinib and nintedanib ) used in the treatment of non-small cell lung cancer ( NSCLC ) was developed and validated in human plasma . Separation was performed on an Accucore", "source": "https://pubmed.ncbi.nlm.nih.gov/29883880/"}
{"doc_id": "9659b9335356195a3c706849721c878b", "sentence": "The objective of this study was to compare the effect of sildenafil alone and sildenafil with bosentan on severity of tricuspid regurgitation and duration of hospitalization in new-borns with persistent pulmonary hypertension .", "spans": [{"span_id": 0, "text": "sildenafil", "start": 57, "end": 67, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "sildenafil", "start": 78, "end": 88, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "bosentan", "start": 94, "end": 102, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Comparison Of The Efficacy Of Sildenafil Alone Versus Sildenafil Plus Bosentan In Newborns With Persistent Pulmonary Hypertension. Persistent pulmonary hypertension is a serious disease among new-borns. Inhaled nitric oxide is first line of therapy along with extracorporeal membrane oxygenation. Pulmonary vasodilators such as sildenafil, bosentan and milrinone are also used to treat persistent pulmonary hypertension especially in resource limited centres where inhaled nitric oxide is not available. The objective of this study was to compare the effect of sildenafil alone and sildenafil with bosentan on severity of tricuspid regurgitation and duration of hospitalization in new-borns with persistent pulmonary hypertension . ### methods This was single blinded clinical trial conducted at The Children's Hospital & the Institute of Child Health, Multan, Pakistan, from July 2016 to December 2016. New-borns with pulmonary hypertension were admitted and divided into two groups. Group A was treated with sildenafil (2mg per kg per dose three times a day) and group B with both sildenafil (2 mg per kg per dose three times a day) and bosentan (1 mg per kg per dose twice a day). ### results There were 50 new-borns in each group. The mean age, sex distribution and baseline TR measurement (mmHg) at the time of admission was similar in both the groups. Measurement of TR (mmHg) after 72 hours admission was significantly less in Group B as compared to group A (11\u00b14.62 versus 23\u00b14.78), p-value<0.0001. The mean duration of hospital stays (days) was 10.12\u00b15.20 in group A and 7.56\u00b13.77 in group B (p-value <0.0001). There was no mortality in any group and no case of hypotension in both groups. ### conclusions The combined use of sildenafil and bosentan is more effective than sildenafil alone for control of pulmonary hypertension in resource limited centres.", "source": "https://pubmed.ncbi.nlm.nih.gov/30465360/"}
{"doc_id": "63a1e75c482c440bda7c2429d0e862c2", "sentence": "In Crohn 's disease in remission after 6 months of azathioprine in combination with infliximab , 63.8 % of practitioners discontinued azathioprine .", "spans": [{"span_id": 0, "text": "azathioprine", "start": 51, "end": 63, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "infliximab", "start": 84, "end": 94, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "azathioprine", "start": 134, "end": 146, "token_start": 21, "token_end": 22}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Tumour necrosis factor antagonists and inflammatory bowel diseases: a national practice survey. Although the use of tumour necrosis factor (TNF) antagonists is increasingly codified, several unresolved issues remain. ### aim To conduct a French national survey on TNF antagonists use in inflammatory bowel disease (IBD). ### methods A postal questionnaire was sent to all French gastroenterologists among whom 450 prescribe TNF antagonists for IBD. Only anti-TNF prescribers were invited to respond. ### results A total of 333 questionnaires could be analysed, which represented a rate of survey completeness of 74%. Scheduled maintenance infliximab treatment was prescribed by 92% of gastroenterologists. In Crohn's disease in remission after 1 year of TNF antagonists, 77.4% of physicians continued treatment. In luminal Crohn's disease, 97% of hospital practitioners introduced infliximab as first-line anti-TNF therapy vs. 78% of physicians with nonhospital activity (P = 0.002); only 22.5% of gastroenterologists opted for adalimumab as first-line therapy. In Crohn 's disease in remission after 6 months of azathioprine in combination with infliximab , 63.8 % of practitioners discontinued azathioprine . In case of pregnancy during anti-TNF treatment, 35.1% of physicians discontinued therapy at the time of conception and did not administer anti-TNF therapy during pregnancy. ### conclusions The attitudes of French gastroenterologists generally reflect the recommendations regarding the use of anti-TNF and concomitant immunosuppressive therapy in IBD.", "source": "https://pubmed.ncbi.nlm.nih.gov/19764940/"}
{"doc_id": "d7309a2a214cb56ff2ccb1bf082db6cf", "sentence": "Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 ( Enzalutamide ) or Casodex ( Bicalutamide ) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling .", "spans": [{"span_id": 0, "text": "Enzalutamide", "start": 62, "end": 74, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Casodex", "start": 80, "end": 87, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "Bicalutamide", "start": 90, "end": 102, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 ( Enzalutamide ) or Casodex ( Bicalutamide ) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling . Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.", "source": "https://pubmed.ncbi.nlm.nih.gov/23928703/"}
{"doc_id": "41e58f3e0a78ae5a454f27fb445d0174", "sentence": "Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone .", "spans": [{"span_id": 0, "text": "ketoconazole", "start": 81, "end": 93, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "hydrocortisone", "start": 98, "end": 112, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone . The combination of high dose ketoconazole and hydrocortisone (HDK) is active against androgen independent prostate cancer (AIPC). Median response times with HDK tend to be brief but a significant minority of AIPC patients benefit with extended responses. Well characterized response and survival information, especially in the cohort of patients who experience these longer, more durable, responses has not been previously reported. Characterization of this subgroup is of particular interest since men with long-term responses derive the greatest benefit from HDK therapy. ### Materials And Methods The medical records of 78 patients with AIPC treated with HDK between March 1991 and February 1999 were retrospectively reviewed. Baseline clinical and laboratory factors predictive of prolonged response and survival were identified. ### results The median baseline prostate specific antigen (PSA) before the initiation of HDK was 25.1. The number of patients with zero, 1 to 3, and more than 3 lesions on bone scan were 25, 35 and 18, respectively. Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively. In a Cox proportional hazard regression, prolonged survival was predicted by percent PSA decrease, extent of disease on bone scan and baseline PSA. ### conclusions ketoconazole can induce prolonged responses, occasionally lasting for years. Long responses are more likely to occur in men initiating HDK earlier in the course of disease before the cancer burden becomes excessive.", "source": "https://pubmed.ncbi.nlm.nih.gov/15879788/"}
{"doc_id": "4bdf5d29e8c2dd9daefde62c6baaea1e", "sentence": "Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia .", "spans": [{"span_id": 0, "text": "betahistine", "start": 20, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "oxcarbazepine", "start": 69, "end": 82, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "carbamazepine", "start": 87, "end": 100, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia . Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT. ### methods VP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed. ### results In total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group ( ### conclusion These results demonstrated that OXC+BMT may be suitable as an alternative method in VP patients with CBZ hypersensitivity, and the synergistic effect could be increased along with the increased dose of BMT.", "source": "https://pubmed.ncbi.nlm.nih.gov/29695895/"}
{"doc_id": "e5243e9e9c05ab3335f5b06ee025acee", "sentence": "Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer : a study of the Princess Margaret Hospital Phase II Consortium .", "spans": [{"span_id": 0, "text": "Sorafenib", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gemcitabine", "start": 30, "end": 41, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer : a study of the Princess Margaret Hospital Phase II Consortium . Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. ### methods Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. gemcitabine (1000 mg/m intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. ### results Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. ### conclusion This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response.", "source": "https://pubmed.ncbi.nlm.nih.gov/20847613/"}
{"doc_id": "c2e7991bf6a9c974641dbfcce66e7a7e", "sentence": "Pharmacological inhibition of p70S6 K using the PI3K/mTOR inhibitor NVP-BEZ235 , the specific mTOR inhibitor Rapamycin and the specific p70S6 K inhibitor PF-4708671 potentiated Selumetinib effects in resistant cells .", "spans": [{"span_id": 0, "text": "Rapamycin", "start": 109, "end": 118, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "Selumetinib", "start": 177, "end": 188, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "NVP-BEZ235", "start": 68, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "PF-4708671", "start": 154, "end": 164, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [1, 3], "is_context_needed": false}], "paragraph": "Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. selumetinib (AZD6244, ARRY-142886) is a MEK1/2 inhibitor that has gained interest as an anti-tumour agent. We have determined the degree of sensitivity/resistance to selumetinib in a panel of colorectal cancer cell lines using cell proliferation and soft agar assays. Sensitive cell lines underwent G1 arrest, whereas selumetinib had no effect on the cell cycle of resistant cells. Some of the resistant cell lines showed high levels of ERK1/2 phosphorylation in the absence of serum. selumetinib inhibited phosphorylation of ERK1/2 and RSK and had no effect on AKT phosphorylation in both sensitive and resistant cells. Furthermore, mutations in KRAS, BRAF, or PIK3CA were not clearly associated with selumetinib resistance. Surprisingly, selumetinib was able to inhibit phosphorylation of p70 S6 kinase (p70S6K) and its downstream target ribosomal protein S6 (RPS6) in sensitive cell lines. However, p70S6K and RPS6 phosphorylation remained unaffected or even increased in resistant cells. Moreover, in some of the resistant cell lines p70S6K and RPS6 were phosphorylated in the absence of serum. Interestingly, colorectal primary cultures derived from tumours excised to patients exhibited the same behaviour than established cell lines. Pharmacological inhibition of p70S6 K using the PI3K/mTOR inhibitor NVP-BEZ235 , the specific mTOR inhibitor Rapamycin and the specific p70S6 K inhibitor PF-4708671 potentiated Selumetinib effects in resistant cells . In addition, biological inhibition of p70S6K using siRNA rendered responsiveness to selumetinib in resistant cell lines. Furthermore, combination of p70S6K silencing and PF-47086714 was even more effective. We can conclude that p70S6K and its downstream target RPS6 are potential biomarkers of resistance to selumetinib in colorectal cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/25379021/"}
{"doc_id": "0f26c0de95da1e1eb1b43e59cfb69d93", "sentence": "Vinorelbine , ifosfamide and cisplatin as first-line treatment in patients with inoperable non-small cell lung cancer .", "spans": [{"span_id": 0, "text": "Vinorelbine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "ifosfamide", "start": 14, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "cisplatin", "start": 29, "end": 38, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Vinorelbine , ifosfamide and cisplatin as first-line treatment in patients with inoperable non-small cell lung cancer . To assess, in a multicenter setting, the effectiveness of a combination of vinorelbine, ifosfamide and cisplatin in the treatment of non-small cell lung cancer, 123 patients (males=116) with a mean age of 60 years (range 27-75) with stage IIIb/IV non-small cell lung cancer (NSCLC) and performance status <or=2 were treated with vinorelbine (VNR; 25 mg/m(2)) on days 1 and 8; ifosfamide (IFO; 3 g/m(2)) on day 1; and cisplatin (CDDP; 80 mg/m(2)) on day 1, in repeated cycles of 21 days. Response rates, overall patient survival and toxicity profiles of the three-drug combination were assessed. The number of evaluable patients was 112, with a total of 441 cycles administered (mean=3.6 cycles/patient). Dose intensities (mg/m(2)/week; calculated in patients who concluded the proposed treatment and expressed as mean, median, and standard deviation) were: VNR 13.65, 13.32, 4.7; IFO 918.88, 868.97, 258.1; CDDP 23, 24.68, 6.98. Response rates were: complete response=3 (2.4%); partial response=58 (47.2%%); stable disease=20 (16.3%). The most frequent toxic events were nausea and vomiting (G1=33%, G2=31%, G3=8%). Neutropenia was the dose limiting toxicity (G1=6%, G2=11%, G3=10%, G4=7%). Alopecia G3 was a common undesirable effect in all the patients. Time to progression was 296 days (95% confidence interval 261-332) and the mean survival time was 338 days (95% CI 301-374). We conclude that the described therapeutic schedule is effective with good survival rates and response ratios together with a good tolerance and an acceptable toxicity level.", "source": "https://pubmed.ncbi.nlm.nih.gov/11679190/"}
{"doc_id": "660a7bcd6ef6ac8e461f7dbbcefb3758", "sentence": "Two large Phase III trials conducted in the Americas and across Europe , Australia , and Asia showed lower cumulative pregnancy rates in the NOMAC/E2 groups compared to the drospirenone ( DRSP ) 3 mg in combination with ethinyl estradiol ( EE ) 30 \u00b5g ( DRSP/EE ) groups but this difference was not statistically significant .", "spans": [{"span_id": 0, "text": "drospirenone", "start": 173, "end": 185, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "ethinyl estradiol", "start": 220, "end": 237, "token_start": 38, "token_end": 40}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Nomegestrol acetate/17-beta estradiol: a review of efficacy, safety, and patient acceptability. Nomegestrol acetate (NOMAC) 2.5 mg with 17-beta estradiol (E2) 1.5 mg is a new combined oral contraceptive (COC) formulation and is the first monophasic E2 pill to be marketed, having been licensed for use in Europe in 2011. It is available to be taken daily in a regimen of 24 active pills followed by four placebo pills. NOMAC is a highly selective 19-nor progestogen derivative with specific binding to progesterone receptors, anti-estrogenic activity and no androgenic, mineralocorticoid nor glucocorticoid effects. E2 is an estrogen that is identical to endogenous estrogen. While it has been in use for only a short period of time, current evidence suggests that NOMAC/E2 is just as effective, safe, and acceptable as existing COC preparations. Two large Phase III trials conducted in the Americas and across Europe , Australia , and Asia showed lower cumulative pregnancy rates in the NOMAC/E2 groups compared to the drospirenone ( DRSP ) 3 mg in combination with ethinyl estradiol ( EE ) 30 \u00b5g ( DRSP/EE ) groups but this difference was not statistically significant . NOMAC/E2 exhibits a good safety profile and has less effects on cardiovascular risk, hemostatic, metabolic, and endocrine factors in comparison to COCs containing EE in combination with levonorgestrel (LNG) or DRSP. NOMAC/E2 has also been found to cause less breast cell proliferation when compared to E2 alone and has some anti-proliferative effect on human breast cancer cells. NOMAC/E2 is considered acceptable as its compliance, continuation rates, and bleeding patterns were similar to COCs containing DRSP/EE and LNG 150 \u00b5g combined with EE 30 \u00b5g or LNG 100 \u00b5g combined with EE 20 \u00b5g (LNG/EE). However, discontinuation was found to be slightly higher in the NOMAC/E2 groups in the two large Phase III trials comparing NOMAC/E2 use with DRSP/EE. As the scientific literature has limited information on NOMAC/E2, further experience with NOMAC/E2 is required.", "source": "https://pubmed.ncbi.nlm.nih.gov/29386925/"}
{"doc_id": "99921793a9d8f1905ea6c17410b4f174", "sentence": "Using 146 surgically resected specimens of NSCLC , p53 status was immunohistochemically evaluated , and in vitro chemosensitivity to 5-fluorouracil ( 5-Fu ) , cisplatin ( CDDP ) , mitomycin C ( MMC ) , etoposide ( VP-16 ) , doxorubicin hydrochloride ( ADM ) , and vindesine sulfate ( VDS ) was examined by a collagen gel-droplet embedded culture drug sensitivity test ( CD-DST , Int J Oncol , 1997;11:449 ) .", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 133, "end": 147, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "5-Fu", "start": 150, "end": 154, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "cisplatin", "start": 159, "end": 168, "token_start": 24, "token_end": 25}, {"span_id": 3, "text": "CDDP", "start": 171, "end": 175, "token_start": 26, "token_end": 27}, {"span_id": 4, "text": "mitomycin", "start": 180, "end": 189, "token_start": 29, "token_end": 30}, {"span_id": 5, "text": "MMC", "start": 194, "end": 197, "token_start": 32, "token_end": 33}, {"span_id": 6, "text": "etoposide", "start": 202, "end": 211, "token_start": 35, "token_end": 36}, {"span_id": 7, "text": "doxorubicin", "start": 224, "end": 235, "token_start": 40, "token_end": 41}, {"span_id": 8, "text": "ADM", "start": 252, "end": 255, "token_start": 43, "token_end": 44}, {"span_id": 9, "text": "vindesine sulfate", "start": 264, "end": 281, "token_start": 47, "token_end": 49}, {"span_id": 10, "text": "VDS", "start": 284, "end": 287, "token_start": 50, "token_end": 51}], "rels": [], "paragraph": "Immunohistochemical p53 protein status in nonsmall cell lung cancer is a promising indicator in determining in vitro chemosensitivity to some anticancer drugs. The tumor suppressor oncogene p53 abnormalities have been closely associated with resistance or sensitivity of cancer cells to some chemotherapeutic agents. We examined the association between p53 protein status in nonsmall cell lung cancer (NSCLC) and in vitro chemosensitivity to several chemotherapeutic agents. ### methods Using 146 surgically resected specimens of NSCLC , p53 status was immunohistochemically evaluated , and in vitro chemosensitivity to 5-fluorouracil ( 5-Fu ) , cisplatin ( CDDP ) , mitomycin C ( MMC ) , etoposide ( VP-16 ) , doxorubicin hydrochloride ( ADM ) , and vindesine sulfate ( VDS ) was examined by a collagen gel-droplet embedded culture drug sensitivity test ( CD-DST , Int J Oncol , 1997;11:449 ) . ### results Sixty-five of 146 materials (45%) showed immunohistochemically abnormal p53 protein accumulation in >10% of cancer cells within the tumor tissue, being regarded as p53+, whereas 81 (55%) were to p53-, in which no or less than 10% positive immunostaining cancer cells were detected. By CD-DST, the incidence of chemosensitive, borderline, and resistant p53- materials (N=81) to 5-Fu was 37%(N=30), 14%(N=11), and 49%(N=40), whereas that of p53+ materials (N=65) was 20%(N=13), 6%(N=4), and 74%(N=48), respectively, showing that p53- materials were significantly more sensitive to 5-Fu than p53+ materials (P=0.011), especially in the adenocarcinoma type. As similar borderline association between p53 protein status and in vitro chemosensitivity was also shown in ADM (P=0.078), but not in other chemoagents. ### conclusions Immunohistochemically detected p53 protein status in NSCLC patients may be a promising indicator in determining in vitro chemosensitivity to some anticancer drugs, especially 5-Fu and ADM.", "source": "https://pubmed.ncbi.nlm.nih.gov/9610658/"}
{"doc_id": "58d7a5eb30426ed2c40cf19b0ca6846b", "sentence": "The objective was to compare the pharmacodynamic ( PD ) and pharmacokinetic ( PK ) effects of ticagrelor with clopidogrel among subjects of Hispanic ethnicity , as the PD and PK effects of antiplatelet agents among Hispanics are not specifically known .", "spans": [{"span_id": 0, "text": "ticagrelor", "start": 94, "end": 104, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "clopidogrel", "start": 110, "end": 121, "token_start": 19, "token_end": 20}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A randomised trial of the pharmacodynamic and pharmacokinetic effects of ticagrelor compared with clopidogrel in Hispanic patients with stable coronary artery disease.  The objective was to compare the pharmacodynamic ( PD ) and pharmacokinetic ( PK ) effects of ticagrelor with clopidogrel among subjects of Hispanic ethnicity , as the PD and PK effects of antiplatelet agents among Hispanics are not specifically known . This was a randomised, open-label, crossover PD/PK study of 40 Hispanic subjects with stable coronary artery disease (CAD). Subjects were allocated to either ticagrelor 180\u00a0mg loading dose (LD)/90\u00a0mg twice-daily maintenance dose (MD) followed by clopidogrel 600\u00a0mg LD/75\u00a0mg once-daily MD with an intervening washout period, or vice versa. The primary endpoint was on-treatment reactivity (OTR) at 2\u00a0h post-LD according to the VerifyNow P2Y12 test. OTR was significantly lower at 2\u00a0h post-LD with ticagrelor compared with clopidogrel (34 PRU vs. 201 PRU, least square means difference\u00a0=\u00a0-167 PRU [95\u00a0% CI, -197, -137], P\u00a0<\u00a00.001). OTR was also lower with ticagrelor at 30\u00a0min and 8\u00a0h post-LD (P\u00a0<\u00a00.001). The greater magnitude of antiplatelet effect with ticagrelor persisted after 7\u00a0days of MD (52 PRU [95\u00a0% CI, 30, 73] vs. 182 PRU [95\u00a0% CI, 160, 205], P\u00a0<\u00a00.001). Mean plasma concentration of ticagrelor and its active metabolite were greatest at 2\u00a0h post-LD, with similar levels at 2\u00a0h post-MD after 7\u00a0days of MD. Among Hispanic subjects with stable CAD, ticagrelor provides a more rapid onset of platelet inhibition and a significantly greater antiplatelet effect compared with clopidogrel during both the loading and maintenance phases of treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/25305090/"}
{"doc_id": "bf2ed1a581b3786c1931ffde4782c39f", "sentence": "For example , the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids , such as probenecid , salicylates and penicillin , which compete for tubular secretion , resulting in delayed clearance of methotrexate .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 37, "end": 49, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "probenecid", "start": 153, "end": 163, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "salicylates", "start": 166, "end": 177, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "penicillin", "start": 182, "end": 192, "token_start": 30, "token_end": 31}, {"span_id": 4, "text": "methotrexate", "start": 267, "end": 279, "token_start": 43, "token_end": 44}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 3], "is_context_needed": false}], "paragraph": "Pharmacokinetic drug interactions of commonly used anticancer drugs. With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example , the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids , such as probenecid , salicylates and penicillin , which compete for tubular secretion , resulting in delayed clearance of methotrexate . The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/2426030/"}
{"doc_id": "9920556fa0edb1a7ba30504dc54c88d2", "sentence": "To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin ( NPL-DOX ) combined to Cyclophosphamide ( CTX ) and followed by weekly Paclitaxel , in older patients ( \u226565 years ) with diagnosis of high risk breast cancer .", "spans": [{"span_id": 0, "text": "Doxorubicin", "start": 70, "end": 81, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "Cyclophosphamide", "start": 106, "end": 122, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "Paclitaxel", "start": 154, "end": 164, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients.  To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin ( NPL-DOX ) combined to Cyclophosphamide ( CTX ) and followed by weekly Paclitaxel , in older patients ( \u226565 years ) with diagnosis of high risk breast cancer . The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). ### methods The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. ### results Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. ### conclusions This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.", "source": "https://pubmed.ncbi.nlm.nih.gov/27886643/"}
{"doc_id": "ec9541a245e674b905a510f820f1c0b6", "sentence": "The high incidence of imported malaria ( 0.70 % ) and the low costs of providing chemoprophylaxis resulted in a cost-benefit ratio of 0.19 for chloroquine and proguanil and 0.57 for a regimen containing mefloquine .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 143, "end": 154, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "proguanil", "start": 159, "end": 168, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "mefloquine", "start": 203, "end": 213, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Is travel prophylaxis worth while? Economic appraisal of prophylactic measures against malaria, hepatitis A, and typhoid in travellers. To estimate the costs and benefits of prophylaxis against travel acquired malaria, typhoid fever, and hepatitis A in United Kingdom residents during 1991. ### design Retrospective analysis of national epidemiological and economic data. ### Main Outcome Measures Incidence of travel associated infections in susceptible United Kingdom residents per visit; costs of prophylaxis provision from historical data; benefits to the health sector, community, and individuals in terms of avoided morbidity and mortality based on hospital and community costs of disease. ### results The high incidence of imported malaria ( 0.70 % ) and the low costs of providing chemoprophylaxis resulted in a cost-benefit ratio of 0.19 for chloroquine and proguanil and 0.57 for a regimen containing mefloquine . Hepatitis A infection occurred in 0.05% of visits and the cost of prophylaxis invariably exceeded the benefits for immunoglobulin (cost-benefit ratio 5.8) and inactivated hepatitis A vaccine (cost-benefit ratio 15.8). Similarly, low incidence of typhoid (0.02%) and its high cost gave whole cell killed, polysaccharide Vi, and oral Ty 21a typhoid vaccines cost-benefit ratios of 18.1, 18.0, and 22.0 respectively. ### conclusions Fewer than one third of travellers receive vaccines but the total cost of providing typhoid and hepatitis A prophylaxis of 25.8m pounds is significantly higher than the treatment costs to the NHS (1.03m pounds) of cases avoided by prophylaxis. Neither hepatitis A prophylaxis nor typhoid prophylaxis is cost effective, but costs of treating malaria greatly exceed costs of chemoprophylaxis, which is therefore highly cost effective.", "source": "https://pubmed.ncbi.nlm.nih.gov/7726905/"}
{"doc_id": "4014e3f6e9dace4cbb1fb59841c57db0", "sentence": "Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 64, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "oxaliplatin", "start": 79, "end": 90, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer. The antibody cetuximab, targeting epidermal growth factor receptor (EGFR), is used to treat metastatic colorectal cancer (mCRC). Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin . The aim of this study was to investigate potential negative interactions between cetuximab and oxaliplatin. ### methods Thiazolyl blue tetrazolium bromide (MTT) assay and Calcusyn software were used to characterize drug interactions. Reactive oxygen species (ROS) were measured by flow cytometry and real-time polymerase chain reaction oxidative stress arrays identified genes regulating ROS production. Chromatin immunoprecipitation (ChIP) measured signal transducer and activator of transcription 1 (STAT-1) binding to dual oxidase 2 (DUOX2) promoter. SW48, DLD-1 KRAS wild-type cell lines and DLD-1 xenograft models exposed to cetuximab, oxaliplatin, or oxaliplatin + cetuximab (control [saline]; n = 3 mice per treatment group) were used. Statistical tests were two-sided. ### results cetuximab and oxaliplatin exhibited antagonistic effects on cellular proliferation and apoptosis (caspase 3/7 activity reduced by 1.4-fold, 95% confidence interval [CI] = 0.78 to 2.11, P = .003) as opposed to synergistic effects observed with the irinotecan metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38). Although both oxaliplatin and SN-38 produced ROS, only oxaliplatin-mediated apoptosis was ROS dependent. Production of ROS by oxaliplatin was secondary to STAT1-mediated transcriptional upregulation of DUOX2 (3.1-fold, 95% CI = 1.75 to 2.41, P < .001). Inhibition of DUOX2 induction and p38 activation by cetuximab reduced oxaliplatin cytotoxicity. ### conclusions Inhibition of STAT1 and DUOX2-mediated ROS generation by cetuximab impairs p38-dependent apoptosis by oxaliplatin in preclinical models and may contribute to reduced efficacy in clinical settings. Understanding the rationale for unexpected trial results will inform improved rationales for combining EGFR inhibitors with chemotherapeutic agents in future therapeutic use.", "source": "https://pubmed.ncbi.nlm.nih.gov/26719345/"}
{"doc_id": "38545112e53419e113dc91fa390d8757", "sentence": "L-carnitine was administered 1 h before doxorubicin injection and daily thereafter for 15 days .", "spans": [{"span_id": 0, "text": "L-carnitine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 40, "end": 51, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "L-carnitine ameliorates doxorubicin-induced nephrotic syndrome in rats. Effects of l-carnitine on nephrotoxicity and oxidative stress induced by doxorubicin (DOX) in rats were investigated. ### methods The rats were divided into four groups: group 1, control (0.9% NaCl); group 2, DOX injection (7.5 mg/kg, i.v.); group 3, DOX plus low dose (40 mg/kg) l-carnitine; and group 4, DOX plus high dose (200 mg/kg) l-carnitine. L-carnitine was administered 1 h before doxorubicin injection and daily thereafter for 15 days . ### results Rats in group 2 were associated with hypoalbuminaemia, hyperlipidaemia, high urinary excretion of protein and elevated plasma creatinine and urea nitrogen. The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) decreased with increased renal vascular resistance (RVR). Kidney catalase (CAT) activity was decreased. In group 3 and 4, plasma triglyceride and cholesterol declined. l-carnitine improved renal functions by elevated GFR and ERPF and decreased plasma creatinine and urea nitrogen. The kidney CAT activity were increased significantly compared with group 2. From histopathological results, group 2 rats were found to have glomerular capillary dilation and tubular dilation. The lesions were less in group 3 and 4 rats. ### conclusion l-carnitine can protect renal impairment functionally, biochemically and histopathologically with a corresponding reduction of oxidative stress.", "source": "https://pubmed.ncbi.nlm.nih.gov/16889571/"}
{"doc_id": "a1772c44e757e1514b82a6df2b030604", "sentence": "New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 36, "end": 47, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "fluorouracil", "start": 151, "end": 163, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Current and emerging treatments for pancreatic cancer. The worldwide annual pancreatic cancer death rate equals its estimated annual incidence. Surgery has been considered the only curative modality for this disease, but only 5 to 15% of patients are candidates for potentially curative resection. Evidence that postoperative adjuvant treatment improves outcome has been limited to a single randomised trial of a well tolerated split-course chemoradiation regimen. More intensive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative adjuvant ('neoadjuvant') chemoradiation in these patients. Although experience suggests that such an approach is feasible, its ultimate impact awaits further evaluation. Combined modality therapy has produced the most promising results in patients with unresectable or locally advanced disease. However, only modest improvements in median survival and minimal increases in long term survival have so far been achieved. This observation has encouraged many investigators to devise innovative methods of delivering therapy, including radioisotope implantation and intraoperative radiation therapy (IORT). Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. IORT may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by the radiobiological disadvantage associated with single dose boost therapy. Although new radiosensitising drugs are being tested, the problem of distant metastasis remains significant. New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil . Investigations into the optimal integration of different therapeutic modalities, along with continued advances in surgery, radiation and systemic therapy, should lead to the increased use of modern multimodality interventions. In turn, this will lead us towards further improvements in outcomes for patients with pancreatic carcinoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/9342558/"}
{"doc_id": "8e80b2ee5e4c1611cf8e52e7988d7b76", "sentence": "Comparative effectiveness of rituximab , abatacept , and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors : prospective cohort study .", "spans": [{"span_id": 0, "text": "rituximab", "start": 29, "end": 38, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "abatacept", "start": 41, "end": 50, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "tocilizumab", "start": 57, "end": 68, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Comparative effectiveness of rituximab , abatacept , and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors : prospective cohort study . To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) \u03b1 inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis. ### design Population based prospective study. ### setting 53 university and 54 non-university clinical centres in France. ### participants 3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months. ### intervention Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis. ### Main Outcome Measure The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LED ### results Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LED ### conclusion Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.", "source": "https://pubmed.ncbi.nlm.nih.gov/30679233/"}
{"doc_id": "40c387814e8b0757ef731fa545f66bcc", "sentence": "Recoveries of both amino acids were increased bilaterally by local perfusion with veratridine ( 100 microM , given under halothane anaesthesia ) , pretreatment with reserpine ( 4 mg/kg , i.p . , 24 h beforehand ) , unilateral pretreatment of the medial forebrain bundle with 6-OHDA ( 8 microg/4 microl ) , and by the systemic ( 1 mg/kg , i.p . ) or bilateral intrastriatal ( 7 microg/0.5 microl under halothane anaesthesia ) administration of the dopamine D2 receptor antagonist haloperidol , but not raclopride ( 2 mg/kg , i.p . ) .", "spans": [{"span_id": 0, "text": "halothane", "start": 121, "end": 130, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "reserpine", "start": 165, "end": 174, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "halothane", "start": 401, "end": 410, "token_start": 72, "token_end": 73}, {"span_id": 3, "text": "haloperidol", "start": 479, "end": 490, "token_start": 82, "token_end": 83}, {"span_id": 4, "text": "veratridine", "start": 82, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 5, "text": "6-OHDA", "start": 275, "end": 281, "token_start": 46, "token_end": 47}, {"span_id": 6, "text": "raclopride", "start": 501, "end": 511, "token_start": 86, "token_end": 87}], "rels": [{"class": "POS", "spans": [1, 4], "is_context_needed": false}, {"class": "POS", "spans": [3, 5], "is_context_needed": false}, {"class": "NEG", "spans": [5, 6], "is_context_needed": false}], "paragraph": "Extracellular levels of glutamate and aspartate in the entopeduncular nucleus of the rat determined by microdialysis: regulation by striatal dopamine D2 receptors via the indirect striatal output pathway? This study used intracerebral microdialysis to monitor the outputs of excitatory amino acids in the entopeduncular nucleus (EPN) of conscious or halothane-anaesthetized rats, in an attempt to obtain direct biochemical evidence for the theory that neuronal inputs to the EPN by the indirect striatal output pathway are glutamatergic and regulated primarily by dopamine D2 receptors in the striatum. In dopamine-intact animals, both glutamate and asparate were readily detectable in EPN dialysates. Recoveries of both amino acids were increased bilaterally by local perfusion with veratridine ( 100 microM , given under halothane anaesthesia ) , pretreatment with reserpine ( 4 mg/kg , i.p . , 24 h beforehand ) , unilateral pretreatment of the medial forebrain bundle with 6-OHDA ( 8 microg/4 microl ) , and by the systemic ( 1 mg/kg , i.p . ) or bilateral intrastriatal ( 7 microg/0.5 microl under halothane anaesthesia ) administration of the dopamine D2 receptor antagonist haloperidol , but not raclopride ( 2 mg/kg , i.p . ) . The dopamine D1 receptor antagonist SCH 23390 was ineffective both systemically (0.25 mg/kg, i.p.) and intrastriatally (0.125 microg/0.5 microl/side), as also were control intrastriatal injections of saline (0.5 microl/side). By contrast, the dopamine D2/3 receptor agonist quinpirole (4 mg/kg, i.p.) lowered the outputs of glutamate and aspartate in the EPN of reserpine-treated and normal individuals, whilst the dopamine D1 receptor agonist SKF 38393 (30 mg/kg, i.p.) was inactive; however, both drugs caused behavioural arousal. The dopamine D2/3 receptor agonist RU 24213 reversed reserpine-induced akinesia, yet paradoxically increased glutamate (not aspartate) output in the EPN still further. The combination of benserazide (30 mg/kg, i.p.) and L-DOPA (50 mg/kg, i.p.) evoked intense contraversive circling in unilaterally 6-OHDA-lesioned rats, together with a drop in EPN glutamate (but not aspartate) output in the intact but not lesioned hemisphere. These results offer biochemical support for the hypothesis that excitatory neurones innervating the EPN via the indirect striatal output pathway, may utilise glutamate and/or aspartate as their neurotransmitter. They further endorse the view that the EPN receives information from striatal D2 and not D1 receptors via excitatory synapses, which become hyperactive following dopamine depletion or inactivation, and which are subject to control by the contralateral as well as by the ipsilateral hemisphere. The results obtained with RU 24213 and L-DOPA, however, indicate that dopaminergic behaviours can also occur independently of glutamate or aspartate release in the EPN.", "source": "https://pubmed.ncbi.nlm.nih.gov/9125444/"}
{"doc_id": "58c98ab45fc1f4589ee167ae35e2162b", "sentence": "Combined initial cyclophosphamide with repeated methylprednisolone pulse therapy for severe paraquat poisoning from dermal exposure .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 17, "end": 33, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "methylprednisolone", "start": 48, "end": 66, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combined initial cyclophosphamide with repeated methylprednisolone pulse therapy for severe paraquat poisoning from dermal exposure . The article presents a patient with severe paraquat poisoning from dermal exposure, who had chemical bums to more than 10% of his body surface area, serum paraquat level 0.13 microg/mL 60 hr after exposure, and severe hypoxemia (PaO2 41.6 mmHg). The patient was successfully treated with combined initial megadoses of cyclophosphamide (15 mg/kg/day, total 2 days) with repeated methylprednisolone pulse therapy (15 mg/kg/day, total 6 days) and continuous dexamethasone administration (5 mg every 8 hr), and recovered completely without sequelae 3 months later. This treatment deserves further investigation in future clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/14677801/"}
{"doc_id": "5b6afe03121f818dd0a426d51cd826d3", "sentence": "These adverse effects were all more frequent than with docetaxel or pemetrexed .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 55, "end": 64, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "pemetrexed", "start": 68, "end": 78, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Crizotinib. Patients with advanced-stage or metastatic non-small cell lung cancer have a grim prognosis when first-line chemotherapy fails. Some cytotoxic drugs such as docetaxel and pemetrexed prolong overall survival by a few months, but at a cost of severe toxicity. crizotinib (Xalkori*, Pfizer), a drug that inhibits ALK (among other tyrosine kinases) has been authorised for use in patients whose tumours overexpress this tyrosine kinase. Preliminary results of a comparative, randomised but unblinded trial in 347 patients suggest that crizotinib delays cancer progression and death more effectively than pemetrexed or docetaxel (median 7.7 months versus 3 months). However, it remains to be seen whether or not this translates into longer overall survival. Two uncontrolled trials including 136 and 119 patients also suggest that crizotinib delays tumour progression and death by about 8 months. crizotinib is highly toxic, causing gastrointestinal, visual and hepatic disorders, cardiac arrhythmias (including QT prolongation) and pneumonia. These adverse effects were all more frequent than with docetaxel or pemetrexed . Some of these effects are more difficult to predict and manage than haematological disorders, which are the main adverse effects of docetaxel and pemetrexed. crizotinib is extensively metabolised by cytochrome P450 isoenzymes and also inhibits P-glycoprotein, creating a risk of numerous pharmacokinetic interactions. Other interactions, with drugs that prolong the QT interval, may increase the risk of serious adverse effects. In practice, in patients with non-small cell lung cancer overexpressing ALK tyrosine kinase in whom first-line chemotherapy has failed, crizotinib appears to delay cancer progression and death, but at a cost of serious adverse effects. Further evaluation of crizotinib in well-designed comparative trials is needed before deciding whether or not to include it in the therapeutic arsenal.", "source": "https://pubmed.ncbi.nlm.nih.gov/24427836/"}
{"doc_id": "e5700462572f4de98ab4591b1d026ef0", "sentence": "Hyper-CVAD , given in odd-number courses ( Courses 1 , 3 , 5 , and 7 ) , was alternated with methotrexate and cytarabine ( MTX/Ara-C ) , given in even-number courses ( Courses 2 , 4 , 6 , and 8) .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 93, "end": 105, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "cytarabine", "start": 110, "end": 120, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Hyperglycemia, which is not uncommon during the treatment of acute lymphocytic leukemia (ALL), has been shown to be an independent predictor of adverse outcomes among hospitalized patients with undiagnosed diabetes; it also may have the potential to affect leukemic cell proliferation through altered metabolism. The purpose of the current study was to determine the prevalence of hyperglycemia during induction chemotherapy for ALL using a regimen comprised of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and to determine its effect on survival, duration of disease remission, and treatment-related complications. ### methods Two hundred seventy-eight adult patients with previously untreated ALL who achieved a complete remission with the hyper-CVAD regimen were evaluated. Hyperglycemia was defined as > or = 2 glucose determinations of > or = 200 mg/dL during the first 30 days of induction chemotherapy. Induction chemotherapy was comprised of fractionated cyclophosphamide at a dose of 300 mg/m2 twice daily on Days 1-3, doxorubicin at a dose of 50 mg/m2 on Day 4, vincristine at a dose of 2 mg on Days 4 and 11, and dexamethasone at a dose of 40 mg on Days 1-4 and Days 11-14 (hyper-CVAD). Hyper-CVAD , given in odd-number courses ( Courses 1 , 3 , 5 , and 7 ) , was alternated with methotrexate and cytarabine ( MTX/Ara-C ) , given in even-number courses ( Courses 2 , 4 , 6 , and 8) . MTX/Ara-C was comprised of MTX at a dose of 200 mg/m2 over 2 hours followed by 800 mg/m2 over 22 hours on Day 1, Ara-C at a dose of 3 g/m2 every 12 hours for 4 doses over 2 days (Days 2 and 3), and intravenous methylprednisolone given at a dose of 50 mg twice daily on Days 1-3. The complete remission duration (CRD), survival, and treatment-related complications were determined for patients with and without hyperglycemia; differences between the two groups were assessed using standard statistical methods. ### results Hyperglycemia was found to occur in 103 patients (37%). Patients with hyperglycemia had a shorter median CRD (24 months vs. 52 months; P = 0.001) and a shorter median survival (29 months vs. 88 months; P < 0.001); they also were more likely to develop sepsis (16.5% vs. 8.0%; P = 0.03) or any complicated infection (sepsis, pneumonia, or fungal) (38.8% vs. 25.1%; P = 0.016) compared with patients without hyperglycemia. ### conclusions Patients with hyperglycemia during induction chemotherapy for ALL with the hyper-CVAD regimen were found to have a shorter CRD, experience a significant increase in overall mortality, and be at an increased risk for developing complicated infections.", "source": "https://pubmed.ncbi.nlm.nih.gov/15022284/"}
{"doc_id": "d68d2fb14b6930de59e1746f6be132ff", "sentence": "Despite systemic chemotherapy combining pemetrexed , bevacizumab and Cisplatinum , the disease relapsed eight months later with multiple metastatic lung nodules leading to a treatment shift .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 40, "end": 50, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "bevacizumab", "start": 53, "end": 64, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "Cisplatinum", "start": 69, "end": 80, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "The necessity of a more aggressive initial surgical treatment in patients with mesothelioma of the testicular tunica vaginalis. Mesothelioma of the tunica vaginalis of the testis (MTVM) is a rare tumor encountering for less than 1% of mesothelioma. Patients suffering from these tumors have poor survival due to local and distant metastasis despite treatment. Actually, no specific treatment recommendations exist for this tumor, yet radical orchidectomy is the gold standard in limited disease. We herein report the case of a 71 patient with MTVM who underwent radical orchidectomy without inguinal lymph node dissection and recurred 2 years later with metastasis in pelvic and mediastinal lymph nodes. Despite systemic chemotherapy combining pemetrexed , bevacizumab and Cisplatinum , the disease relapsed eight months later with multiple metastatic lung nodules leading to a treatment shift . We believe that systematic inguinal-iliac lymph node resection should be included in the initial treatment of this tumor.", "source": "https://pubmed.ncbi.nlm.nih.gov/31692693/"}
{"doc_id": "7b50d48684b8c2fee436950bf35cb0d1", "sentence": "Trastuzumab , which is still the first-line therapy in breast cancer , increases the pCR rate more than lapatinib .", "spans": [{"span_id": 0, "text": "Trastuzumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "lapatinib", "start": 104, "end": 113, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Effects of lapatinib or trastuzumab, alone and in combination, in human epidermal growth factor receptor 2-positive breast cancer: a meta-analysis of randomized controlled trials. This meta-analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. For dichotomous variables, the relative risk ratio (RR) and 95% confidence interval (CI) were used to investigate outcome measures: pathological complete response (pCR), neutropenia, diarrhea, dermatologic toxicity, and congestive heart failure (CHF). Eight randomized controlled trials of 2350 participants (837 receiving lapatinib, 913 trastuzumab, and 555 combination therapy) were selected to compare the efficiency and safety of lapatinib to trastuzumab. A significant difference was found between lapatinib and trastuzumab for pCR (RR\u00a0=\u00a00.82, 95% CI: 0.73-0.93; Z\u00a0=\u00a03.00; P\u00a0=\u00a00.003). In six studies, a significant difference was found between trastuzumab and combination therapy for pCR (RR\u00a0=\u00a01.33, 95% CI: 1.18-1.50; Z\u00a0=\u00a04.70; P\u00a0<\u00a00.00001), diarrhea (RR\u00a0=\u00a014.59, 95% CI: 7.69-27.67; Z\u00a0=\u00a08.20; P\u00a0<\u00a00.00001), and dermatologic toxicity (RR\u00a0=\u00a03.10, 95% CI: 1.61-5.96; Z\u00a0=\u00a03.39; P\u00a0=\u00a00.007), but none was found for neutropenia (RR\u00a0=\u00a01.38, 95% CI: 0.82-2.31; Z\u00a0=\u00a01.22; P\u00a0=\u00a00.22) or CHF (RR\u00a0=\u00a00.14, 95% CI: 0.02-1.17; Z\u00a0=\u00a01.02; P\u00a0=\u00a00.07). Combination therapy compared to trastuzumab alone increases the pCR rate of HER2-positive breast cancer patients with no additional cardiac events. Trastuzumab , which is still the first-line therapy in breast cancer , increases the pCR rate more than lapatinib .", "source": "https://pubmed.ncbi.nlm.nih.gov/27882700/"}
{"doc_id": "ff41f8ada1aa59e48542817d10e7a13b", "sentence": "Recently , several novel agents are under clinical development for advanced colorectal cancer , including irinotecan , oxaliplatin , oral fluoropyrimidines , raltitrexed , monoclonal antibody 17 - 1A and tumour vaccines .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 106, "end": 116, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "oxaliplatin", "start": 119, "end": 130, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "raltitrexed", "start": 158, "end": 169, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Novel agents for colorectal cancer. The compound 5-fluorouracil (5-FU) has been investigated for over four decades; research has focussed on examining various schedules and biochemical modulators in an attempt to improve its therapeutic activity in advanced colorectal cancer. Combination chemotherapy regimens have not been developed because of the lack of other active agents. Recently , several novel agents are under clinical development for advanced colorectal cancer , including irinotecan , oxaliplatin , oral fluoropyrimidines , raltitrexed , monoclonal antibody 17 - 1A and tumour vaccines . Both irinotecan and oxaliplatin have uniquely different mechanisms of action compared to 5-FU, and have demonstrated activity in patients whose disease has progressed with 5-FU treatment. Recent randomised trials comparing 5-FU plus leucovorin (5-FU/LV) to combinations of either irinotecan or oxaliplatin plus 5-FU/LV have demonstrated that the addition of these novel agents to 5-FU improve response rates (RRs) and time to progression (TTP). The role and acceptance of these combinations need to be defined, but are rapidly being introduced into the adjuvant therapy of colorectal cancer. Oral fluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU, and S-1) provide the convenience of oral delivery with a marked reduction in febrile neutropenia and mucositis. To gain clinical acceptance, oral fluoropyrimidines must provide not only convenience and toxicity reduction, but also maintenance of survival advantages associated with optimal use of iv. 5-FU/LV regimens. These novel agents discussed herein provide treatment options which may allow for more individualised treatment strategies.", "source": "https://pubmed.ncbi.nlm.nih.gov/11139816/"}
{"doc_id": "bdf4194d4f3640ac2215ef4cbaacba52", "sentence": "Pretreatment with NaHCO3 , NH4Cl , SKF 525A , piperonyl butoxide , progesterone , cysteamine , phenobarbital or metyrapone prior to the administration of [methyl-14C]nicotine was studied .", "spans": [{"span_id": 0, "text": "NaHCO3", "start": 18, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "NH4Cl", "start": 27, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "SKF 525A", "start": 35, "end": 43, "token_start": 6, "token_end": 8}, {"span_id": 3, "text": "piperonyl butoxide", "start": 46, "end": 64, "token_start": 9, "token_end": 11}, {"span_id": 4, "text": "progesterone", "start": 67, "end": 79, "token_start": 12, "token_end": 13}, {"span_id": 5, "text": "cysteamine", "start": 82, "end": 92, "token_start": 14, "token_end": 15}, {"span_id": 6, "text": "phenobarbital", "start": 95, "end": 108, "token_start": 16, "token_end": 17}, {"span_id": 7, "text": "metyrapone", "start": 112, "end": 122, "token_start": 18, "token_end": 19}, {"span_id": 8, "text": "[methyl-14C]nicotine", "start": 154, "end": 174, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [8, 7], "is_context_needed": true}, {"class": "POS", "spans": [8, 4], "is_context_needed": true}], "paragraph": "Inhibition by metyrapone of the accumulation of nicotine-14C in bronchial epithelium of mice. Further studies have been conducted in an attempt to define the mechanism of the intense accumulation of radioactivity in bronchial epithelium following the administration of nicotine-14C to mice. Male and female pigmented (C57B1/6J) and nonpigmented (A/HeJ) mice were studied by whole-body autoradiography following administration of either nicotine-14C (methyl- or 2'-labeled) or nicotine-1'-N-oxide-14C. When each of these compounds was administered at the same specific activity the radioactivity retained in the bronchial epithelium was much greater for the methyl-labeled nicotine-14C than for the ring-labeled. Following administration of the N-oxide very little radioactivity was retained at this site and this was seen only at a few time intervals. Pretreatment with NaHCO3 , NH4Cl , SKF 525A , piperonyl butoxide , progesterone , cysteamine , phenobarbital or metyrapone prior to the administration of [methyl-14C]nicotine was studied . metyrapone totally prevented the accumulation of radioactivity in the bronchial epithelium and progesterone reduced this accumulation; the other substances used for pretreatment had no effect on the uptake of radioactivity. These results are interpreted to indicate that the accumulation of nicotine in bronchial epithelium is not accounted for by transcellular pH gradients but is due to a high affinity of nicotine for a cytochrome P-450 in this tissue which demethylates the nicotine. The relationship and significance of metabolism of nicotine in this tissue to metabolism at other sites in the body are discussed.", "source": "https://pubmed.ncbi.nlm.nih.gov/708156/"}
{"doc_id": "495b0332d40be56154a40837c4031e51", "sentence": "Capecitabine is an oral pro-drug of fluorouracil .", "spans": [{"span_id": 0, "text": "Capecitabine", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "fluorouracil", "start": 36, "end": 48, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "[New drugs for colorectal cancer]. Drug treatment of colorectal cancer has made impressive progress during the past 10 years. In addition to fluorouracil new anticancer drugs like irinotecan and oxaliplatin have become available. The activity of fluorouracil was optimized by using schedules of prolonged infusion. Capecitabine is an oral pro-drug of fluorouracil . When colorectal metastases are limited to the liver they should be resected if possible. Sometimes they can be reduced in size by primary chemotherapy (downstaging) and resected later. Very new and exciting are reports with the monoclonal antibody bevacizumab in combination with chemotherapy. bevacizumab blocks angiogenesis. So far it is available only in the USA.", "source": "https://pubmed.ncbi.nlm.nih.gov/15487860/"}
{"doc_id": "278d71de134cee74edc0ce47d5f18854", "sentence": "However , the current artemisinin FDC products , such as \u03b2-artemether and lumefantrine , are inherently unstable and require controlled distribution and storage conditions , which are not always available in resource-limited settings .", "spans": [{"span_id": 0, "text": "artemisinin", "start": 22, "end": 33, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "lumefantrine", "start": 74, "end": 86, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "A rapid stability-indicating, fused-core HPLC method for simultaneous determination of \u03b2-artemether and lumefantrine in anti-malarial fixed dose combination products. artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However , the current artemisinin FDC products , such as \u03b2-artemether and lumefantrine , are inherently unstable and require controlled distribution and storage conditions , which are not always available in resource-limited settings . Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of \u03b2-artemether and lumefantrine FDC products. ### methods Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30\u00b0C, were evaluated. \u03b2-artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1 mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 \u03bcl injection volume. Quantification was performed at 210 nm and 335 nm for \u03b2-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0\u00ae. ### results Both \u03b2-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (\u00b1 RSD) of 99.7 % (\u00b1 0.7%) for \u03b2-artemether and 99.7 % (\u00b1 0.6%) for lumefantrine. All identified \u03b2-artemether-related impurities were predicted in Derek Nexus v2.0\u00ae to have toxicity risks similar to \u03b2-artemether active pharmaceutical ingredient (API) itself. ### conclusions A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of \u03b2-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus\u00ae indicated that the overall toxicity risk for \u03b2-artemether-related impurities is comparable to that of \u03b2-artemether API.", "source": "https://pubmed.ncbi.nlm.nih.gov/23631682/"}
{"doc_id": "06aa63233bdab39481aa15cf612fb2a3", "sentence": "Because the mass invaded the pancreas and superior mesenteric vein as well as duodenum and the disease was disseminated to liver and peritoneum , she received palliative chemotherapy using vincristine , doxorubicin , cyclophosphamide , ifosfamide , and etoposide .", "spans": [{"span_id": 0, "text": "vincristine", "start": 189, "end": 200, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "doxorubicin", "start": 203, "end": 214, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "cyclophosphamide", "start": 217, "end": 233, "token_start": 33, "token_end": 34}, {"span_id": 3, "text": "ifosfamide", "start": 236, "end": 246, "token_start": 35, "token_end": 36}, {"span_id": 4, "text": "etoposide", "start": 253, "end": 262, "token_start": 38, "token_end": 39}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": false}], "paragraph": "A case of desmoplastic small round cell tumor diagnosed in a young female patient. Desmoplastic small round cell tumor is a very rare malignancy. We report the case of a 26-year-old woman who suffered from dyspepsia and abdominal pain for 2 months. We performed an endoscopic biopsy of the duodenal mass and diagnosed her disease as desmoplastic small round cell tumor using immunohistochemical staining, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction. Because the mass invaded the pancreas and superior mesenteric vein as well as duodenum and the disease was disseminated to liver and peritoneum , she received palliative chemotherapy using vincristine , doxorubicin , cyclophosphamide , ifosfamide , and etoposide . The maximal response to chemotherapy was stable disease. The patient expired 9 months after diagnosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/20057970/"}
{"doc_id": "33615bfabfbbd2bf4dec81f0c8c3cae4", "sentence": "In HCV genotype 1 infection and F3 or F4 liver fibrosis , treatment with boceprevir or telaprevir in addition to pegylated interferon and ribavirin is recommended .", "spans": [{"span_id": 0, "text": "boceprevir", "start": 73, "end": 83, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "telaprevir", "start": 87, "end": 97, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "pegylated interferon", "start": 113, "end": 133, "token_start": 20, "token_end": 22}, {"span_id": 3, "text": "ribavirin", "start": 138, "end": 147, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 2, 3], "is_context_needed": false}, {"class": "POS", "spans": [1, 2, 3], "is_context_needed": false}], "paragraph": "[Treatment of chronic hepatitis C in human immunodeficiency virus infected patients]. Treatment of HCV infection offers the possibility of viral eradication, thus every person with a detectable HCV viral load is a candidate for treatment. Treatment is recommended to all HCV/HIV co-infected patients with: 1) repeatedly elevated aminotransferase levels; 2) F2 stage of liver fibrosis or higher, regardless of alanine aminotransferase values; and 3) more than 200 CD4+ lymphocytes per microL of blood. Treatment with a combination of pegylated interferon and weight-based ribavirin (1000 mg/day if < 75 kg and 1200 mg/day if > 75 kg) is recommended. Pegylated interferon is used as 180 microg for the alfa-2a form and 1.5 mg/kg for the alfa-2b form once weekly subcutaneously. HCV RNA should be measured after 4 weeks of treatment, and later as needed, in weeks 12, 24, 48 or 72. For evaluation of a sustained virologic response, HCV RNA should be measured 24 weeks after the end of treatment. Treatment duration for patients who have a rapid viral response (undetectable levels of HCV RNA after 4 weeks of treatment) is 24 weeks (genotypes 2 and 3) or 48 weeks (genotypes 1 and 4). For patients without a rapid virologic response, but with an adequate response after 12 and 24 weeks, we generally recommend treatment for 48 weeks. Treatment discontinuation is recommended for patients with < 2 log viral load decline after 12 weeks or with a detectable viral load after 24 weeks of treatment. In HCV genotype 1 infection and F3 or F4 liver fibrosis , treatment with boceprevir or telaprevir in addition to pegylated interferon and ribavirin is recommended . In case of persistent HCV replication during therapy stopping rules should be applied.", "source": "https://pubmed.ncbi.nlm.nih.gov/24984336/"}
{"doc_id": "d7ad522d1f7eaa6dd4f5b41387f73a8a", "sentence": "Membrane-modifying agents such as reserpine , calcium antagonists ( nicardipine , verapamil ) and calmodulin inhibitor ( trifluoperazine ) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 ( C 6/ACNU ) glioma .", "spans": [{"span_id": 0, "text": "reserpine", "start": 34, "end": 43, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "nicardipine", "start": 68, "end": 79, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "verapamil", "start": 82, "end": 91, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "trifluoperazine", "start": 121, "end": 136, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "[Possibility of overcoming of ACNU resistance in an ACNU-resistant subline of C6 rat glioma].  Membrane-modifying agents such as reserpine , calcium antagonists ( nicardipine , verapamil ) and calmodulin inhibitor ( trifluoperazine ) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 ( C 6/ACNU ) glioma . In in vitro experiments, uptake and retention studies with [14C] ACNU revealed that intracellular uptake and retention of ACNU in C 6 cells were larger than those in C 6/ACNU cells, and that these membrane-modifying agents increased the cellular uptake and retention of ACNU in C 6, especially in C 6/ACNU cells. The amount of ACNU in C 6/ACNU cells reached the same level as that detected in C 6/ACNU cells. When these drugs were added along with ACNU at the concentration of 10 to 20 microM to the culture in vitro, ACNU resistance was completely overcome. In in vivo experiment, reserpine, nicardipine, verapamil and trifluoperazine in doses 250 to 500 micrograms/kg intrathecally administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly enhanced the chemotherapeutic effect of ACNU in C 6/ACNU bearing (C 6/ACNU-MG) rats. It might be concluded that the mechanism of enhancement of ACNU cytotoxicity presented in in vitro and in vivo is explained by the enhanced accumulation of ACNU by these membrane-modifying agents in C 6, especially in ACNU-resistant (C 6/ACNU) cells, and, furthermore, that combination chemotherapy with ACNU and such membrane interacting drugs as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) could lead to the capability of overcoming resistance to ACNU in glioma.", "source": "https://pubmed.ncbi.nlm.nih.gov/3468959/"}
{"doc_id": "e814c77d08e9c7d24b065d8ba760cf4a", "sentence": "To investigate the efficacy of temozolomide in relation to response rate , toxicity , time to progression . and median survival time , a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea , procarbazine and vincristine .", "spans": [{"span_id": 0, "text": "temozolomide", "start": 31, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "procarbazine", "start": 298, "end": 310, "token_start": 46, "token_end": 47}, {"span_id": 2, "text": "vincristine", "start": 315, "end": 326, "token_start": 48, "token_end": 49}], "rels": [], "paragraph": "Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study.  To investigate the efficacy of temozolomide in relation to response rate , toxicity , time to progression . and median survival time , a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea , procarbazine and vincristine . ### Patients And Methods Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. ### results Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%-35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. ### conclusions On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma.", "source": "https://pubmed.ncbi.nlm.nih.gov/11300334/"}
{"doc_id": "77d0a181f8d82c9a814b0cc95af49608", "sentence": "Ketoconazole inhibited the entire pathway , while exposure to genistein resulted in increased hormone levels upstream of 3-\u03b2-hydroxysteroid dehydrogenase ( 3\u03b2-HSD ) and decreases downstream .", "spans": [{"span_id": 0, "text": "Ketoconazole", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "genistein", "start": 62, "end": 71, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "H295R cells as a model for steroidogenic disruption: a broader perspective using simultaneous chemical analysis of 7 key steroid hormones. The effects of three model endocrine disruptors, prochloraz, ketoconazole and genistein on steroidogenesis were tested in the adrenocortical H295R cell line to demonstrate that a broader mechanistic understanding can be achieved in one assay by applying chemical analysis to the H295R assay. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone and 17\u03b2-estradiol) were analyzed using a novel and thoroughly validated GC-MS/MS method. In addition to the simultaneous quantification of 7 steroid hormones, the present method also negates the potential problems of cross-reactivity that can be encountered in some immunoassays. Although all 3 test compounds decrease the concentrations of the main sex steroids, the chemicals exerted different effects upstream in the pathway. Exposure to prochloraz resulted in increased hormone levels upstream of steroid 17 alpha-hydroxylase/17,20 lyase (P450c17) and decreases downstream. Ketoconazole inhibited the entire pathway , while exposure to genistein resulted in increased hormone levels upstream of 3-\u03b2-hydroxysteroid dehydrogenase ( 3\u03b2-HSD ) and decreases downstream . The results demonstrate that chemical analysis combined with the H295R cell assay is an useful tool for studying the mechanisms by which endocrine disruptors interfere with the steroidogenic pathway.", "source": "https://pubmed.ncbi.nlm.nih.gov/22198065/"}
{"doc_id": "a67a955015d89bd9210042765e9bfba1", "sentence": "Melphalan , cisplatin , carboplatin , doxorubicin , and etoposide cytotoxicities were determined by DIMSCAN assay .", "spans": [{"span_id": 0, "text": "Melphalan", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cisplatin", "start": 12, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "carboplatin", "start": 24, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "doxorubicin", "start": 38, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "etoposide", "start": 56, "end": 65, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Drug resistance in human neuroblastoma cell lines correlates with clinical therapy. To determine if neuroblastoma acquires a sustained drug-resistant phenotype from patient exposure to therapy, we studied neuroblastoma cell lines established at different points of therapy: at diagnosis prior to therapy, at progressive disease after induction therapy and at relapse after intensive chemoradiotherapy and bone marrow transplantation (post-BMT). Melphalan , cisplatin , carboplatin , doxorubicin , and etoposide cytotoxicities were determined by DIMSCAN assay . Drug resistance progressively increased with therapy and 3/5 post-BMT lines showed high resistance to most drugs. IC 90s 37, 78, 719 and 256 times higher than clinically achievable drug levels were obtained in post-BMT cell lines for melphalan, cisplatin, doxorubicin and etoposide, respectively. Resistance correlated with the therapies patients received: considerable etoposide and doxorubicin resistance (> 1000-fold resistance) was seen in cell lines obtained from patients treated with these drugs. These cell lines indicate that neuroblastoma acquires resistance to cytotoxic drugs that is probably due to stable genetic alterations occurring during therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/9516842/"}
{"doc_id": "8eaa87363fa72a9071d0b5d4982767c3", "sentence": "As a treatment at the time of progression after pemetrexed-based chemotherapy , erlotinib conferred a survival benefit when compared to docetaxel ( p=0.024 ; hazard ratio , 0.377 ) .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 80, "end": 89, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "docetaxel", "start": 136, "end": 145, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Clinical and biological significance of erlotinib therapy after pemetrexed in non-small cell lung cancer with wild-type EGFR. pemetrexed is a\u00a0multi-targeted anti-folate agent that confers favorable benefits to patients with non-small cell lung cancer (NSCLC). However, the optimal use including treatment schedule of pemetrexed and other drugs in clinical practice remains to be determined, particularly for NSCLC with wild-type epidermal growth factor receptor (EGFR). The present study investigated a\u00a0potential therapeutic strategy for NSCLC patients with wild-type EGFR who were treated with pemetrexed. To identify factors associated with a\u00a0survival, medical record data from 130 patients were retrospectively reviewed, using the Kaplan-Meier method with log-rank test. Factors identified in the clinical analysis were further investigated within in vitro studies. Patients who underwent the treatment schedule of erlotinib at the time of progression after pemetrexed-based chemotherapy prolonged overall survival, compared to those treated with other schedules (p=0.010; hazard ratio, 0.418). This survival benefit was also observed in the treatment schedule of pemetrexed monotherapy and subsequent erlotinib (p=0.008; hazard ratio, 0.220). As a treatment at the time of progression after pemetrexed-based chemotherapy , erlotinib conferred a survival benefit when compared to docetaxel ( p=0.024 ; hazard ratio , 0.377 ) . The cell growth assay confirmed that treatment with pemetrexed followed by erlotinib significantly inhibited proliferation of NSCLC cells regardless of EGFR mutation status. In conclusion, use of erlotinib at the time of progression after pemetrexed therapy confers a\u00a0survival benefit in NSCLC patients with wild-type EGFR. The result of this study provides an important clue to the optimal treatment schedule for NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/26458306/"}
{"doc_id": "27a22f42ae6e4491d8b1c48b5b59e484", "sentence": "The combination of ifosfamide with oral etoposide appears to have significant but manageable toxicity and encouraging efficacy in platinum resistant ovarian cancer .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 19, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "etoposide", "start": 40, "end": 49, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Ifosfamide plus oral etoposide salvage chemotherapy for platinum-resistant paclitaxel-pretreated ovarian cancer. The prognosis of platinum resistant ovarian cancer is very poor and the treatment of choice has not been clearly defined. ### Patients And Methods We conducted a phase II study with the combination of ifosfamide i.v. at 2.25 g/m2 (days 1, 2) and etoposide per os at 100 mg daily (days 1-10) every four weeks. To be eligible for the study patients had to be resistant to platinum and paclitaxel pretreated. ### results Forty-one patients entered the study. The median interval from the previous chemotherapy was 3.9 months. The median number of previous chemotherapeutic regimens was 2. Severe toxicities included neutropenia (41% of patients), leukopenia (29%) and thrombocytopenia (13%). Thirty-five patients are assessable for response. Nine patients responded (22% of the eligible, 26% of the assessable), four of them demonstrated complete response to chemotherapy (10% and 12%, respectively), while three patients demonstrated stabilization of their progressive disease. After a median follow-up of 18 months, time to progression is 3 months (range 0.9-14.4), duration of response is 9 months (2.5-11) and median survival is 13 months (2.5-37.4+). ### conclusions The combination of ifosfamide with oral etoposide appears to have significant but manageable toxicity and encouraging efficacy in platinum resistant ovarian cancer .", "source": "https://pubmed.ncbi.nlm.nih.gov/10907957/"}
{"doc_id": "315a17c64404a20e865c08463645946d", "sentence": "After switching from ranibizumab treatment to aflibercept , ORTs remained present in 75 % of eyes , and significant reductions in CMT , PED , and SRF , and presence of intraretinal cysts were observed .", "spans": [{"span_id": 0, "text": "ranibizumab", "start": 21, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "aflibercept", "start": 46, "end": 57, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Evaluation of outer retinal tubulations in eyes switched from intravitreal ranibizumab to aflibercept for treatment of exudative age-related macular degeneration. To evaluate the changes of outer retinal tubulations (ORTs) as seen on spectral-domain optical coherence tomography (SD OCT) in eyes with neovascular age-related macular degeneration (AMD) where treatment was switched from intravitreal ranibizumab to intravitreal aflibercept. ### methods This was a prospective study of eyes diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept, conducted at a single centre (Department of Ophthalmology at Piti\u00e9 Salpetriere Hospital, Paris VI University) from January to July 2015. Before and after treatment was switched from ranibizumab to aflibercept, SD-OCT was used to evaluate the presence of ORTs. Additional assessments in this patient group included best-corrected visual acuity (BCVA), fluorescein angiography (FA), indocyanine green angiography (ICGA). Changes in pigment epithelium detachments (PED), presence of intraretinal cysts, and presence of subretinal fluid (SRF) were also noted. ### results Twenty-four eyes of 24 consecutive patients (15 female/nine male, mean age 70\u00a0years) diagnosed with neovascular AMD and previously treated with >6 intravitreal ranibizumab injections and switched to aflibercept were included in the analysis. After receiving aflibercept, patients were followed for a mean of 6.1\u00a0months. Prior to treatment switch, 97\u00a0% of eyes showed ORTs, while after treatment switch to aflibercept, at the end of the study period, 75\u00a0% had ORTs (p\u2009=\u2009 0.219). Changes in BCVA (LogMAR) were not statistically significant (1.16 \u00b1 0.44 to 1.18 \u00b1 1.06, p\u2009=\u2009 0.12), however, a significant reduction in central macular thickness (CMT) (from 406\u00a0\u03bcm \u00b1 112 to 263\u00a0\u03bcm \u00b1 68, p\u2009=\u2009 0.001), PED (from 70.8\u00a0% to 41.7\u00a0% , p\u2009=\u2009 0.016), presence of intraretinal cysts (from 83.3\u00a0% to 33.3\u00a0%, p\u2009=\u2009 0.002) and SRF (from 91.7\u00a0% to 25\u00a0%, p\u2009= 0.001\u2009) were noted. ### conclusion After switching from ranibizumab treatment to aflibercept , ORTs remained present in 75 % of eyes , and significant reductions in CMT , PED , and SRF , and presence of intraretinal cysts were observed .", "source": "https://pubmed.ncbi.nlm.nih.gov/27397583/"}
{"doc_id": "a8c99f7a4aa7a4ab7501fc6360bafe72", "sentence": "Vinorelbine , gemcitabine , docetaxel , paclitaxel , and irinotecan are all new chemotherapeutic agents which have shown promising activity in this disease .", "spans": [{"span_id": 0, "text": "Vinorelbine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gemcitabine", "start": 14, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "docetaxel", "start": 28, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "paclitaxel", "start": 40, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "irinotecan", "start": 57, "end": 67, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "A brief historical review of the development of chemotherapy for the treatment of advanced non-small cell lung cancer: why we should look beyond platinum. We are approaching the end of the fifth decade and the most productive period in the development of chemotherapy for the treatment of advanced non-small cell lung cancer. We began this decade by establishing cisplatin-based combination chemotherapy regimens of the 1980s as effective at improving survival for patients with advanced disease. The observed improvement in survival from these trials appears to be primarily attributed to cisplatin. Furthermore, this decade, unlike the prior, has identified an abundance of novel active agents for the treatment of this disease. Vinorelbine , gemcitabine , docetaxel , paclitaxel , and irinotecan are all new chemotherapeutic agents which have shown promising activity in this disease . In contrast to the cisplatin-based chemotherapy trials of the 1980s, these newer chemotherapeutic agents when given in combination with cisplatin add to the survival outcomes for these patients. With these survival advances has come a focus on chemotherapy-induced adverse events, lung cancer symptom management, and overall quality of life. The results of the cisplatin combination trials will be discussed.", "source": "https://pubmed.ncbi.nlm.nih.gov/10585002/"}
{"doc_id": "11921a640de5c5c816f5ac48cfbc7fbd", "sentence": "This Phase I , randomized , open-label study evaluated the gastric pH-altering effects of omeprazole , a proton pump inhibitor , and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir , an HIV protease inhibitor , on the pharmacokinetics and safety of the hepatitis C virus ( HCV ) non-structural protein 5A ( NS5A ) inhibitor GSK2336805 in healthy male and female subjects .", "spans": [{"span_id": 0, "text": "omeprazole", "start": 90, "end": 100, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "ritonavir", "start": 193, "end": 202, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "GSK2336805", "start": 346, "end": 356, "token_start": 55, "token_end": 56}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effects of omeprazole and ritonavir on absorption and elimination of the hepatitis C virus NS5A inhibitor GSK2336805 in healthy adults.  This Phase I , randomized , open-label study evaluated the gastric pH-altering effects of omeprazole , a proton pump inhibitor , and the CYP3A enzyme/P-glycoprotein (Pgp)-inhibitory effects of ritonavir , an HIV protease inhibitor , on the pharmacokinetics and safety of the hepatitis C virus ( HCV ) non-structural protein 5A ( NS5A ) inhibitor GSK2336805 in healthy male and female subjects . Co-administration of GSK2336805 60\u2009mg with omeprazole decreased GSK2336805 plasma AUC(0-\u221e) by 10% and Cmax by 18%; no marked effect was observed on t\u00bd . Co-administration of GSK2336805 30\u2009mg with ritonavir increased GSK2336805 plasma AUC(0-\u221e) by 52%, Cmax by 43%, and t\u00bd by 40%; CL/F was decreased by 34%. All adverse events were minor in intensity. The gastric acid-suppressive effect of omeprazole had minimal impact on the extent and rate of GSK2336805 absorption in vivo; therefore, GSK2336805 may be co-administered with omeprazole without concern about lower GSK2336805 exposures and compromised antiviral efficacy. The modest increases in AUC and Cmax following co-administration of GSK2336805 plus ritonavir suggest that GSK2336805 when given concomitantly with a single CYP3A/Pgp inhibiting drug will not likely require dose adjustment. Final dose recommendation will be based on GSK2336805 efficacy and safety profiles from Phase III trials in HCV-infected patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/27129005/"}
{"doc_id": "5015ab706c206dd92fe59662d7436a52", "sentence": "This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia , notably , chloroquine , hydroxychloroquine , azithromycin , and lopinavir/ritonavir .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 205, "end": 216, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "hydroxychloroquine", "start": 219, "end": 237, "token_start": 32, "token_end": 33}, {"span_id": 2, "text": "azithromycin", "start": 240, "end": 252, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society. The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia , notably , chloroquine , hydroxychloroquine , azithromycin , and lopinavir/ritonavir . During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1)\u00a0discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.", "source": "https://pubmed.ncbi.nlm.nih.gov/32299753/"}
{"doc_id": "fb0288ced0a121729799b63624779e1b", "sentence": "Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 25, "end": 35, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "sorafenib", "start": 40, "end": 49, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma . There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. ### objective We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. ### design Multicenter, prospective phase II trial. Setting Referral centers for ACC. ### methods Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. ### results Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. ### conclusions Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.", "source": "https://pubmed.ncbi.nlm.nih.gov/22189997/"}
{"doc_id": "140cd4dac5f73cd731f2811f3a528bc7", "sentence": "This study indicates that cyclophosphamide , doxorubicin , and methotrexate are , at best , marginally active as single agents , and new drugs with more efficacy are needed before combination chemotherapy can be expected to result in any meaningful prolongation of survival in non-small cell lung cancer .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 26, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxorubicin", "start": 45, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "methotrexate", "start": 63, "end": 75, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Random prospective study cyclophosphamide, doxorubicin, and methotrexate (CAM) combination chemotherapy versus single-agent sequential chemotherapy in non small cell lung cancer. A group of 104 patients with unresectable non-small cell lung cancer were randomized to receive combination chemotherapy with cyclophosphamide, doxorubicin, and methotrexate (CAM) or single-agent sequential chemotherapy with the same three agents. CAM combination chemotherapy produced a 22% objective response rate, including two complete remissions, compared to a 9% response rate, including one complete remission, produced by single-agent therapy (P = 0.16). The median survival time was 32 weeks (range, 3-116) for CAM, compared to 25 weeks (range, 4-179 +) for sequential single agents (P = 0.24). Overall survival was 31% (1-year), (16%) (1 1/2-year), and 5% (2-year), with no difference between the study arms. Although there was no statistically significant survival advantage for the CAM arm, both arms had survival superior to that in historical controls, presumably because of better patient selection. This study indicates that cyclophosphamide , doxorubicin , and methotrexate are , at best , marginally active as single agents , and new drugs with more efficacy are needed before combination chemotherapy can be expected to result in any meaningful prolongation of survival in non-small cell lung cancer .", "source": "https://pubmed.ncbi.nlm.nih.gov/6291763/"}
{"doc_id": "347b9e96b7e1c1a9c50392e1f5a37cdb", "sentence": "The combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the curcumin and docetaxel-treated group alone .", "spans": [{"span_id": 0, "text": "curcumin", "start": 26, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "docetaxel", "start": 39, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "curcumin", "start": 129, "end": 137, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer. docetaxel is the most commonly used chemotherapeutic agent to target androgen signaling in metastatic prostate cancer (PCa); however, prolonged treatment with docetaxel results in drug-resistant cancer cells. Combination therapies have the potential of increasing the effectiveness of drug treatment as well as decreasing the side effects. curcumin is a nontoxic organic compound with multifaceted chemopreventive potential. In this study, we evaluated whether curcumin can reinforce the effect of docetaxel on PCa cells. The PCa cell lines DU145 and PC3 were treated with curcumin and docetaxel alone or in combination. After completion of the treatment cell proliferation and the expression of pro-survival and anti-apoptotic markers and the signaling molecules were analyzed. The combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the curcumin and docetaxel-treated group alone . Interestingly, the combined treatment with curcumin and docetaxel modulates the expression of RTKs, PI3K, phospho-AKT, NF-kappa B, p53, and COX-2. These results suggest that curcumin can be a potential therapeutic contender in enhancing the efficacy of docetaxel in PCa treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/28199187/"}
{"doc_id": "cb9d977dcda8131a2befc404d99b78d3", "sentence": "Previously , a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma .", "spans": [{"span_id": 0, "text": "dabrafenib", "start": 60, "end": 70, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "trametinib", "start": 75, "end": 85, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "dabrafenib", "start": 135, "end": 145, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.  Previously , a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma . The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. ### methods We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. ### findings Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25\u00b71 months (95% CI 19\u00b72-not reached) in the dabrafenib and trametinib group versus 18\u00b77 months (15\u00b72-23\u00b77) in the dabrafenib only group (hazard ratio [HR] 0\u00b771, 95% CI 0\u00b755-0\u00b792; p=0\u00b70107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11\u00b70 months (95% CI 8\u00b70-13\u00b79) in the dabrafenib and trametinib group and 8\u00b78 months (5\u00b79-9\u00b73) in the dabrafenib only group (HR 0\u00b767, 95% CI 0\u00b753-0\u00b784; p=0\u00b70004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. ### interpretation The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. ### funding GlaxoSmithKline.", "source": "https://pubmed.ncbi.nlm.nih.gov/26037941/"}
{"doc_id": "16eaebaa0ed50f343e560ffb251ba9e0", "sentence": "compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin", "spans": [{"span_id": 0, "text": "clindamycin", "start": 57, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "gentamicin", "start": 74, "end": 84, "token_start": 11, "token_end": 12}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli. The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.", "source": "https://pubmed.ncbi.nlm.nih.gov/9055997/"}
{"doc_id": "b17febf31275cf49cdf832e97290339d", "sentence": "We suggest topoisomerase II inhibition by Aroclor 1254 , trovafloxacin , doxorubicin , and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA .", "spans": [{"span_id": 0, "text": "trovafloxacin", "start": 57, "end": 70, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "doxorubicin", "start": 73, "end": 84, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "etoposide", "start": 91, "end": 100, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Topoisomerase II inhibition involves characteristic chromosomal expression patterns. The phenomenon of co-localization of transcriptionally upregulated genes showing similar expression levels is known across all eukaryotic genomes. We recently mapped the Aroclor 1254-regulated transcriptome back onto the genome and provided evidence for the statistically significant co-localization of regulated genes. They did, however, not always show similar expression levels, and many of the regulated genes were, in fact, repressed. ### results In this study, we were able to reproduce this observation with microarray data stemming from 1) human hepatocytes treated with the gyrase and potential topoisomerase II inhibitor trovafloxacin, 2) human hepatocytes treated with the topoisomerase II inhibitor doxorubicin and 3) mouse lymphoma cells treated with the topoisomerase II inhibitor etoposide. We found statistically significant co-localization of regulated gene pairs--induced and repressed--within the window size of 0-100 kbp. Notably, by using microarray data stemming from lung tissue of a mouse transgenic line overexpressing the transcription factor c-myc, which served as a negative control, we found regulated genes to be located with regard to each other nearly in the same way as genes distributed randomly all over the genome (0-100 kbp). ### conclusion We suggest topoisomerase II inhibition by Aroclor 1254 , trovafloxacin , doxorubicin , and etoposide to be responsible for significant co-localization of regulated genes through the inability of the stabilized enzyme complexes to religate DNA . Within the permanently opened chromatin domains, neighbored genes might be allowed to be regulated. Overexpression of c-myc, however, does not inhibit topoisomerase II activity. Consequently, the enzyme is able to perform its normal function of transiently breaking and rejoining the DNA double strand. As a result, exclusively target genes are regulated.", "source": "https://pubmed.ncbi.nlm.nih.gov/18611269/"}
{"doc_id": "db74702684949a6a29e36d1550198204", "sentence": "All but one received two induction courses of the 3 day-AVI ( doxorubicin 50 mg/m(2 ) day 1 , etoposide 120 mg/m(2 ) day 1 , 2 , 3 , ifosfamide 2000 mg/m(2 ) day 1 , 2 ) regimen .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 62, "end": 73, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "etoposide", "start": 94, "end": 103, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "ifosfamide", "start": 133, "end": 143, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "The prognostic value of etoposide area under the curve (AUC) at first chemotherapy cycle in small cell lung cancer patients: a multicenter study of the groupe Lyon-Saint-Etienne d'Oncologie Thoracique (GLOT). To assess the potential relationships between systemic exposure to doxorubicin, etoposide and ifosfamide at first chemotherapy cycle and therapeutic effect, tumor response, toxicity, and survival, in small cell lung cancer (SCLC) patients. ### Patients And Methods Twenty-four patients referred to five different centers with either thorax-limited or metastatic SCLC entered the study. All but one received two induction courses of the 3 day-AVI ( doxorubicin 50 mg/m(2 ) day 1 , etoposide 120 mg/m(2 ) day 1 , 2 , 3 , ifosfamide 2000 mg/m(2 ) day 1 , 2 ) regimen . Individual plasma samples were collected at the first course and complete concentration data on 24 courses were available. Drugs exposures were estimated using a population pharmacokinetic method and expressed as clearance (Cl), area under the curve (AUC), and AUC-intensity (AUC/cycle duration). Responding patients received thoracic irradiation+concomitant cisplatinum-etoposide (limited disease) or four more courses of AVI (extensive disease). The impact of exposure parameters on haematological toxicity, tumor response and overall survival was assessed using linear regression, the Mann-Whitney U-test and the log-rank test/Kaplan-Meier estimation, respectively. ### results Twenty-three patients could be evaluated for response and survival. We found no relationship between drug exposure and haematological toxicity but all patients had received Granulocyte-Colony Stimulating Factor support. Tumor response was marginally influenced by ifosfamide AUC. In patients with etoposide AUC>254.8 mg h/l, 1-year survival was 50.0 vs. 9.1% in the other group (median 11.4 vs. 7.1 months, P=0.02), with respect to established prognostic factors. In patients with extensive disease only (n=15), 1-year survival was 42.9 vs. 0% (median 11.3 vs. 5.3 months, P=0.01). ### conclusion This study strongly suggests that SCLC patients should benefit from sufficient etoposide exposure at first cycle to improve survival. Adaptative control based on plasma concentration measurements should be tested in further studies assessing various polychemotherapy regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/11165404/"}
{"doc_id": "da76229247c8564117087d25cfd3c76d", "sentence": "Although anti-HER2 ( trastuzumab ) and anti-VEGFR ( ramucirumab ) may yield survival benefit , anti-EGFR and anti-HGFR therapies have failed to improve outcomes .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 21, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "ramucirumab", "start": 52, "end": 63, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Recent insights in the therapeutic management of patients with gastric cancer. Gastric cancer remains frequent and one of the most lethal malignancies worldwide. In this article, we aimed to comprehensively review recent insights in the therapeutic management of gastric cancer, with focus on the surgical and perioperative management of resectable forms, and the latest advances regarding advanced diseases. Surgical improvements comprise the use of laparoscopic surgery including staging laparoscopy, a better definition of nodal dissection, and the development of hyperthermic intraperitoneal chemotherapy. The best individualized perioperative management should be assessed before curative-intent surgery for all patients and can consists in perioperative chemotherapy, adjuvant chemo-radiation therapy or adjuvant chemotherapy alone. The optimal timing and sequence of chemotherapy and radiation therapy with respect to surgery should be further explored. Patients with advanced gastric cancer have a poor prognosis. Nevertheless, they can benefit from doublet or triplet chemotherapy combination, including trastuzumab in HER2-positive patients. Upon progression, second-line therapy can be considered in patients with good performance status. Although anti-HER2 ( trastuzumab ) and anti-VEGFR ( ramucirumab ) may yield survival benefit , anti-EGFR and anti-HGFR therapies have failed to improve outcomes . Nevertheless, combination regimens containing cytotoxic drugs and targeted therapies should be further evaluated; keeping in mind that gastric cancer biology is different between Asia and the Western countries.", "source": "https://pubmed.ncbi.nlm.nih.gov/27156069/"}
{"doc_id": "c41ce50ac2ab1d723b7b845c5638e79f", "sentence": "In the phase I trial , 19 patients received bolus doxorubicin ( 50 mg/m2 ) followed after a 16-hour interval by paclitaxel ( given at dose levels ranging from 130 to 250 mg/m2 ) by 3-hour infusion every 3 weeks , for a maximum of eight cycles .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 50, "end": 61, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "paclitaxel", "start": 112, "end": 122, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Paclitaxel plus doxorubicin in breast cancer: an Italian experience. Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forl\u00ec, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial , 19 patients received bolus doxorubicin ( 50 mg/m2 ) followed after a 16-hour interval by paclitaxel ( given at dose levels ranging from 130 to 250 mg/m2 ) by 3-hour infusion every 3 weeks , for a maximum of eight cycles . paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/9374087/"}
{"doc_id": "2c7a84317e4530aa3022349a39e71c9b", "sentence": "New monoclonal antibodies ( ofatumumab ) , second-generation proteasome inhibitors ( carfilzomib ) , mammalian target of rapamycin inhibitors , and Bruton 's tyrosine kinase inhibitors are promising and may expand future treatment options .", "spans": [{"span_id": 0, "text": "ofatumumab", "start": 28, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "carfilzomib", "start": 85, "end": 96, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "rapamycin", "start": 121, "end": 130, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Treatment recommendations for patients with Waldenstr\u00f6m macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Waldenstr\u00f6m macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies ( ofatumumab ) , second-generation proteasome inhibitors ( carfilzomib ) , mammalian target of rapamycin inhibitors , and Bruton 's tyrosine kinase inhibitors are promising and may expand future treatment options . A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.", "source": "https://pubmed.ncbi.nlm.nih.gov/25027391/"}
{"doc_id": "a302d53a221927af726a71d0414d8b6b", "sentence": "Exposure of LLC-PK1 cells to hydrogen peroxide ( 2.5 mM ) resulted in a significant increase in the bleomycin-detectable iron ( iron capable of catalyzing free radical reactions ) content that was prevented by cimetidine , but not ranitidine .", "spans": [{"span_id": 0, "text": "hydrogen peroxide", "start": 29, "end": 46, "token_start": 5, "token_end": 7}, {"span_id": 1, "text": "cimetidine", "start": 210, "end": 220, "token_start": 34, "token_end": 35}, {"span_id": 2, "text": "ranitidine", "start": 231, "end": 241, "token_start": 38, "token_end": 39}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "NEG", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells. The current study was designed to test the role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity, and to determine whether it may serve as a source of catalytic iron. Hydrogen peroxide led to iron release (as measured by iron/bathophenanthroline complex) from the microsomes prepared from LLC-PK1 cells. cimetidine, which inhibits cytochrome P-450 by interacting with the heme iron, significantly blocked iron release, whereas ranitidine, which has a similar structure as cimetidine but is a weak inhibitor of P-450, did not have an effect (H2O2, 0.42 +/- 0.04; H2O2 + cimetidine, 0.23 +/- 0.02 nmol/mg protein; N = 4, P < 0.01). Exposure of LLC-PK1 cells to hydrogen peroxide ( 2.5 mM ) resulted in a significant increase in the bleomycin-detectable iron ( iron capable of catalyzing free radical reactions ) content that was prevented by cimetidine , but not ranitidine . We then examined the effect of the inhibitors of cytochrome P-450 on cell death (as measured by Trypan blue exclusion) after exposure of LLC-PK1 cells to 2.5 mM hydrogen peroxide for 120 minutes. Inhibition of cytochrome P-450 by cimetidine significantly reduced the cell death; the effect was observed with 0.05 mM and was concentration dependent with 1 mM affording almost complete protection (H2O2, 59 +/- 1.3% vs. H2O2 + cimetidine, 11 +/- 0.7%; N = 5, P < 0.01). In contrast, ranitidine did not show any protection. We confirmed that the protective effect of cimetidine was not related to scavenging hydrogen peroxide or hydroxyl radicals or chelating iron. A second inhibitor of cytochrome P-450, piperonyl butoxide, had a similar dose-dependent beneficial effect against hydrogen peroxide-induced cell injury. Our data thus indicate an important role of cytochrome P-450 in hydrogen peroxide-induced cytotoxicity to LLC-PK1 cells and suggest that cytochrome P-450 may serve as a source of catalytic iron.", "source": "https://pubmed.ncbi.nlm.nih.gov/8887268/"}
{"doc_id": "ab42998ac768359fe5c45841e496b11f", "sentence": "Patients who did or did not respond to previous DIMARD therapy either on i.m . gold , D-Penicillamine or Chloroquine , did usually well when treated with Auranofin , even if severe side effects leading to withdrawal had occurred on previous therapy .", "spans": [{"span_id": 0, "text": "Chloroquine", "start": 105, "end": 116, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "Auranofin", "start": 154, "end": 163, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Longterm results of auranofin therapy. The results of longterm therapy with the oral gold preparation auranofin in patients with rheumatoid arthritis (RA) were evaluated based on the following data: 1) Two multicenter open uncontrolled studies (MTC06) and (162EMUA-RA), 2) the reevaluation of these data for the MTC06 study after 4 years from the beginning of the study and 3) the results of a postmarketing surveillance program (PMSP) of patients on auranofin therapy. The specific rheumatologic documentation and information system (IKR inhaltkodierte rheumatologic) serves as the basis of the follow-up studies and longterm observations. The first year data on 207 patients (MTC06) indicating that duration of the disease less than 2 years was the only discriminating factor regarding a positive treatment outcome were confirmed by the two-year (151 patients). Patients, who responded favourably to auranofin did usually well for the four-year or longer observation period. The data base of these two studies and the PMSP failed to outline any new severe or threatening side effects. Diarrhea and loose stools were more common at the beginning of the treatment. The overall withdrawal for untoward events was 11.2%. Patients who did or did not respond to previous DIMARD therapy either on i.m . gold , D-Penicillamine or Chloroquine , did usually well when treated with Auranofin , even if severe side effects leading to withdrawal had occurred on previous therapy . The favourable safety profile was confirmed by the PMSP data.", "source": "https://pubmed.ncbi.nlm.nih.gov/3690986/"}
{"doc_id": "afab31fe96472f7a8f44b42d27b3b11e", "sentence": "Patients were randomly assigned 1:1 centrally to either the docetaxel , prednisone , and custirsen combination or docetaxel and prednisone alone .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 60, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "prednisone", "start": 72, "end": 82, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "custirsen", "start": 89, "end": 98, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "docetaxel", "start": 114, "end": 123, "token_start": 17, "token_end": 18}, {"span_id": 4, "text": "prednisone", "start": 128, "end": 138, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. ### methods SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel , prednisone , and custirsen combination or docetaxel and prednisone alone . Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m ### findings Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23\u00b74 months [95% CI 20\u00b79-24\u00b78] with docetaxel, prednisone, and custirsen vs 22\u00b70 months [19\u00b75-24\u00b70] with docetaxel and prednisone; hazard ratio [HR] 0\u00b793, 95% CI 0\u00b779-1\u00b710; p=0\u00b7415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. ### interpretation Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. ### funding OncoGenex Technologies.", "source": "https://pubmed.ncbi.nlm.nih.gov/28283282/"}
{"doc_id": "bd82da91336f74adb6da284e168c8f9b", "sentence": "[ Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer ] .", "spans": [{"span_id": 0, "text": "Carboplatin", "start": 2, "end": 13, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "etoposide", "start": 18, "end": 27, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer ] . The objective of this phase II study was to determine the efficacy and toxicity of a combination of carboplatin and etoposide as salvage treatment, in previously treated patients with persistent or recurrent ovarian cancer following first-line cisplatin-based chemotherapy. ### Patients And Methods From July 1990 to August 1994, 58 patients were treated with 3-week cycles of chemotherapy consisting of carboplatin (200 mg/m2, D1) and etoposide (120 mg/m2, D1, D2). Criteria for evaluating previous response to cisplatin were strictly defined. ### results The overall response rate was 36%, with five complete responses (CR, 9%), 16 partial responses (PR, 27%) and the median duration of response was 10 months (range: 4 to 38). In the group of patients who progressed during the first year following the diagnosis, the response was 1 CR and 2 PR (12%) and in the group of patients who progressed from the second year after diagnosis, 4 CR and 14 PR (56%), with a median survival of 8.5 and 21 months respectively (p = 0.0013). The response rate was 59% in the potentially platinum sensitive group versus 8.7% in the primary resistant group (0.02 < p < 0.05). Myelotoxicity was the main side-effect but did not appear to be cumulative. Grade 3 and grade 4 anemia were observed in 26% and 3% of the patients respectively, neutropenia in 14% and 2% and thrombocytopenia in 14% and 8.5%. One patient died of sepsis associated with neutropenia. ### conclusion Treatment was easily manageable and well tolerated. The advantage of carboplatin and etoposide combination in potentially responsive patients is represented by the reduced nephrotoxicity, neurotoxicity and ototoxicity as compared with cisplatin containing regimen, with durable feasibility in outpatients. This second-line chemotherapy for ovarian cancer is effective as salvage treatment in potentially responsive patients with late recurrent tumors, while paclitaxel is the drug of choice for patients who have developped primary or secondary resistance to platin therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/8680083/"}
{"doc_id": "b5eed2d8dcc1d4fa698054dce7cab8b2", "sentence": "One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer : results of a multicentre , phase II trial .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 9, "end": 19, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "carboplatin", "start": 25, "end": 36, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer : results of a multicentre , phase II trial . The aim of this phase II study was to determine the activity and toxicity of paclitaxel (administered by 1-h infusion) and carboplatin in advanced non-small cell lung cancer when used in a multicentre, community-based treatment setting. 100 chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer were treated between March 1995 and February 1996. All patients had Karnofsky performance status 70-100, measurable disease and adequate bone marrow, kidney and liver function. All patients received intravenous (i.v.) paclitaxel 225 mg/m2 by 1-h infusion followed immediately by carboplatin at a targeted area under the concentration time curve (AUC) of 6.0 using the Calvert formula. Courses were repeated every 21 days. Colony stimulating factors were not used routinely. 38 of 94 evaluable patients (40%) had objective responses to treatment (3 complete responses, 35 partial responses). An additional 32 patients had stable disease at initial re-evaluation. Weight gain during treatment was experienced by 47% of patients with objective response or stable disease. The median survival in this group of 100 patients was 8 months, with an actuarial 1-year survival of 42%. Leucopenia was common, but hospitalisation for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy was common, but usually appeared after the third or fourth course and was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. There was one treatment-related death due to sepsis. This large multicentre community-based phase II trial demonstrated the efficacy of paclitaxel and carboplatin combination chemotherapy in advanced non-small cell lung cancer. When paclitaxel is given by 1-h infusion, this regimen is easily administered in the outpatient setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/9713269/"}
{"doc_id": "cf2e5fbc7f16a5145e9318057da96476", "sentence": "Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging ; this combination will be tested in both early stage and late stage disease .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 27, "end": 38, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bevacizumab", "start": 72, "end": 83, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging ; this combination will be tested in both early stage and late stage disease .", "source": "https://pubmed.ncbi.nlm.nih.gov/17660958/"}
{"doc_id": "e1b808c61aae414e8d95d9918cb78e59", "sentence": "The immuno-oncology-based combinations with different types of immune checkpoint inhibitors ( PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab , pembrolizumab , atezolizumab , durvalumab , ipilimumab , tremelimumab ) , or the association of immune checkpoint inhibitors plus anti-angiogenic agents ( bevacizumab , lenvatinib , cabozantinib ) , have led to a breakthrough in the treatment of hepatocellular carcinoma .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 135, "end": 144, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "pembrolizumab", "start": 147, "end": 160, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "atezolizumab", "start": 163, "end": 175, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "durvalumab", "start": 178, "end": 188, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "ipilimumab", "start": 191, "end": 201, "token_start": 25, "token_end": 26}, {"span_id": 5, "text": "tremelimumab", "start": 204, "end": 216, "token_start": 27, "token_end": 28}, {"span_id": 6, "text": "bevacizumab", "start": 302, "end": 313, "token_start": 41, "token_end": 42}, {"span_id": 7, "text": "lenvatinib", "start": 316, "end": 326, "token_start": 43, "token_end": 44}, {"span_id": 8, "text": "cabozantinib", "start": 329, "end": 341, "token_start": 45, "token_end": 46}], "rels": [], "paragraph": "The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular Carcinoma. Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based on immune checkpoint inhibitors has revolutionized the systemic therapies since showing long survival rates without any tumor progression or recurrence for some patients in partial or complete response, and possibly for some patients in stable disease. However, the rate of responders under immuno-oncology monotherapy is too low to increase significantly the median overall survival of the treated patients. The immuno-oncology-based combinations with different types of immune checkpoint inhibitors ( PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab , pembrolizumab , atezolizumab , durvalumab , ipilimumab , tremelimumab ) , or the association of immune checkpoint inhibitors plus anti-angiogenic agents ( bevacizumab , lenvatinib , cabozantinib ) , have led to a breakthrough in the treatment of hepatocellular carcinoma . Indeed, the first phase-3 trial, combining atezolizumab with bevacizumab, has dramatically changed the outcome of patients. Data from several other types of combinations assessed in phase-3 trials are pending, and if positive, will drastically arm the physicians to efficiently treat the patients, and disrupt the current algorithm of hepatocellular carcinoma treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/33440630/"}
{"doc_id": "3c6b70d58429d686c73e83b352f07573", "sentence": "A decrease in VEGF-A expression in the tumor node and salivary gland was found after monotherapy with melatonin and cyclophosphamide and , especially , after combined treatment , which proves maximum therapeutic efficiency of combined administration of chemical agents with various mechanisms of action .", "spans": [{"span_id": 0, "text": "melatonin", "start": 102, "end": 111, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "cyclophosphamide", "start": 116, "end": 132, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Expression of vascular endothelial growth factor (VEGF-A) in rat mandibular salivary gland during paraneoplastic process and treatment with cyclophosphamide and melatonin. Expression of VEGF-A in Walker 256 carcinosarcoma and mandibular salivary gland of rats during paraneoplastic process and various regimens of chemotherapy with melatonin and cyclophosphamide were studied by immunohistochemical methods. VEGF-A expression increased in the tumor node and salivary gland after monotherapy with melatonin and cyclophosphamide during progression of tumor growth and paraneoplastic syndrome. A decrease in VEGF-A expression in the tumor node and salivary gland was found after monotherapy with melatonin and cyclophosphamide and , especially , after combined treatment , which proves maximum therapeutic efficiency of combined administration of chemical agents with various mechanisms of action . Overexpression of VEGF-A in the mandibular salivary gland can have diagnostic and predictive value in early diagnostics of neoplasms.", "source": "https://pubmed.ncbi.nlm.nih.gov/25778658/"}
{"doc_id": "349d1fcc0bd239b41bf562c7dc761e11", "sentence": "The combination of rituximab , bendamustine , and cytarabine ( R-BAC ) was highly active in a pilot trial of mantle cell lymphoma , but its use was restricted by high haematological toxicity .", "spans": [{"span_id": 0, "text": "rituximab", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bendamustine", "start": 31, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "cytarabine", "start": 50, "end": 60, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi.  The combination of rituximab , bendamustine , and cytarabine ( R-BAC ) was highly active in a pilot trial of mantle cell lymphoma , but its use was restricted by high haematological toxicity . We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). ### methods In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60-65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m ### findings Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67-75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3-4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1-2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. ### interpretation RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. ### funding Fondazione Italiana Linfomi and Mundipharma.", "source": "https://pubmed.ncbi.nlm.nih.gov/27927586/"}
{"doc_id": "437b8cee1d2a36e2af081d283529e4be", "sentence": "Despite treatment with PH specific therapy ( sildenafil , ambrisentan , and epoprostenol ) , her condition worsened rapidly with acute right heart failure ( RHF ) .", "spans": [{"span_id": 0, "text": "sildenafil", "start": 45, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ambrisentan", "start": 58, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "epoprostenol", "start": 76, "end": 88, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Subacute right heart failure revealing three simultaneous causes of post-embolic pulmonary hypertension in metastatic dissemination of breast cancer. A 72-year-old woman with history of breast cancer only treated surgically was referred to our department for pulmonary hypertension (PH) suspicion. Echocardiogram revealed elevated right ventricular systolic pressure. Computed tomography (CT) angiogram showed no pulmonary embolism (PE), but lung scan revealed two ventilation-perfusion mismatch areas. Right cardiac catheterization established precapillary PH. Despite treatment with PH specific therapy ( sildenafil , ambrisentan , and epoprostenol ) , her condition worsened rapidly with acute right heart failure ( RHF ) . She died 22\u2009days after admission. Post-mortem microscopic examination showed a rare combination of PH etiologies consistent with metastasis of breast cancer in pulmonary vasculature including the rare pulmonary tumour thrombotic microangiopathy (PTTM).", "source": "https://pubmed.ncbi.nlm.nih.gov/28217316/"}
{"doc_id": "a9d8ce2f770a3ecc77884a8a973f8efa", "sentence": "Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin , with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle .", "spans": [{"span_id": 0, "text": "ixabepilone", "start": 81, "end": 92, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "carboplatin", "start": 98, "end": 109, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "ixabepilone", "start": 117, "end": 128, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I and pharmacokinetic study of ixabepilone in combination with Carboplatin in patients with advanced solid malignancies. To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety. ### Experimental Design Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B). ### results Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B). ### conclusions Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin , with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle .", "source": "https://pubmed.ncbi.nlm.nih.gov/19088046/"}
{"doc_id": "4068259c823edd9ba35db8fef046b4ca", "sentence": "Compared to other glucose lowering agents except metformin , gliclazide was slightly more effective ( -0.13 % ( 95%CI : -0.25 , -0.02 , I(2 ) 55 % ) ) .", "spans": [{"span_id": 0, "text": "metformin", "start": 49, "end": 58, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "gliclazide", "start": 61, "end": 71, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials. gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156). ### Data Sources Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database. ### selection Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used. ### results Nineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin , gliclazide was slightly more effective ( -0.13 % ( 95%CI : -0.25 , -0.02 , I(2 ) 55 % ) ) . One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I\u00b2 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes. ### conclusions The methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/24533045/"}
{"doc_id": "17b4fa14d7486f05c30b5ad38ba9389f", "sentence": "Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide ( 1000 mg/m2 ) , carboplatin ( 120 mg/m2 ) and etoposide ( 120 mg/m2 ) given intravenously on day 1 to 3 every 4 weeks .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 77, "end": 87, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "carboplatin", "start": 105, "end": 116, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "etoposide", "start": 135, "end": 144, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase II study with ifosfamide, carboplatin, etoposide (ICE regimen) at intermediate dosage for advanced non small cell lung cancer (NSCLC). We have evaluated the combination of ifosfamide, carboplatin and etoposide (ICE regimen) along with mesna in 26 previously untreated patients with non small cell lung cancer (NSCLC). Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide ( 1000 mg/m2 ) , carboplatin ( 120 mg/m2 ) and etoposide ( 120 mg/m2 ) given intravenously on day 1 to 3 every 4 weeks . Except for one patient who experienced grade 3 transient thrombocytopenia no major events of hematological or systemic toxicity were observed. Response rate (27%, 95% C.I., 10 to 44%), median duration of response (9 months, range 6-15), and survival (9.5 months, range 2-44+) were comparable to those achieved with conventional cisplatin-containing regimens. Our ICE combination, as compared to standard or high dose schedules appears effective, safe, well tolerated, and devoid of severe hematological toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/9876059/"}
{"doc_id": "9d575fee5bce79fec6085979adb25d0d", "sentence": "This study compared immediate ( overnight ) and progressive switching to oxcarbazepine monotherapy in patients with partial seizures unsatisfactorily treated with carbamazepine monotherapy .", "spans": [{"span_id": 0, "text": "oxcarbazepine", "start": 73, "end": 86, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "carbamazepine", "start": 163, "end": 176, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Immediate (overnight) switching from carbamazepine to oxcarbazepine monotherapy is equivalent to a progressive switch.  This study compared immediate ( overnight ) and progressive switching to oxcarbazepine monotherapy in patients with partial seizures unsatisfactorily treated with carbamazepine monotherapy . Patients were randomised to either an overnight (n = 140) or a progressive switch (n = 146) from carbamazepine to oxcarbazepine monotherapy at a dose ratio of 1:1.5. The difference between the two switch groups in the mean monthly seizure frequency supported the equivalence of overnight and progressive switching (difference of 0.02 excluding outliers; 95% confidence interval (CI) -0.74, 0.78). Following the switch from carbamazepine to oxcarbazepine, there was a reduction in median monthly seizure frequency in both the overnight group (from 1.5 to 0; P = 0.0005) and the progressive group (from 1.0 to 0.4; P = 0.003). The proportion of seizure-free patients increased from 38 to 51% (P = 0.002) and 39 to 49% (P = -0.01) in the overnight and progressive groups, respectively. In addition, the proportion of patients experiencing no clinically significant adverse events did not differ between the two switch methods (difference of 2.5; 95% CI -4.1, 9.0). For patients who are unsatisfactorily treated with carbamazepine monotherapy, overnight switch to oxcarbazepine monotherapy is as effective and well tolerated as a progressive switch, therefore allowing simple and flexible individualised treatment. Switching to oxcarbazepine monotherapy appears to be beneficial for patients who are unsatisfactorily treated with carbamazepine monotherapy, independently of the switch method used.", "source": "https://pubmed.ncbi.nlm.nih.gov/15121136/"}
{"doc_id": "c6cedbb5fed19bf8144d7f964131c07b", "sentence": "In conclusion , prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity .", "spans": [{"span_id": 0, "text": "prasugrel", "start": 16, "end": 25, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "clopidogrel", "start": 86, "end": 97, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Use of prasugrel in the setting of clopidogrel hypersensitivity: Case report and systematic review of the literature. Allergic reactions to clopidogrel soon after coronary stent implantation pose an important and challenging clinical problem. We describe a 44-year-old man who developed a diffuse maculopapular rash four days after initiation of clopidogrel with drug-eluting coronary stent placement. An initial treat-through strategy was unsuccessful due to patient intolerance to corticosteroids. Because of persistent hypersensitivity, clopidogrel was substituted with prasugrel which was continued successfully for one year without reaction. A systematic review of the literature was performed which identified 10 prior case reports of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel. Patient characteristics and clinical outcomes of these patients plus the current case were reviewed. There were 9 men and 2 women with ages from 44 to 76 years. All patients had undergone coronary stent procedures. prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82%). Cross-reactivity was reported in two patients who developed hypersensitivity reactions to prasugrel similar to those experienced on clopidogrel. In conclusion , prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity . However, potential cross-reactivity between these two thienopyridines may occur in some patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/27494368/"}
{"doc_id": "354e50c6bec6e5f799e569449cf54fa4", "sentence": "Fresh , clinical P. falciparum isolates were also tested in the presence of several drugs , including chloroquine , mefloquine , quinine , halofantrine , atovaquone and qinghaosu derivatives .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 102, "end": 113, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "mefloquine", "start": 116, "end": 126, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "quinine", "start": 129, "end": 136, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "halofantrine", "start": 139, "end": 151, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "atovaquone", "start": 154, "end": 164, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "The microculture tetrazolium assay (MTA): another colorimetric method of testing Plasmodium falciparum chemosensitivity. Malarial lactate dehydrogenase (LDH), which uses 3-acetyl pyridine adenine dinucleotide as coenzyme in a reaction leading to the formation of pyruvate from L-lactate, may be used to study the susceptibility of Plasmodium falciparum to a drug in vitro. Several methods to determine the activity of this enzyme are available. One, the colorimetric method of Makler and colleagues, was modified slightly, by using sodium-2,3-bis-[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5 - carboxanilide (XTT) and following the reaction by measuring the optical density at 450 nm. Using two, culture-adapted strains of P. falciparum, this LDH assay was compared with the unmodified Makler's assay and with the isotopic microtest based on the incorporation of tritium-labelled hypoxanthine. Fresh , clinical P. falciparum isolates were also tested in the presence of several drugs , including chloroquine , mefloquine , quinine , halofantrine , atovaquone and qinghaosu derivatives . The results of the three assays were correlated for all the drugs tested except atovaquone. The two enzymatic assays are non-radioactive, rapid, reliable, inexpensive to perform and semi-automatic. However, they do require an initial parasitaemia of 2% with a haematocrit of 1.8%.", "source": "https://pubmed.ncbi.nlm.nih.gov/10492669/"}
{"doc_id": "8b855ef5d611be57b0e69fb8aa6f117f", "sentence": "The null hypothesis was there is no difference with respect to pain scores between ketorolac and iliac crest bupivacaine infusion as analgesic adjuncts to intravenous opioids .", "spans": [{"span_id": 0, "text": "ketorolac", "start": 83, "end": 92, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "bupivacaine", "start": 109, "end": 120, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Continuous bupivacaine infusion post-iliac crest bone graft harvesting in pediatric cleft surgery: role and comparison with ketorolac. To investigate the use of intravenous ketorolac and iliac crest bupivacaine infusion in the management of iliac crest donor-site pain in the pediatric cleft population. The null hypothesis was there is no difference with respect to pain scores between ketorolac and iliac crest bupivacaine infusion as analgesic adjuncts to intravenous opioids . ### methods A total of 54 children and adolescents (27 boys, 27 girls) undergoing alveolar cleft repair or Le Fort I osteotomy were assigned randomly in a prospective, single-blinded fashion to one of three groups: intravenous ketorolac plus iliac crest normal saline infusion, intravenous ketorolac plus iliac crest bupivacaine infusion, or iliac crest bupivacaine infusion alone. Iliac crest infusions and ketorolac were administered for 48 hours or until discharge, whichever occurred first. All patients received morphine via a patient-controlled analgesia device. ### Main Outcome Measure S Primary outcome was pain score, and secondary outcomes were morphine consumption and satisfaction scores. ### results Pain scores, morphine consumption, and satisfaction scores were not significantly different among groups. Estimated costs were significantly higher for bupivacaine infusion than intravenous ketorolac. ### conclusions Iliac crest donor-site pain is well managed in this patient population. Intravenous ketorolac and iliac crest bupivacaine infusion provide comparable analgesia for iliac crest bone graft donor-site pain in children and adolescents.", "source": "https://pubmed.ncbi.nlm.nih.gov/21091369/"}
{"doc_id": "c807c19adaebe7abb343c158259a5a8c", "sentence": "Etoposide in combination with low-dose CAG ( cytarabine , aclarubicin , G-CSF ) for the treatment of relapsed or refractory acute myeloid leukemia : a multicenter , randomized control trial in southwest China .", "spans": [{"span_id": 0, "text": "Etoposide", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cytarabine", "start": 45, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "aclarubicin", "start": 58, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "G-CSF", "start": 72, "end": 77, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Etoposide in combination with low-dose CAG ( cytarabine , aclarubicin , G-CSF ) for the treatment of relapsed or refractory acute myeloid leukemia : a multicenter , randomized control trial in southwest China . In a well-controlled multi-center randomized trial in southwestern China, 228 patients with refractory or relapsed AML were received a low-dose CAG regimen either with etoposide (E-CAG) or without etoposide (CAG). The complete remission (CR) rate, overall survival (OS) and toxicity were evaluated. Patients with E-CAG had a higher CR rate (71.1% vs. CAG 50.9%, P=0.0002). The tolerability appeared to be equivalent. Patients with CR who underwent allogenic hematopoietic stem cell transplantation (allo-HSCT) had a higher five-year OS over those without allo-HSCT (73.8% vs. 10.8%, P=0.000). The E-CAG regimen is expected to become a bridge between relapsed or refractory AML and allo-HSCT.", "source": "https://pubmed.ncbi.nlm.nih.gov/23537708/"}
{"doc_id": "628a6d576b395f5bcea10e9d60b16658", "sentence": "were randomized in an open-label , crossover fashion to treatment A ( dolasetron 100 mg on day 1 ) and treatment B ( dolasetron 100 mg plus aprepitant 125 mg on day 1 , aprepitant 80 mg on days 2 - 3 ) .", "spans": [{"span_id": 0, "text": "dolasetron", "start": 70, "end": 80, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "dolasetron", "start": 117, "end": 127, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "aprepitant", "start": 140, "end": 150, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "aprepitant", "start": 169, "end": 179, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label , crossover fashion to treatment A ( dolasetron 100 mg on day 1 ) and treatment B ( dolasetron 100 mg plus aprepitant 125 mg on day 1 , aprepitant 80 mg on days 2 - 3 ) . For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.", "source": "https://pubmed.ncbi.nlm.nih.gov/16809805/"}
{"doc_id": "d7a9823a05c84cd6642567852a3a0b2b", "sentence": "The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible , tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 15, "end": 26, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "ifosfamide", "start": 41, "end": 51, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "anthracycline", "start": 56, "end": 69, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "[Gemcitabine based combination chemotherapy, a new salvage regimen for recurrent platinum resistant epithelial ovarian cancer]. To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer. ### methods gemcitabine 800 mg/m(2) (day 1, 8), ifosfamide 1.5 g/m(2) (day 1 - 3), adriamycin 40 mg/m(2) or epirubicin 60 mg/m(2) (day 1) or mitoxantrone 10 mg/m(2) (day 1, 8) were used in recurrent platinum resistant/refractory ovarian cancer patients, the cycle was repeated at interval of 21 to 28 days. ### results A total of 60 patients received 172 cycles combined chemotherapy. There were no one cases complete response, while partial response 22 (37%, 22/60), stable 23 (38%, 23/60) and progression 15 (25%, 15/60) were observed, with clinical benefit rate 75% (45/60). The median time of progression-free survival was 7 months, and the median overall survival time was 20 months. The main side effect was hematologic toxicity with leukopenia rate of 82% (49/60), among which III-IV accounted for 31% (15/49). Digestive reaction was all in I-II, accounted for 42% (25/60). ### conclusion The regimen of gemcitabine combined with ifosfamide and anthracycline is feasible , tolerable and effective in patients with recurrent platinum resistant/refractory epithelial ovarian cancer .", "source": "https://pubmed.ncbi.nlm.nih.gov/21211276/"}
{"doc_id": "ce6a8e4d2639c00add811419673116fe", "sentence": "Second-line treatments consisted of cetuximab plus irinotecan for arm A , and oxaliplatin plus either 5-fluorouracil ( FOLFOX ) or capecitabine ( CapeOX ) for the control arms .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 36, "end": 45, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "irinotecan", "start": 51, "end": 61, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "oxaliplatin", "start": 78, "end": 89, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "5-fluorouracil", "start": 102, "end": 116, "token_start": 15, "token_end": 16}, {"span_id": 4, "text": "capecitabine", "start": 131, "end": 143, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}, {"class": "POS", "spans": [2, 4], "is_context_needed": true}], "paragraph": "Second-line cetuximab/irinotecan versus oxaliplatin/fluoropyrimidines for metastatic colorectal cancer with wild-type KRAS. The goal of the present study was to compare the efficacy of the combination of cetuximab and irinotecan to the combination of oxaliplatin and fluoropyrimidines as second-line chemotherapy in patients with irinotecan-refractory and oxaliplatin-na\u00efve metastatic colorectal cancer (mCRC) harboring wild-type KRAS. The study included 120 patients with mCRC who had progressed after irinotecan-containing first-line chemotherapy and were never treated with oxaliplatin; 40 patients with wild-type KRAS were accrued prospectively in the experimental arm (arm A), and 80 patients accrued retrospectively were divided into control arms B (n\u00a0=\u00a046) and C (n\u00a0=\u00a034) according to KRAS genotype. Second-line treatments consisted of cetuximab plus irinotecan for arm A , and oxaliplatin plus either 5-fluorouracil ( FOLFOX ) or capecitabine ( CapeOX ) for the control arms . The median progression-free survival (PFS) was 8.3, 5.8 and 3.9\u00a0months, for arms A, B and C, respectively, with statistical significance favoring arm A (P\u00a0=\u00a00.007). Differences in overall survival did not reach statistical significance (18.3 vs 12.6 vs 12.9, P\u00a0=\u00a00.138), although there was a trend toward longer overall survival in arm A. In terms of benefit from oxaliplatin-containing regimens either as second-line or third-line therapy, the median PFS was 5.0\u00a0months in arms B and C as second-line therapy, and 4.0\u00a0months in arm A as third-line therapy, with no statistical significance (P\u00a0=\u00a00.385). Second-line cetuximab plus irinotecan is a valid treatment strategy for mCRC patients with irinotecan-refractory and oxaliplatin-na\u00efve tumors harboring wild-type KRAS. oxaliplatin-containing chemotherapy resulted in equivalent PFS both as a second-line and a third-line therapy, enabling delay of the administration of FOLFOX and CapeOX until subsequent treatment cycles.", "source": "https://pubmed.ncbi.nlm.nih.gov/23298313/"}
{"doc_id": "7f313ee61854c59c64f076e46778537a", "sentence": "In the UT-EC-1 cell line the growth inhibition was 72 % with paclitaxel , 54 % with carboplatin and 73 % with the combination of these compounds .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 61, "end": 71, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "carboplatin", "start": 84, "end": 95, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Paclitaxel, Carboplatin and 1,25-D3 Inhibit Proliferation of Endometrial Cancer Cells  Endometrial cancer cells are known to be sensitive to carboplatin and paclitaxel. Furthermore, vitamin D (1,25-D3) has been reported to inhibit endometrial cancer cell growth both as a single agent and combined with carboplatin. However, there are no studies comparing the effect of paclitaxel and carboplatin as single agents vs. in combination in endometrial cancer cell lines. Neither has the effect of 1,25-D3 been studied with paclitaxel. The present study investigated the effect of paclitaxel, carboplatin and 1,25-D3 on the growth of endometrial cancer cells in vitro. ### Materials And Methods Two endometrial adenocarcinoma cell lines (UT-EC-1 and UT-EC-3) were cultured with different doses of paclitaxel, carboplatin and 1,25-D3. The cellular VDR (vitamin D receptor) mRNA levels were measured and the expression of estrogen (ER) and progesterone (PR) receptors by the cells was determined. ### results In the UT-EC-1 cell line the growth inhibition was 72 % with paclitaxel , 54 % with carboplatin and 73 % with the combination of these compounds . The corresponding numbers in UT-EC-3 were 70%, 33% and 65%, respectively. 1,25-D3 suppressed cell growth 88% with paclitaxel, 63% with carboplatin and 87% with their combination in the UT-EC-1 cell line. ### conclusion In both cell lines, single-agent paclitaxel was as effective as the combination of the compounds and more effective than single carboplatin. 1,25-D3 may further contribute to the cytotoxic effect of these agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/29187432/"}
{"doc_id": "1557b8cc8b1f0bca1472c9420dce5370", "sentence": "Several lines of evidence implicate serotonin ( 5-HT ) as the mediator of this enhancement : ( 1 ) Tranyclypromine-enhanced nicotine reinforcement was blocked by the 5-HT\u2082 receptor antagonists , ritanserin and ketanserin ; ( 2 ) parachloroamphetamine ( PCA ) , a 5-HT releaser , also enhanced nicotine self-administration in animals in which MAO activity was inhibited ; ( 3 ) pretreatment with tranylcypromine increased PCA-induced 5-HT overflow in the nucleus accumbens .", "spans": [{"span_id": 0, "text": "nicotine", "start": 124, "end": 132, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "ketanserin", "start": 210, "end": 220, "token_start": 32, "token_end": 33}, {"span_id": 2, "text": "nicotine", "start": 293, "end": 301, "token_start": 48, "token_end": 49}, {"span_id": 3, "text": "tranylcypromine", "start": 395, "end": 410, "token_start": 64, "token_end": 65}, {"span_id": 4, "text": "parachloroamphetamine", "start": 229, "end": 250, "token_start": 37, "token_end": 38}, {"span_id": 5, "text": "ritanserin", "start": 195, "end": 205, "token_start": 30, "token_end": 31}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 4], "is_context_needed": true}, {"class": "COMB", "spans": [0, 5], "is_context_needed": true}], "paragraph": "Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration. Although nicotine is generally considered to be the main psychoactive component of tobacco, growing evidence highlights the importance of nonnicotine compounds in smoking reinforcement. Monoamine oxidase (MAO) inhibition is a major consequence of smoking and MAO inhibitors, such as tranylcypromine, increase nicotine reinforcement. tranylcypromine has multiple pharmacological effects, increasing monoamine release for a few hours immediately after its administration and blocking MAO activity for several days. To assess the relative role of these two actions, adult male rats were tested in consecutive daily 3-h sessions for self-administration of nicotine (3 \u03bcg kg\u207b\u00b9) inj\u207b\u00b9, i.v.) either 20 or 1 h following administration of tranylcypromine (3 mg kg\u207b\u00b9). Both paradigms were shown to produce highly significant inhibition of MAO activity. However, whereas animals readily acquired self-administration when pretreated with tranylcypromine 1 h prior to testing, they did not with the longer pretreatment interval. Such animals did immediately acquire nicotine self-administration when the tranylcypromine pretreatment interval was switched to 1 h prior to testing on Day 4, indicating that an acute effect of the MAO inhibitor was responsible for enhanced nicotine reinforcement. Several lines of evidence implicate serotonin ( 5-HT ) as the mediator of this enhancement : ( 1 ) Tranyclypromine-enhanced nicotine reinforcement was blocked by the 5-HT\u2082 receptor antagonists , ritanserin and ketanserin ; ( 2 ) parachloroamphetamine ( PCA ) , a 5-HT releaser , also enhanced nicotine self-administration in animals in which MAO activity was inhibited ; ( 3 ) pretreatment with tranylcypromine increased PCA-induced 5-HT overflow in the nucleus accumbens . These findings suggest that MAO inhibition enhances serotonergic transmission, which serves a critical role in the reinforcing effects of nicotine.", "source": "https://pubmed.ncbi.nlm.nih.gov/20936688/"}
{"doc_id": "9d5b1dd36deadb367392e8c2cbef88d4", "sentence": "Measurement and simulation results obtained in the batch experiments , spiked with the diclofenac and carbamazepine content of preclarified municipal wastewater shows comparably high biotransformation rates in the presence of growth substrates .", "spans": [{"span_id": 0, "text": "diclofenac", "start": 87, "end": 97, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "carbamazepine", "start": 102, "end": 115, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "An activated sludge modeling framework for xenobiotic trace chemicals (ASM-X): assessment of diclofenac and carbamazepine. Conventional models for predicting the fate of xenobiotic organic trace chemicals, identified, and calibrated using data obtained in batch experiments spiked with reference substances, can be limited in predicting xenobiotic removal in wastewater treatment plants (WWTPs). At stake is the level of model complexity required to adequately describe a general theory of xenobiotic removal in WWTPs. In this article, we assess the factors that influence the removal of diclofenac and carbamazepine in activated sludge, and evaluate the complexity required for the model to effectively predict their removal. The results are generalized to previously published cases. Batch experimental results, obtained under anoxic and aerobic conditions, were used to identify extensions to, and to estimate parameter values of the activated sludge modeling framework for Xenobiotic trace chemicals (ASM-X). Measurement and simulation results obtained in the batch experiments , spiked with the diclofenac and carbamazepine content of preclarified municipal wastewater shows comparably high biotransformation rates in the presence of growth substrates . Forward dynamic simulations were performed using full-scale data obtained from Bekkelaget WWTP (Oslo, Norway) to evaluate the model and to estimate the level of re-transformable xenobiotics present in the influent. The results obtained in this study demonstrate that xenobiotic loading conditions can significantly influence the removal capacity of WWTPs. We show that the trace chemical retransformation in upstream sewer pipes can introduce considerable error in assessing the removal efficiency of a WWTP, based only on parent compound concentration measurements. The combination of our data with those from the literature shows that solids retention time (SRT) can enhance the biotransformation of diclofenac, which was not the case for carbamazepine. Model approximation of the xenobiotic concentration, detected in the solid phase, suggest that between approximately 1% and 16% of the total solid carbamazepine and diclofenac concentrations, respectively, is due to sorption-the remainder being non-bioavailable and sequestered. We demonstrate the effectiveness of the model's predictive power over conventional tools in a statistical analysis, performed at four levels of structural complexity. To assess WWTP retrofitting needs to remove xenobiotic trace chemicals, we suggest using mechanistic models, e.g., ASM-X, in regional risk assessments. For preliminary evaluations, we present operating charts that can be used to estimate average xenobiotic removal rates in WWTPs as a function of SRT and the xenobiotics mass loads normalised to design treatment capacity.", "source": "https://pubmed.ncbi.nlm.nih.gov/22565415/"}
{"doc_id": "3e46fd4068d1a8ced5f4ad0790a02540", "sentence": "Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat .", "spans": [{"span_id": 0, "text": "Ursodeoxycholic acid", "start": 0, "end": 20, "token_start": 0, "token_end": 2}, {"span_id": 1, "text": "taurine", "start": 40, "end": 47, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat . Secretin induces bicarbonate-rich hydrocholeresis in healthy individuals, but not in untreated patients with primary biliary cirrhosis (PBC). Ursodeoxycholic acid (UDCA)--the first choice treatment for PBC--restores the secretin response. Compared with humans, secretin has poor effect in experimental normal-rat models with biliary drainage, although it may elicit hydrocholeresis when the bile-acid pool is maintained. In view of the benefits of UDCA in PBC, we used normal-rat models to unravel the acute contribution of UDCA (and/or taurine-conjugated TUDCA) for eliciting the biliary secretin response. ### methods Intravascular and/or intrabiliary administration of agonists and inhibitors was performed in normal rats with biliary monitoring. Secretin/bile-acid interplay was analyzed in 3D cultured rat cholangiocytes that formed expansive cystic structures with intralumenal hydroionic secretion. ### results In vivo, secretin stimulates hydrocholeresis upon UDCA/TUDCA infusion, but does not modify the intrinsic hypercholeretic effect of dehydrocholic acid (DHCA). The former effect is dependent on microtubule polymerization, and involves PKC\u03b1, PI3K and MEK pathways, as shown by colchicine (i.p.) and retrograde biliary inhibitors. In vitro, while secretin alone accelerates the spontaneous expansion of 3D-cystic structures, this effect is enhanced in the presence of TUDCA, but not UDCA or DHCA. Experiments with inhibitors and Ca(2+)-chelator confirmed that the synergistic effect of secretin plus TUDCA involves microtubules, intracellular Ca(2+), PKC\u03b1, PI3K, PKA and MEK pathways. Gene silencing also demonstrated the involvement of the bicarbonate extruder Ae2. ### conclusions UDCA is conjugated in order to promote secretin-stimulated hydrocholeresis in rats through Ae2, microtubules, intracellular Ca(2+), PKC\u03b1, PI3K, PKA, and MEK.", "source": "https://pubmed.ncbi.nlm.nih.gov/22194894/"}
{"doc_id": "76f84f3b23071ee7871063887fb9eaf3", "sentence": "This study assessed the efficacy and safety of telaprevir in combination with peginterferon-\u03b1-2b ( PEG IFN ) and ribavirin ( RBV ) , for Japanese difficult-to-treat patients with hepatitis C virus ( HCV ) genotype 2 who had not achieved sustained virological response ( SVR ) during prior treatment .", "spans": [{"span_id": 0, "text": "telaprevir", "start": 47, "end": 57, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "peginterferon-\u03b1-2b", "start": 78, "end": 96, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "ribavirin", "start": 113, "end": 122, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Efficacy of telaprevir-based therapy for difficult-to-treat patients with genotype 2 chronic hepatitis C in Japan.  This study assessed the efficacy and safety of telaprevir in combination with peginterferon-\u03b1-2b ( PEG IFN ) and ribavirin ( RBV ) , for Japanese difficult-to-treat patients with hepatitis C virus ( HCV ) genotype 2 who had not achieved sustained virological response ( SVR ) during prior treatment . ### methods In total, 108 relapsed (median age, 59.0 years) and 10 non-responding (median age, 59.0 years) patients with genotype 2 HCV participated. Patients received telaprevir (750\u2009mg, every 8\u2009h) for 12 weeks and PEG IFN/RBV for 24 weeks. ### results The SVR rates for relapsers and non-responders were 88.0% (95/108) and 50.0% (5/10), respectively. The SVR rates did not differ significantly between patients with rs8099917 TT and non-TT. The SVR rates for relapsers and non-responders with extended rapid viral response (eRVR) were 97.6% (82/84) and 100% (5/5), respectively. On the other hand, the SVR rates for relapsers and non-responders completing the treatment protocol were 98.4% (61/62) and 100% (5/5), respectively. The overall safety profiles of telaprevir-based regimens were similar for Japanese patients with genotype 1 and 2 HCV infection who experienced treatment failure. ### conclusion telaprevir, in combination with PEG IFN/RBV, provided a high SVR rate for genotype 2 HCV, difficult-to-treat patients who had not achieved SVR during prior IFN-based treatment. The eRVR had a strong influence on the cure rate of telaprevir-based therapy. In addition, the continuation of telaprevir-based treatment for up to 24 weeks was a significant predictor of SVR.", "source": "https://pubmed.ncbi.nlm.nih.gov/25196718/"}
{"doc_id": "3e1d02e4636033bbd6a561cdeb9a34d9", "sentence": "The binding affinity profile of 5-HT1D binding sites [ 5-CT > 5-HT > d-LSD > 5-MeOT > sumatriptan > RU 24,969 > metergoline > tryptamine = rauwolscine = methylsergide > yohimbine = methiothepin > TFMPP = 8-OH-DPAT > 2-methyl-5-HT > mCPP = quipazine = CP 93,129 > ketanserin > (-)-propranolol = haloperidol = ipsapirone ] compares well to that reported for 5-HT1D receptor sites in human caudate and cortex ( correlation coefficient : 0.99 and 0.98 ) .", "spans": [{"span_id": 0, "text": "sumatriptan", "start": 86, "end": 97, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "yohimbine", "start": 169, "end": 178, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "ketanserin", "start": 263, "end": 273, "token_start": 47, "token_end": 48}, {"span_id": 3, "text": "haloperidol", "start": 294, "end": 305, "token_start": 51, "token_end": 52}], "rels": [], "paragraph": "Identification of 5-hydroxytryptamine1D binding sites in sheep caudate nucleus membranes. Radioligand binding measurements were performed in membranes of sheep caudate nucleus using [3H]5-hydroxytryptamine (5-HT). [3H]5-HT labeled a population of high affinity binding sites with a Kd of 1.9 +/- 0.1 nM and a Bmax of 19.8 +/- 2.2 fmol/mg tissue. Combined 5-HTID/E binding sites were the predominant 5-HT1 subtype, accounting for 78% of the total population of 5-HT1 binding sites. 5-Carboxamidotryptamine (5-CT) and sumatriptan yielded inhibition curves which best fitted a two-site model with high affinity values of 0.8 and 10.1 nM, and 1000 and 206 nM for their low affinity components. The proportion of the high affinity 5-CT and sumatriptan binding sites was 79 and 72%. The binding affinity profile of 5-HT1D binding sites [ 5-CT > 5-HT > d-LSD > 5-MeOT > sumatriptan > RU 24,969 > metergoline > tryptamine = rauwolscine = methylsergide > yohimbine = methiothepin > TFMPP = 8-OH-DPAT > 2-methyl-5-HT > mCPP = quipazine = CP 93,129 > ketanserin > (-)-propranolol = haloperidol = ipsapirone ] compares well to that reported for 5-HT1D receptor sites in human caudate and cortex ( correlation coefficient : 0.99 and 0.98 ) . The present results indicate that sheep caudate nucleus is a valid tissue for studying interaction of compounds with 5-HT1D binding sites in the relative absence of 5-HT1E binding sites.", "source": "https://pubmed.ncbi.nlm.nih.gov/8394085/"}
{"doc_id": "da874424ca816f4450484050fadb2cc8", "sentence": "The MX2 cells are cross-resistant to etoposide , teniposide , bisantrene , dactinomycin , 4'-(9-acridinylamino)methanesulfon-m-anisidide , and the anthracyclines daunorubicin and doxorubicin but retain sensitivity to the Vinca alkaloids melphalan and mitomycin C. In addition , the MX2 cells display slight collateral sensitivity to bleomycin .", "spans": [{"span_id": 0, "text": "etoposide", "start": 37, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "teniposide", "start": 49, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "daunorubicin", "start": 162, "end": 174, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "doxorubicin", "start": 179, "end": 190, "token_start": 21, "token_end": 22}, {"span_id": 4, "text": "melphalan", "start": 237, "end": 246, "token_start": 29, "token_end": 30}, {"span_id": 5, "text": "mitomycin", "start": 251, "end": 260, "token_start": 31, "token_end": 32}, {"span_id": 6, "text": "bleomycin", "start": 333, "end": 342, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Multidrug resistance in mitoxantrone-selected HL-60 leukemia cells in the absence of P-glycoprotein overexpression. A multidrug-resistant variant of the human HL-60 promyelocytic leukemia cell line (HL-60/MX2) has been isolated in vitro by subculturing these cells in progressively increasing concentrations of mitoxantrone. The MX2 cells are cross-resistant to etoposide , teniposide , bisantrene , dactinomycin , 4'-(9-acridinylamino)methanesulfon-m-anisidide , and the anthracyclines daunorubicin and doxorubicin but retain sensitivity to the Vinca alkaloids melphalan and mitomycin C. In addition , the MX2 cells display slight collateral sensitivity to bleomycin . Despite being 30-35-fold less sensitive to mitoxantrone, net [14C]mitoxantrone accumulation at 60 min was reduced by only 10% in the mitoxantrone-resistant cells compared to the parental line. Furthermore, at later time points, e.g., 120 and 180 min, mitoxantrone accumulation in the MX2 cells exceeded that in HL-60 cells by 8.5 and 6.4%, respectively. No significant differences were observed between the sensitive and resistant cell lines in the initial (first 60 s) accumulation of mitoxantrone, and only minor (3-6%) enhancement of mitoxantrone efflux was detected in the resistant cell type. Monoclonal antibodies to P-glycoprotein had no detectable reactivity with membrane vesicles from either the sensitive or resistant cell types as determined by standard immunoblotting techniques. The mitoxantrone-resistant cells displayed a reciprocal translocation [rcpt(1;3)-(q21;p23)] not found in the sensitive parent, but there were no demonstrable double minute chromosomes or homogeneous staining regions in cells from either line. Thus, these mitoxantrone-resistant human leukemia cells display many features which are atypical for the \"classic\" multidrug resistance phenotype and should provide a useful model for the study of multidrug resistance which is not mediated by P-glycoprotein.", "source": "https://pubmed.ncbi.nlm.nih.gov/2568172/"}
{"doc_id": "de0dcd8c471a172926ff4fda7ff64e35", "sentence": "Combination of a betalactam antibiotic ( ampicillin or azlocillin ) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice .", "spans": [{"span_id": 0, "text": "ampicillin", "start": 41, "end": 51, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "azlocillin", "start": 55, "end": 65, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "polymyxin", "start": 71, "end": 80, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "rifampicin", "start": 88, "end": 98, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 3], "is_context_needed": true}, {"class": "POS", "spans": [1, 3], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "[A method of sequential administration of antibiotics in preventive treatment of experimental plague in albino mice].  Combination of a betalactam antibiotic ( ampicillin or azlocillin ) or polymyxin B with rifampicin were studied with their administration in succession at various intervals in an experimental model of plague infection of albino mice . It was shown that when the administration of the betalactams or polymyxin B preceded the administration of rifampicin, the efficacy of the preventive therapy considerably increased. The time of the intervals was noted to be of importance and should be predetermined for every subsequent administration.", "source": "https://pubmed.ncbi.nlm.nih.gov/7857160/"}
{"doc_id": "4ff7eb5de90244479006b9ab113b7bef", "sentence": "Between August 1993 and September 1994 , 6010 patients were randomized to receive either reteplase ( n = 3004 ) or streptokinase ( n = 3006 ) .", "spans": [{"span_id": 0, "text": "reteplase", "start": 89, "end": 98, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "streptokinase", "start": 115, "end": 128, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Mega-trials and equivalence trials: experience from the INJECT study. As treatments for acute myocardial infarction have grown in number and effectiveness, the post-infarction mortality rate has fallen, and new therapies can provide only a small additional advantage in extending survival. To prove such an advantage of a new drug over its predecessors in the same drug class requires a trial of at least 20,000 patients. Proving 'equivalence' rather than superiority requires only 6000 patients. The INJECT trial was designed with the modest goal of determining whether the novel agent reteplase (recombinant plasminogen activator) has an effect on mortality equivalent to that of streptokinase. Between August 1993 and September 1994 , 6010 patients were randomized to receive either reteplase ( n = 3004 ) or streptokinase ( n = 3006 ) . Both treatment groups had similar rates of bleeding events, extension or recurrence of myocardial infarction, and in-hospital stroke followed by 6 months of disability. reteplase recipients had a lower incidence of cardiac events in hospital and fewer allergic reactions. Although the number of diagnosed haemorrhagic strokes was higher in reteplase recipients, more patients receiving streptokinase had strokes of uncertain aetiology. At 35 days, the mortality rate associated with reteplase use was approximately 0.5% lower than that associated with streptokinase administration, and the upper limit of the 90% confidence interval for the difference between these rates was a superiority of streptokinase of 0.73%. Because the INJECT trial provided a probability of 0.95 that the mortality rate associated with reteplase use would be either lower than that with streptokinase administration or at most 0.73% worse, reteplase and streptokinase were proved equivalent according to the trial definition and limits.", "source": "https://pubmed.ncbi.nlm.nih.gov/11824001/"}
{"doc_id": "c30fd03fd3ba28d6e84af21763f91461", "sentence": "In patients coinfected and treated for both HIV-1 and hepatitis C virus ( HCV ) , administration of ribavirin ( RBV ) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5'-monophosphate dehydrogenase .", "spans": [{"span_id": 0, "text": "ribavirin", "start": 100, "end": 109, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "inosine", "start": 235, "end": 242, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1.  In patients coinfected and treated for both HIV-1 and hepatitis C virus ( HCV ) , administration of ribavirin ( RBV ) may result in altered intracellular drug levels of nucleoside reverse transcriptase inhibitors through inhibition of inosine 5'-monophosphate dehydrogenase . Drug interactions between tenofovir and RBV were studied in vitro in order to provide insights into the safety of co-administration of tenofovir disoproxil fumarate (DF) and RBV in HCV/HIV-1-coinfected patients. In accordance with previous in vitro studies, strongly increased anti-HIV activity was observed when RBV was combined with didanosine (ddl). In contrast, low-level anti-HIV antagonism was observed when RBV was combined with either tenofovir or abacavir. Significantly stronger anti-HIV antagonism was observed when RBV was combined with either zidovudine, stavudine, emtricitabine or lamivudine. Thus, although tenofovir and ddl are both adenosine analogues, their in vitro interactions with RBV are markedly different. These results suggest a low potential for increased toxicity upon co-administration of tenofovir DF with RBV in patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/15865229/"}
{"doc_id": "93bf31fa37027c4b544f7054db9cbb20", "sentence": "Previous treatments with rituximab and with rituximab plus high dose glucocorticoids , as well as with cyclophosphamide , azathioprine , plasma exchange , hyperbaric therapy , VAC therapy , prostacyclin , mycophenolate mofetil and surgery , had previously failed .", "spans": [{"span_id": 0, "text": "rituximab", "start": 25, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "rituximab", "start": 44, "end": 53, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "cyclophosphamide", "start": 103, "end": 119, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "azathioprine", "start": 122, "end": 134, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "mycophenolate", "start": 205, "end": 218, "token_start": 31, "token_end": 32}, {"span_id": 5, "text": "glucocorticoids", "start": 69, "end": 84, "token_start": 10, "token_end": 11}], "rels": [{"class": "NEG", "spans": [1, 5], "is_context_needed": false}, {"class": "NEG", "spans": [1, 2], "is_context_needed": false}, {"class": "NEG", "spans": [1, 3], "is_context_needed": false}], "paragraph": "Sequential therapy with belimumab followed by rituximab in Sj\u00f6gren's syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. The overexpression of B-cell activating factor (BAFF) in mucosa-associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sj\u00f6gren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated. ### methods We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids , as well as with cyclophosphamide , azathioprine , plasma exchange , hyperbaric therapy , VAC therapy , prostacyclin , mycophenolate mofetil and surgery , had previously failed . Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab. ### results This sequential belimumab-rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years. ### conclusions Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS.", "source": "https://pubmed.ncbi.nlm.nih.gov/24802131/"}
{"doc_id": "e1adee12863f0b3a46ecd91b601ae0e4", "sentence": "The decision to test a triple combination has led to the development of Fansimef , a fixed combination with tablets containing 250 mg mefloquine , 500 mg sulfadoxine and 25 mg pyrimethamine .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 134, "end": 144, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "sulfadoxine", "start": 154, "end": 165, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "pyrimethamine", "start": 176, "end": 189, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Current drugs for the treatment of tropical malaria]. The occurrence in the early 60's of stable resistance to chloroquine among Plasmodium falciparum strains in the Amazonas and on the Thai-Cambodian border has been a shock for all malariologists. This led to the search for new antimalarials without cross resistance with chloroquine. For each new drug, one of the major concerns was to define how rapidly parasites would develop resistance to this compound. Drug combinations were taken into consideration so as to achieve a delay in the appearance of resistance. The decision to test a triple combination has led to the development of Fansimef , a fixed combination with tablets containing 250 mg mefloquine , 500 mg sulfadoxine and 25 mg pyrimethamine . A very relevant delay in the development of resistance was found both in-vivo--in the P. berghei model--and in-vitro using P. falciparum. Fansimef has also been under investigations for malaria. Controlled clinical trials were performed in Africa, South America and South East Asia. The documentation for this new indication will be submitted to registration authorities in 1991. A preference alternative to continuous chemoprophylaxis is stand-by malaria treatment for travellers to regions where the malaria risk is relatively low. Stand-by treatment is under investigations in France and in Switzerland. In the search for alternative remedies against drug resistant P. falciparum malaria our attention was directed to Yingzhaosu, a new sesquiterpene peroxide of plant origin from traditional Chinese medicine. A short and convenient synthesis of this ring system gave access to a variety of structural analogues of Yingzhaosu.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/1998081/"}
{"doc_id": "60a28eefe9aa1c0cc21287ec8b322bb8", "sentence": "The aim of this study was to evaluate three active agents , bleomycin ( BLM ) , epirubicin and carboplatin in a new combination ( BECA ) in terms of feasibility , activity and toxicity in patients with recurrent and metastatic squamous cell carcinoma of the head and neck .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 60, "end": 69, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "epirubicin", "start": 80, "end": 90, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "carboplatin", "start": 95, "end": 106, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Bleomycin, epirubicin, carboplatin (BECA) in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.  The aim of this study was to evaluate three active agents , bleomycin ( BLM ) , epirubicin and carboplatin in a new combination ( BECA ) in terms of feasibility , activity and toxicity in patients with recurrent and metastatic squamous cell carcinoma of the head and neck . From April 1992 to February 1993 15 pts (12M/3F), median age 53 years, all pretreated (6 surgery + radiotherapy; 3 radiotherapy + chemotherapy; 6 radiotherapy), were treated with BLM 15 mg/m2 days 1-14; epirubicin 30 mg/m2 days 1-14 and carboplatin 300 mg/m2 day 1 every 28 days. In the 14 evaluable pts we observed 1 complete response, CR (7.1%), 4 partial responses, PR (28.6%), 5 stable disease, SD and 4 disease progression, PD with an overall response of 35.7%. The treatment was globally well tolerated, 1 pt with grade 3 leukopenia and 1 pt with grade 3 thrombocytopenia, 1 pt with grade 3 emesis and 1 pt with grade 3 mucositis. At the last follow-up the duration of CR was 34 months, the duration of PRs were respectively 22-10-10-7 months, but the SD ranged from 4 to 6 months. The overall median survival was 8 months (3-36), 14 for responders and 4 for non-responders. This final report seems to confirm the activity and efficacy of the BECA regimen, suitable for outpatient administration with an overall response equal to other more aggressive combinations.", "source": "https://pubmed.ncbi.nlm.nih.gov/9106022/"}
{"doc_id": "9ff502fca23aae0a92144e74f6e602cd", "sentence": "Survival Benefits of Second-line Axitinib Versus Everolimus After First Line Sunitinib Treatment in Metastatic Renal Cell Carcinoma .", "spans": [{"span_id": 0, "text": "Axitinib", "start": 33, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "Everolimus", "start": 49, "end": 59, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "Sunitinib", "start": 77, "end": 86, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Survival Benefits of Second-line Axitinib Versus Everolimus After First Line Sunitinib Treatment in Metastatic Renal Cell Carcinoma . Targeted therapies significantly improve clinical outcomes among patients with metastatic renal cell carcinoma (mRCC). Several new agents have been approved for first- and second-line use. However, there is a lack of compelling evidence comparing sequencing strategies, and available comparative data regarding the real-world effectiveness of different therapeutic sequences are limited. ### Materials And Methods We identified mRCC patients who initiated targeted therapy between January 1, 2008 and May 31, 2017 from the National Health Insurance Fund (NHIF) database of Hungary. Overall survival (OS) and duration of first-line treatment (DFT) were obtained for patients receiving sunitinib-everolimus, sunitinib-axitinib, or pazopanib-everolimus treatment sequences. OS of sunitinib-everolimus and sunitinib-axitinib sequences was also determined for patients having better or worse response to sunitinib first-line therapy. ### results Median OS was significantly longer among patients treated with sunitinib-axitinib compared to those receiving sunitinib-everolimus. Median DFT was also significantly longer in the sunitinib-axitinib vs. sunitinib-everolimus group. sunitinib-axitinib was associated with significantly longer median OS compared to sunitinib-everolimus in patients with better response to first-line sunitinib in the pooled sunitinib population. In patients with worse response to sunitinib, sunitinib-axitinib was associated with a trend towards greater OS compared to sunitinib-everolimus, but the difference did not reach statistical significance. ### conclusions In this nationwide database analysis, mRCC patients treated with the sunitinib-axitinib sequence had significantly longer OS compared to those receiving sunitinib-everolimus therapy. The OS benefits of second-line axitinib were consistent among patients with better response to sunitinib defined by DFT values.", "source": "https://pubmed.ncbi.nlm.nih.gov/32291570/"}
{"doc_id": "6ddb94cc099e39aa12aa362ef6bf389c", "sentence": "A phase II trial of cytarabine , cisplatin , and etoposide was conducted in 38 patients with refractory stage III and IV non-Hodgkin 's lymphoma .", "spans": [{"span_id": 0, "text": "cytarabine", "start": 20, "end": 30, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "cisplatin", "start": 33, "end": 42, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "etoposide", "start": 49, "end": 58, "token_start": 10, "token_end": 11}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Cytarabine, cisplatin, and etoposide chemotherapy for refractory non-Hodgkin's lymphoma.  A phase II trial of cytarabine , cisplatin , and etoposide was conducted in 38 patients with refractory stage III and IV non-Hodgkin 's lymphoma . There were two complete and nine partial responses (32%) among 35 evaluable patients. Response rate in patients with large cell lymphoma was 45%. The dose-limiting toxic effect was myelosuppression in 66% of patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/3802114/"}
{"doc_id": "4d51155fe860c0a0ffe3f7da6461332d", "sentence": "The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients .", "spans": [{"span_id": 0, "text": "camrelizumab", "start": 19, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "gemcitabine", "start": 37, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "cisplatin", "start": 53, "end": 62, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Platinum-based doublet chemotherapy regimens, preferentially gemcitabine plus cisplatin, are generally considered the first-line standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma. However, no consensus has been reached regarding treatment following progression after first-line therapy. camrelizumab (SHR-1210) is a humanised anti-programmed death-1 (anti PD-1) antibody. We present safety and preliminary antitumour activity of camrelizumab alone as second-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma and combined with gemcitabine and cisplatin as first-line therapy in this patient population. ### methods We report the results from two single-arm, phase 1 trials. Both trials included patients aged 18-70 years with histologically or cytologically confirmed nasopharyngeal carcinoma and confirmed metastatic disease or locoreginal recurrence, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who received at least one previous line of treatment were enrolled at five academic hospitals in China into the dose-escalation and expansion trial to receive camrelizumab monotherapy intravenously at escalating doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled from a single centre in China to receive six cycles of camrelizumab 200 mg (day 1), gemcitabine 1 g/m ### findings In the camrelizumab monotherapy trial, between March 31, 2016, and Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients were enrolled across the dose-escalation and expansion cohorts and received at least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had treatment-related adverse events of grade 3 or 4, the most common of which were elevated conjugated bilirubin concentration (three [3%] of 93 patients), stomatitis, anaemia, and increased concentrations of aspartate aminotransferase, alanine aminotransferase, and total bilirubin, each of which occurred in two (2%) patients. Eight (9%) patients had a treatment-related serious adverse event. No dose-limiting toxic effects were observed during the dose-escalation phase. 31 (34%; 95% CI 24-44) of 91 evaluable patients on camrelizumab monotherapy had an overall response with a median follow-up of 9\u00b79 months (IQR 8\u00b71-11\u00b77). In the camrelizumab combination trial, between April 18, 2017, and Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients were enrolled and treated (safety population). 20 (87%) of 23 patients had grade 3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients), anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia (seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%] patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two patients had treatment-related serious adverse events. No treatment-related deaths occurred in these trials. 20 (91% [95% CI 72-97]) of 22 evaluable patients had an overall response with a median follow-up time of 10\u00b72 months (IQR 9\u00b77-10\u00b78). ### interpretation camrelizumab is a well tolerated, potential treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma. The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients . Randomised controlled trials are needed to further establish the role of immune checkpoint inhibition for nasopharyngeal carcinomas. ### funding Hengrui Medicine Co, Chinese National Natural Science Foundation project, Science and Technology Program of Guangdong, Pearl River Nova Program of Guangzhou.", "source": "https://pubmed.ncbi.nlm.nih.gov/30213452/"}
{"doc_id": "15545b66b51591bff60b6079fb33a85d", "sentence": "His infection failed to respond to combinations of surgery , fluconazole and itraconazole .", "spans": [{"span_id": 0, "text": "fluconazole", "start": 61, "end": 72, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "itraconazole", "start": 77, "end": 89, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Experience with infection by Scedosporium prolificans including apparent cure with fluconazole therapy. Five cases of human infection with Scedosporium prolificans are described. There were two groups of patients. In group one, two were immunocompetent males with localized bone and joint infections, a man with post-traumatic septic arthritis, responded to surgical treatment alone and a boy with post-traumatic septic arthritis, appeared to respond to treatment with oral fluconazole, without surgery. The second group consisted of three immunocompromised patients. S. prolificans was isolated at autopsy from the lungs of one patient with acute leukaemia, and from the lungs, liver, and kidneys of another. Nosocomial S. prolificans infection of a synthetic vascular graft occurred in the third patient with end-stage renal failure on corticosteroid therapy for idiopathic hypereosinophilia. His infection failed to respond to combinations of surgery , fluconazole and itraconazole . All isolates of S. prolificans were resistant in vitro to antifungal drugs, including the first case, which responded clinically to fluconazole.", "source": "https://pubmed.ncbi.nlm.nih.gov/8945709/"}
{"doc_id": "1f85070a60bf9fba78c465d651b3df65", "sentence": "The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone .", "spans": [{"span_id": 0, "text": "tianeptine", "start": 25, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "tianeptine", "start": 76, "end": 86, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "naloxone", "start": 109, "end": 117, "token_start": 15, "token_end": 16}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Anticonvulsant activity of the antidepressant drug, tianeptine, against pentylenetetrazole-induced seizures mitigates cognitive impairment in rats. Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. tianeptine was administered in three doses (20, 40 and 80\u2009mg/kg) 30\u2009min before PTZ (60\u2009mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone . Impairment of learning and memory by PTZ was prevented by tianeptine. tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/27561095/"}
{"doc_id": "a85acb22dd609031341e06c9b9af4fea", "sentence": "Twenty-one trials involving 3646 patients were included : 11 trials using beta-blockers ( 6 drugs ; 866 patients ) , 6 clonidine or mivazerol ( 614 patients ) , 3 diltiazem or verapamil ( 121 patients ) , and 1 nitroglycerin ( 45 patients ) .", "spans": [{"span_id": 0, "text": "clonidine", "start": 119, "end": 128, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "diltiazem", "start": 163, "end": 172, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "verapamil", "start": 176, "end": 185, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Pharmacologic myocardial protection in patients undergoing noncardiac surgery: a quantitative systematic review. A number of drugs have been tested in clinical trials to decrease cardiac complications in patients undergoing noncardiac surgery. To compare the results of these studies, we conducted a quantitative systematic review. Medline, Embase, and Cochrane databases were searched for randomized trials that assessed myocardial ischemia, myocardial infarction, 30-day cardiac mortality, and adverse effects. Data were combined using a fixed-effect model and expressed as Peto odds ratios (OR) with 95% confidence interval (CI) and as numbers-needed-to-treat/harm (NNT/H). Twenty-one trials involving 3646 patients were included : 11 trials using beta-blockers ( 6 drugs ; 866 patients ) , 6 clonidine or mivazerol ( 614 patients ) , 3 diltiazem or verapamil ( 121 patients ) , and 1 nitroglycerin ( 45 patients ) . All trials had an inactive control; there were no direct comparisons. beta-blockers decreased ischemic episodes during surgery (7.6% versus 20.2% with placebo; OR 0.32 [95% CI, 0.17-0.58]; NNT 8) and after surgery (15.2% versus 27.9% with control; OR 0.46 [95% CI, 0.26-0.81]; NNT 8). alpha(2)-agonists decreased ischemia during surgery only (19.4% versus 32.8%; OR 0.47 [95% CI, 0.33-0.68]; NNT 7). beta-blockers reduced the risk of myocardial infarction (0.9% versus 5.2%; OR 0.19 [95% CI, 0.08-0.48]; NNT 23) but only when 2 trials with high-risk patients were included. The effect of alpha(2)-agonists on myocardial infarction was not significant (6.1% versus 7.3%; OR 0.85 [95% CI, 0.62-1.14]). beta-blockers significantly decreased the risk of cardiac death from 3.9% to 0.8% (OR 0.25 [95% CI, 0.09-0.73], NNT 32). alpha(2)-agonists significantly decreased the risk of cardiac death from 2.3% to 1.1% (OR 0.50 [95% CI, 0.28-0.91], NNT 83). For calcium channel blockers and nitroglycerin, evidence of any benefit was lacking. The most common adverse effect was bradycardia, which occurred in 24.5% of patients receiving a beta adrenergic blocker versus 9.1% of controls (OR 3.76 [95% CI, 2.45-5.77], NNH 6).", "source": "https://pubmed.ncbi.nlm.nih.gov/12933373/"}
{"doc_id": "a9a3f350e52c4bb1da0057b2840d8031", "sentence": "The sensitivity of human neuroblastoma-derived cell lines , cell line-derived , and patient-derived xenograft ( PDX ) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide ( topo/cyclo ) was examined .", "spans": [{"span_id": 0, "text": "crizotinib", "start": 154, "end": 164, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "topotecan", "start": 179, "end": 188, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "cyclophosphamide", "start": 193, "end": 209, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical. ### Experimental Design The sensitivity of human neuroblastoma-derived cell lines , cell line-derived , and patient-derived xenograft ( PDX ) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide ( topo/cyclo ) was examined . Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy. ### results In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free survival. crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification). ### conclusions Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo-resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multiagent therapy for ALK-aberrant neuroblastoma patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/26438783/"}
{"doc_id": "95b15547d7d7b7581b23bb1097bf9780", "sentence": "Patients were randomised to either receive additional tretinoin ( 45mg/m(2)/day ) for 12 weeks ( arm A ) , or peg-interferon and ribavirin alone ( arm B ) .", "spans": [{"span_id": 0, "text": "tretinoin", "start": 54, "end": 63, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ribavirin", "start": 129, "end": 138, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "peg-interferon", "start": 110, "end": 124, "token_start": 20, "token_end": 21}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "No beneficial effect of all-trans retinoic acid in previous non-responder patients with chronic hepatitis C: the ATRACTION study, a phase II randomised trial. Preclinical data suggested all-trans retinoic acid (tretinoin) as a potential antiviral agent against chronic hepatitis C infection. ### aims To assess efficacy, safety, and tolerability of tretinoin in combination with peg-interferon and ribavirin in genotype-1 infected patients with prior non-response. ### method We performed an open-label multicentre clinical trial. Patients were randomised to either receive additional tretinoin ( 45mg/m(2)/day ) for 12 weeks ( arm A ) , or peg-interferon and ribavirin alone ( arm B ) . Primary endpoint was the slope of the third phase of viral decline (M\u03b4) as determined in an established kinetic model known to correlate with treatment outcome. Secondary endpoints were additional kinetic parameters, viral response rates, safety, and tolerability. ### results 27 patients in arm A and 30 patients in arm B were treated per protocol until week 12. Viral kinetic parameters did not differ. Rates of early virological response (>2log10 drop at week 12) were similar (10/27 versus 11/30 patients). In arm A, patients experienced a higher rate and intensity of adverse events, most commonly skin and mucosal dryness, and headache. ### conclusion Addition of tretinoin was safe and acceptably well tolerated. However, it did not influence viral kinetics and thus cannot be further considered as a treatment option.", "source": "https://pubmed.ncbi.nlm.nih.gov/23245590/"}
{"doc_id": "387e1c79c33690ab0ea431972cc837d3", "sentence": "This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 67, "end": 77, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "carboplatin", "start": 82, "end": 93, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Results of a phase II study of weekly paclitaxel plus carboplatin in advanced carcinoma of unknown primary origin: a reasonable regimen for the community-based clinic? Optimal treatment for cancer of unknown primary (CUP) can challenge clinicians. This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP . Forty-two subjects enrolled. Treatment was intravenous paclitaxel (80 mg/m2) plus carboplatin (AUC = 2) on Days 1, 8, and 15 every 28 days. Seven (18 percent) responded (complete = 2, partial = 5); median survival was 8.5 months; estimated survival (12 and 24-month) was 33 and 17 percent, respectively. Median time to progression was 3.7 months, and estimated progression-free survival (12 and 24 months) was 14 and 7 percent, respectively. Median duration of response was 17.3 months. This combination produced modest antitumor activity in advanced CUP.", "source": "https://pubmed.ncbi.nlm.nih.gov/17364554/"}
{"doc_id": "f0b62b80ed586651ac34c24cba622bb2", "sentence": "To investigate the presence of extended spectrum and metallo \u03b2-lactamases ( MBLs ) in Pseudomonas aeruginosa isolates which are resistant to imipenem and ceftazidime that were isolated in a hospital in Mexico .", "spans": [{"span_id": 0, "text": "imipenem", "start": 141, "end": 149, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "ceftazidime", "start": 154, "end": 165, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Unusual diversity of acquired \u03b2-lactamases in multidrug-resistant Pseudomonas aeruginosa isolates in a Mexican hospital.  To investigate the presence of extended spectrum and metallo \u03b2-lactamases ( MBLs ) in Pseudomonas aeruginosa isolates which are resistant to imipenem and ceftazidime that were isolated in a hospital in Mexico . ### results Pulsed-field gel electrophoresis (PFGE) revealed the presence of four clonal types among the 14 isolates. All these genes were found either alone or simultaneously in the P. aeruginosa strains in the following five different arrangements: ; ; ; ; and . Class 1 integrons were detected and contained the cassettes bla(GES-5) and bla(OXA-2), but not that of bla(VIM). bla(VIM) genes occurred only in the chromosome, while bla(GES-5) was located in the chromosome and in the plasmids. ### conclusions To our knowledge, this is the first description of P. aeruginosa strains simultaneously producing the VIM-2 and VIM-11 variants, and the combination of GES-5 and MBL carbapenemases, which determines a major challenge for the clinical microbiology laboratory and a remarkable epidemiological risk for the nosocomial spread of multidrug-resistant determinants.", "source": "https://pubmed.ncbi.nlm.nih.gov/22554004/"}
{"doc_id": "1e54b672b78e32994abee52c7548ec9f", "sentence": "The patient achieved complete remission after two cycles of chemotherapy of daunorubicin , cytarabine and etoposide .", "spans": [{"span_id": 0, "text": "daunorubicin", "start": 76, "end": 88, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "cytarabine", "start": 91, "end": 101, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "etoposide", "start": 106, "end": 115, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Trisomy 21 with t(5; 11) chromosomal translocation as new unfavorable cytogenetic abnormalities in pediatric acute myeloid leukemia type M2: One case report of nine-year follow-up and literature review. We report one case of pediatric acute myeloid leukemia type 2 (AML-M2) who presented with karyotypic aberration of trisomy 21 with the t(5;11) chromosomal translocation. The patient achieved complete remission after two cycles of chemotherapy of daunorubicin , cytarabine and etoposide . Then, follow-up cytogenetic analysis from bone marrow cell cultures demonstrated a normal karyotype of 46, XY. After 9 years, the patient relapsed and the karyotypic abnormalities of trisomy 21 with t(5;11) reappeared. It was concluded that trisomy 21 with t(5; 11) is a new unfavorable cytogenetic aberration in AML-M2.", "source": "https://pubmed.ncbi.nlm.nih.gov/29058300/"}
{"doc_id": "4f164dbb352c4d132b31c07b28784632", "sentence": "We included 10 pharmacological ( modafinil , intravenous immunoglobulin ( IVIg ) , pyridostigmine , lamotrigine , amantadine , prednisone ) and three non-pharmacological ( muscle strengthening , rehabilitation in a warm climate ( that is temperature \u00b1 25 \u00b0 C , dry and sunny ) and a cold climate ( that is temperature \u00b1 0 \u00b0 C , rainy or snowy ) , static magnetic fields ) studies with a total of 675 participants with PPS in this review .", "spans": [{"span_id": 0, "text": "modafinil", "start": 33, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "pyridostigmine", "start": 83, "end": 97, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "lamotrigine", "start": 100, "end": 111, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "amantadine", "start": 114, "end": 124, "token_start": 17, "token_end": 18}, {"span_id": 4, "text": "prednisone", "start": 127, "end": 137, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Treatment for postpolio syndrome. Postpolio syndrome (PPS) may affect survivors of paralytic poliomyelitis and is characterised by a complex of neuromuscular symptoms leading to a decline in physical functioning. The effectiveness of pharmacological treatment and rehabilitation management in PPS is not yet established. This is an update of a review first published in 2011. ### objectives To systematically review the evidence from randomised and quasi-randomised controlled trials for the effect of any pharmacological or non-pharmacological treatment for PPS compared to placebo, usual care or no treatment. ### Search Methods We searched the following databases on 21 July 2014: Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and CINAHL Plus. We also checked reference lists of all relevant articles, searched the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment (HTA) Database and trial registers and contacted investigators known to be involved in research in this area. ### Selection Criteria Randomised and quasi-randomised trials of any form of pharmacological or non-pharmacological treatment for people with PPS. The primary outcome was self perceived activity limitations and secondary outcomes were muscle strength, muscle endurance, fatigue, pain and adverse events. ### Data Collection And Analysis We used standard methodological procedures expected by The Cochrane Collaboration. ### Main Results We included 10 pharmacological ( modafinil , intravenous immunoglobulin ( IVIg ) , pyridostigmine , lamotrigine , amantadine , prednisone ) and three non-pharmacological ( muscle strengthening , rehabilitation in a warm climate ( that is temperature \u00b1 25 \u00b0 C , dry and sunny ) and a cold climate ( that is temperature \u00b1 0 \u00b0 C , rainy or snowy ) , static magnetic fields ) studies with a total of 675 participants with PPS in this review . None of the included studies were completely free from any risk of bias, the most prevalent risk of bias being lack of blinding.There was moderate- and low-quality evidence that IVIg has no beneficial effect on activity limitations in the short term and long term, respectively, and inconsistency in the evidence for effectiveness on muscle strength. IVIg caused minor adverse events in a substantial proportion of the participants. Results of one trial provided very low-quality evidence that lamotrigine might be effective in reducing pain and fatigue, resulting in fewer activity limitations without generating adverse events. Data from two single trials suggested that muscle strengthening of thumb muscles (very low-quality evidence) and static magnetic fields (moderate-quality evidence) are safe and beneficial for improving muscle strength and pain, respectively, with unknown effects on activity limitations. Finally, there was evidence varying from very low quality to high quality that modafinil, pyridostigmine, amantadine, prednisone and rehabilitation in a warm or cold climate are not beneficial in PPS. ### Authors Conclusions Due to insufficient good-quality data and lack of randomised studies, it was impossible to draw definite conclusions about the effectiveness of interventions for PPS. Results indicated that IVIg, lamotrigine, muscle strengthening exercises and static magnetic fields may be beneficial but need further investigation to clarify whether any real and meaningful effect exists.", "source": "https://pubmed.ncbi.nlm.nih.gov/25984923/"}
{"doc_id": "dee911198ad44dbe0c7a3ba2c021ac37", "sentence": "Protection against CsA-induced PST cell death was afforded by reduction in extracellular calcium levels in the media or addition of the calcium entry antagonists : verapamil , nifedipine or diltiazem .", "spans": [{"span_id": 0, "text": "verapamil", "start": 164, "end": 173, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "nifedipine", "start": 176, "end": 186, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "diltiazem", "start": 190, "end": 199, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Mechanisms of cyclosporine A toxicity in defined cultures of renal tubule epithelia: a role for cysteine proteases. The mechanisms of toxicity of cyclosporine A (CsA) were studied in primary cultures of individually microdissected rabbit and human renal tubules of proximal and distal regions of the nephron. A direct toxic effect of CsA on renal tubule epithelia was demonstrated using nigrosine uptake and LDH release as indicators of cell death. Proximal convoluted tubules (PCT) and proximal straight tubules (PST) were shown to be highly sensitive, while thick ascending limbs of Henle (TAL) were much less sensitive and cortical collecting tubules (CCT) relatively resistant. The effects of CsA were time and dose dependent over the range 50 ng/ml to 100 micrograms/ml. Protection against CsA-induced PST cell death was afforded by reduction in extracellular calcium levels in the media or addition of the calcium entry antagonists : verapamil , nifedipine or diltiazem . In addition, treatment with the cysteine protease inhibitor, E64, attenuated CsA-induced cell damage. A role for the lysosomal cysteine proteases (cathepsins), however, was ruled out on the basis of identical activity levels in all cell types; no beneficial effects of lysosomal enzyme depletion and no evidence of lysosomal rupture prior to death. By contrast, a role for the cytoplasmic, calcium-dependent cysteine protease calpain was suggested since activity levels were significantly higher in PST than CCT cultures and were inducible by CsA.", "source": "https://pubmed.ncbi.nlm.nih.gov/1802407/"}
{"doc_id": "a3ea338f47124692a7ae19b005445176", "sentence": "This synergy was abrogated through siRNA knockdown of IkB. The synergistic effect of combining selinexor and bortezomib in vitro provides rationale for further investigation of this combination treatment for patients with high-risk neuroblastoma .", "spans": [{"span_id": 0, "text": "selinexor", "start": 95, "end": 104, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "bortezomib", "start": 109, "end": 119, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB. Across many cancer types in adults, upregulation of the nuclear-to-cytoplasmic transport protein Exportin-1 (XPO1) correlates with poor outcome and responsiveness to selinexor, an FDA-approved XPO1 inhibitor. Similar data are emerging in childhood cancers, for which selinexor is being evaluated in early phase clinical studies. Using proteomic profiling of primary tumor material from patients with high-risk neuroblastoma, as well as gene expression profiling from independent cohorts, we have demonstrated that XPO1 overexpression correlates with poor patient prognosis. Neuroblastoma cell lines are also sensitive to selinexor in the low nanomolar range. Based on these findings and knowledge that bortezomib, a proteasome inhibitor, blocks degradation of XPO1 cargo proteins, we hypothesized that combination treatment with selinexor and bortezomib would synergistically inhibit neuroblastoma cellular proliferation. We observed that selinexor promoted nuclear retention of IkB and that bortezomib augmented the ability of selinexor to induce cell-cycle arrest and cell death by apoptosis. This synergy was abrogated through siRNA knockdown of IkB. The synergistic effect of combining selinexor and bortezomib in vitro provides rationale for further investigation of this combination treatment for patients with high-risk neuroblastoma .", "source": "https://pubmed.ncbi.nlm.nih.gov/33975179/"}
{"doc_id": "0eb278770a9abdd4d268af47db1c9aa1", "sentence": "Therapy included 4 or 8 intensive therapy elements N1 ( Etoposide 125 mg/m2 day 1 - 4 , Vindesine 3 mg/m2 day 1 , Cisplatin 40 mg/m2 day 1 - 4 ) and N2 ( Vincristine 1.5 mg/m2 day 1 + 8 , Dacarbazine 200 mg/m2 day 1 - 5 , Ifosfamide 1500 mg/ m2 day 1 - 5 , Doxorubicin 30 mg/m2 day 6 + 7 ) in alternating order .", "spans": [{"span_id": 0, "text": "Etoposide", "start": 56, "end": 65, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "Cisplatin", "start": 114, "end": 123, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "Vincristine", "start": 154, "end": 165, "token_start": 35, "token_end": 36}, {"span_id": 3, "text": "Dacarbazine", "start": 188, "end": 199, "token_start": 43, "token_end": 44}, {"span_id": 4, "text": "Ifosfamide", "start": 222, "end": 232, "token_start": 51, "token_end": 52}, {"span_id": 5, "text": "Doxorubicin", "start": 257, "end": 268, "token_start": 60, "token_end": 61}, {"span_id": 6, "text": "Vindesine", "start": 88, "end": 97, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 6], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3, 4, 5], "is_context_needed": true}], "paragraph": "[Kinetics of myelopoietic regeneration and mobilization of CD34-positive cells within the scope of the NB90 Neuroblastoma Therapy Study]. Hematological and clinical data of 14 children with neuroblastoma treated according to the German neuroblastoma therapy study NB 90 were analyzed. Therapy included 4 or 8 intensive therapy elements N1 ( Etoposide 125 mg/m2 day 1 - 4 , Vindesine 3 mg/m2 day 1 , Cisplatin 40 mg/m2 day 1 - 4 ) and N2 ( Vincristine 1.5 mg/m2 day 1 + 8 , Dacarbazine 200 mg/m2 day 1 - 5 , Ifosfamide 1500 mg/ m2 day 1 - 5 , Doxorubicin 30 mg/m2 day 6 + 7 ) in alternating order . The hematological recovery was studied after 86 therapy elements N1/N2. G-CSF had been given in 23 therapy courses, while no cytokine was administered in 63 therapy courses. Mobilization of CD34+ cells was studied in 13 therapy courses with G-CSF. Severe myelosuppression with an absolute neutrophil count < 500/microL was noted 2-4 weeks after each therapy element. The use of G-CSF did not prevent, but shortened neutropenia. There was no difference in the number of infections nor time delay of therapy between the courses with or without G-CSF. In 11 therapy courses G-CSF was started on the day following the last chemotherapy dose (N1: day 5; N2: day 9). In 12 therapy courses G-CSF was given delayed, starting day 12 after the initiation of therapy. Kinetics of granulocyte recovery was similar in the early or delayed application of G-CSF. Neutrophil recovery after the therapy element N1 was earlier and faster compared to that of therapy element N2. The more rapid rise of the neutrophils after the N1 element was accompanied by an effective mobilization of CD34+ cells. Taking into account the limitations of this retrospective study, the data may help to optimize the application of G-CSF in a very intensive therapy study like NB90.", "source": "https://pubmed.ncbi.nlm.nih.gov/9340428/"}
{"doc_id": "0dd21b716b4b6f9c9648a6933f01760b", "sentence": "Mycophenolate mofetil , the prodrug of mycophenolic acid , is widely used for maintenance immunosuppressive therapy in renal transplant recipients .", "spans": [{"span_id": 0, "text": "Mycophenolate", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "mycophenolic acid", "start": 39, "end": 56, "token_start": 6, "token_end": 8}], "rels": [], "paragraph": "Influence of renal graft function on mycophenolic acid pharmacokinetics during the early period after kidney transplant.  Mycophenolate mofetil , the prodrug of mycophenolic acid , is widely used for maintenance immunosuppressive therapy in renal transplant recipients . The effect of renal graft function on mycophenolic acid pharmacokinetics parameters is still controversial. The aim of this study is to investigate the impact of renal graft function on mycophenolic acid pharmacokinetics during the early posttransplant period. ### Materials And Methods Our study was done on 13 patients with severe renal impairment (glomerular filtration rate < 30 mL/min, impaired group) and 13 patients with normal graft function (glomerular filtration rate < 70 mL/min, control group), at a steady mycophenolic acid plasma level, during the first month after transplant. All patients received a fixed dose of mycophenolate mofetil (1 g twice daily) in combination with cyclosporine and steroids. mycophenolic acid plasma levels were determined by a validated high-performance liquid chromatography method. mycophenolic acid area under the time concentration curve from 0 to 12 hours and apparent mycophenolic acid plasma clearance (CL/f) were measured for each patient. ### results mycophenolic acid area under the time-concentration curve (0-12 h), mycophenolic acid area under the time-concentration curve (6-10 h), first peak concentration (Cmax1), and secondary peak concentration (Cmax2) were higher in the impaired group, while mycophenolic acid plasma clearance was higher in the control group (P < .05). Trough levels (C0) were similar for both groups (P < .05). There was a negative correlation between glomerular filtration rate and area under the time-concentration curve (r=-0.422, P = .04), while there was a positive correlation between glomerular filtration rate and mycophenolic acid plasma clearance (r=0.463, P = .02). ### conclusions mycophenolic acid pharmacokinetics parameters in normal renal function patients and severe renal impairment patients are different, and renal graft function correlates with total mycophenolic acid area under the time-concentration curve and apparent mycophenolic acid plasma clearance. However, the necessity of dosage adjustment based on renal graft function requires further studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/19338489/"}
{"doc_id": "1aaf0d88c992f34d862f98e4754879c3", "sentence": "Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome .", "spans": [{"span_id": 0, "text": "tacrolimus", "start": 23, "end": 33, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "prednisone", "start": 47, "end": 57, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy and safety of tacrolimus and low-dose prednisone in Chinese children with steroid-resistant nephrotic syndrome . tacrolimus, a calcineurin inhibitor, is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome (SRNS), but its clinical application in China is still limited. We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS. ### methods In this prospective non-randomized, non-controlled study, Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus (0.1\u00a0mg/kg/day) and low-dose prednisone (0.25-0.50\u00a0mg/kg/day). We compared the overall remission rate (ORR) and adverse events in the follow-up period with this therapeutic regimen. ### results A total of 76 children were enrolled into the study with an average follow-up period of 18\u2009\u00b1\u20096\u00a0months (maximum 36\u00a0months). ORR achieved by the first, third, and sixth months was 94.7%, 94.7%, and 96.0%, respectively. All patients who attained an initial tacrolimus trough concentration (FK506C ### conclusions Combination of tacrolimus and low-dose prednisone was safe and effective for the treatment of children with SRNS, with high remission rates observed as early as the first month. Relapses were infrequent, but tended to increase significantly with decreases in FK506C", "source": "https://pubmed.ncbi.nlm.nih.gov/31049814/"}
{"doc_id": "5bad8c80ea7a45c05dd96dec6ee34e0b", "sentence": "Vandetanib inhibited hENT1 , hENT2 , hCNT1 , hCNT2 , and hCNT3 , whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1 .", "spans": [{"span_id": 0, "text": "Vandetanib", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "erlotinib", "start": 73, "end": 82, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "gefitinib", "start": 113, "end": 122, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Erlotinib, gefitinib, and vandetanib inhibit human nucleoside transporters and protect cancer cells from gemcitabine cytotoxicity. Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides. ### Experimental Design TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines. ### results erlotinib, gefitinib and vandetanib inhibited [(3)H]uridine transport in yeast and [(3)H]uridine and [(3)H]gemcitabine uptake in the four cell lines. Treatment of cell lines with erlotinib, gefitinib, or vandetanib for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth. ### conclusions Vandetanib inhibited hENT1 , hENT2 , hCNT1 , hCNT2 , and hCNT3 , whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1 . The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/24170548/"}
{"doc_id": "21d29533c154290f74bdd47153d6d15c", "sentence": "Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression .", "spans": [{"span_id": 0, "text": "Genistein", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 53, "end": 63, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "vincristine", "start": 68, "end": 79, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Genistein inversely affects tubulin-binding agent-induced apoptosis in human breast cancer cells. genistein, a natural isoflavone phytoestrogen present in soybeans, has been extensively studied as a chemopreventive or therapeutic agent in several types of cancer. The traditional Asian diet is rich in soy products may explain in part why the incidence of breast cancer in Asian women is relatively low. To improve therapeutic benefits, we investigated the combination of genistein with chemotherapeutic agents in phenotypically dissimilar human breast cancer cells, MCF-7 and MDA-MB-231, in which estrogen receptor expression is positive and negative, respectively. In the present study, genistein significantly decreased cell apoptosis induced by tubulin-binding agents, paclitaxel and vincristine. FACScan analysis revealed that genistein also diminished the accumulation of the G2/M phase in the cell cycle caused by tubulin-binding agents. In situ staining of microtubules revealed that genistein could decrease paclitaxel-induced tubulin polymerization. However, in vivo tubulin polymerization assay revealed that simultaneous treatment of genistein did not change the tubulin/microtubule dynamic. Genistein reduced Bcl-2 phosphorylation triggered by paclitaxel and vincristine without changing Bax protein expression . p53 and p21 expression, monitored by Western blotting, was not altered by genistein. However, the expression of cyclin B1 and CDC2 kinase was markedly decreased in combination with genistein. In conclusion, genistein inversely affected tubulin-binding agent-induced apoptosis via down-regulation of cyclin B1/CDC2 kinase expression resulting in reduced Bcl-2 phosphorylation.", "source": "https://pubmed.ncbi.nlm.nih.gov/15135300/"}
{"doc_id": "42fec02a03a414794d003db8641e9586", "sentence": "Combinations of antibiotics with gentamicin or rifampin in vitro did not significantly alter the killing rate but prevented emergence of subpopulations resistant to the latter .", "spans": [{"span_id": 0, "text": "gentamicin", "start": 33, "end": 43, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "rifampin", "start": 47, "end": 55, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Therapy of methicillin-resistant Staphylococcus epidermidis experimental endocarditis. Antibiotic therapy of methicillin-resistant Staphylococcus epidermidis endocarditis was investigated with the rabbit endocarditis model. Time-kill studies in vitro demonstrated that gentamicin and rifampin had the most rapid early bactericidal rates. With rifampin alone, rifampin-resistant subpopulations emerged. Combinations of antibiotics with gentamicin or rifampin in vitro did not significantly alter the killing rate but prevented emergence of subpopulations resistant to the latter . In the rabbit endocarditis model, gentamicin and vancomycin were the most effective single antibiotic regimens in terms of ability to reduce the bacterial densities on cardiac valve vegetations. Five treatment regimens were equally effective, including vancomycin, gentamicin, vancomycin plus rifampin or gentamicin, and rifampin plus gentamicin. The three-drug combination of vancomycin, rifampin, and gentamicin did not significantly improve the results. cephalothin therapy was significantly less effective than any of the regimens noted above. It was no more effective than no treatment at 2 days and was only slightly more effective at 4 days. This result with cephalothin treatment was not predicted by routine types of in vitro antibiotic susceptibility testing. Treatment of rabbits with methicillin or cephalothin was associated with an increase in the subpopulation of bacteria resistant to the respective drugs. A number of regimens show potential for therapy of these infections, including vancomycin plus rifampin or gentamicin, rifampin plus gentamicin, and vancomycin alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/6919570/"}
{"doc_id": "830ca5507df108bc2bbf567931cc475c", "sentence": "This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil ( FU ) and folinic acid ( FA ) as first-line treatment in metastatic colorectal cancer .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 76, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "fluorouracil", "start": 131, "end": 143, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "folinic acid", "start": 155, "end": 167, "token_start": 25, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.  This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil ( FU ) and folinic acid ( FA ) as first-line treatment in metastatic colorectal cancer . ### Patients And Methods Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. ### results Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). ### conclusion oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.", "source": "https://pubmed.ncbi.nlm.nih.gov/14701765/"}
{"doc_id": "d4d5aaea92988a2d24eba988296fde7f", "sentence": "In xenograft studies , the combination of trastuzumab plus letrozole is equally effective in inhibiting growth of MCF-7Ca tumors as letrozole alone .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 42, "end": 53, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "letrozole", "start": 59, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "letrozole", "start": 132, "end": 141, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Trastuzumab reverses letrozole resistance and amplifies the sensitivity of breast cancer cells to estrogen. In this study, we investigated adaptive mechanisms associated with aromatase inhibitor (AI) resistance in breast cancer cells and show that sensitivity to AIs can be extended through dual inhibition of estrogen receptor (ER) and human epidermal receptor-2 (Her-2) signaling. We used human ER-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). These cells grow as tumors in nude mice and are inhibited by AIs. Despite continued treatment, tumors eventually become insensitive to AI letrozole. The cells isolated from these long-term letrozole-treated tumors (LTLT-Ca) were found to have decreased ERalpha levels. Our results suggest that LTLT-Ca cells survive estrogen deprivation by activation of Her-2/mitogen-activated protein kinase (MAPK) pathway. Here, we show that trastuzumab (antibody against Her-2; IC(50) = 0.4 mg/mL) was very effective in restoring the ERalpha levels and sensitivity of LTLT-Ca cells to endocrine therapy by down-regulation of Her-2/MAPK pathway and up-regulation of ERalpha. In contrast, trastuzumab was ineffective in the parental hormone-responsive MCF-7Ca cells (IC(50) = 4.28 mg/mL) and xenografts. By blocking Her-2, trastuzumab also up-regulates ERalpha and aromatase expression and hypersensitized MCF-7Ca cells to E(2). We show that trastuzumab is beneficial in hormone-refractory cells and xenografts by restoring ER, implicating Her-2 as a negative regulator of ERalpha. In xenograft studies , the combination of trastuzumab plus letrozole is equally effective in inhibiting growth of MCF-7Ca tumors as letrozole alone . However, on the acquisition of resistance and increased Her-2 expression, the combination of letrozole plus trastuzumab provided superior benefit over letrozole or trastuzumab alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/19190349/"}
{"doc_id": "5a9c33040304bf924aecd9aea4f0e248", "sentence": "Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL , but not those by other cell death signals , including tumor necrosis factor-alpha and cycloheximide , etoposide , doxorubicin , tunicamycin and staurosporine .", "spans": [{"span_id": 0, "text": "etoposide", "start": 196, "end": 205, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "doxorubicin", "start": 208, "end": 219, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis in tumor cells and holds a promise as a therapeutic agent against cancer. To elucidate the death signaling evoked by TRAIL, we performed a functional genetic screening and rescued TRAIL-resistant Jurkat clones harboring ribosomal protein S6 (rpS6) cDNA in anti-sense frame. Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL , but not those by other cell death signals , including tumor necrosis factor-alpha and cycloheximide , etoposide , doxorubicin , tunicamycin and staurosporine . Death receptor (DR) 4, but not DR5, was downregulated in rpS6 knockdown cells. Conversely, the sensitivity to TRAIL was increased by the ectopic expression of wild-type rpS6 and further by phospho-defective rpS6 mutant (S6-SS235,6AA), but not by phospho-mimic rpS6 mutant (S6-SS235,6DD). Also, unphosphorylatable rpS6 knock-in mouse embryo fibroblasts (rpS6(P-/-) MEFs) were more sensitive to TRAIL than control MEFs. In addition, SKHep-1 tumor cells, which express less phospho-rpS6 and are more sensitive to TRAIL than other tumor cells, became effectively desensitized to TRAIL after rpS6 knockdown. These results suggest that rpS6, especially in its unphosphorylated form, is a selective mediator of TRAIL-induced apoptosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/18362888/"}
{"doc_id": "5a23872a890b090d0faad993a4ddcad4", "sentence": "The patient showed a substantial response to treatment with a combination of antimicrobial therapies consisting of clarithromycin , amikacin , and cefoxitin for 6 months .", "spans": [{"span_id": 0, "text": "clarithromycin", "start": 115, "end": 129, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "amikacin", "start": 132, "end": 140, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "cefoxitin", "start": 147, "end": 156, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Identification of Cutaneous Mycobacterium massiliense Infections Associated with Repeated Surgical Procedures. Mycobacterium massiliense, an emerging pathogen that is increasingly reported as a causative agent in infections occurring during medical procedures, is difficult to be identified using conventional methods. Here we report the case of a cutaneous M. massiliense infection that was associated with repeated surgical procedures and that was identified via a comparative sequence analysis of rpoB and hsp65. The patient showed a substantial response to treatment with a combination of antimicrobial therapies consisting of clarithromycin , amikacin , and cefoxitin for 6 months .", "source": "https://pubmed.ncbi.nlm.nih.gov/20548899/"}
{"doc_id": "08bc2fa158724cdf7c4a1e19c146ecbe", "sentence": "The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa .", "spans": [{"span_id": 0, "text": "levodopa", "start": 116, "end": 124, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "carbidopa", "start": 129, "end": 138, "token_start": 18, "token_end": 19}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Simultaneous high-performance liquid chromatographic analysis of carbidopa, levodopa and 3-O-methyldopa in plasma and carbidopa, levodopa and dopamine in urine using electrochemical detection. Two assay procedures are described for the analysis of levodopa, carbidopa and 3-O-methyldopa in plasma and levodopa, carbidopa and dopamine in urine. The methods are suitable for quantifying the analytes following therapeutic administration of levodopa and carbidopa. Both were based on reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection and with methyldopa as the internal standard. Plasma samples were prepared by perchloric acid precipitation followed by the direct injection of the supernatant. Urine was prepared by alumina adsorption, and the analytes were desorbed with perchloric acid solution containing disodium EDTA and sodium metabisulfite prior to injection into the HPLC system. The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa .", "source": "https://pubmed.ncbi.nlm.nih.gov/2094725/"}
{"doc_id": "7f288b72f1a2e66fe9a29da2975cafbf", "sentence": "Increasing the temperature from 60 \u00b0 C to 100 \u00b0 C decreased the half-life of amoxicillin ( 372 to 50 min ) , ampicillin ( 741 to 26 min ) , cloxacillin ( 367 to 46 min ) , and penicillin G ( 382 to 43 min ) .", "spans": [{"span_id": 0, "text": "amoxicillin", "start": 77, "end": 88, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "ampicillin", "start": 109, "end": 119, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "cloxacillin", "start": 140, "end": 151, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Effect of heat treatments on stability of \u03b2-lactams in milk. The presence of residues of antimicrobial substances in milk may have serious toxicological and technical consequences. To date, few studies have been done to evaluate the effect of heat treatments on \u03b2-lactam residues in milk. However, the few studies that have been conducted estimate losses of antimicrobial activity under different combinations of temperature and time using microbiological methods. The aims of this study were to calculate the kinetic parameters for the degradation of \u03b2-lactam antibiotics in milk and to develop prediction models to estimate the concentration losses of these compounds in conventional dairy heat treatments. To do so, we employed a quantitative HPLC method to calculate losses in concentrations of 10 \u03b2-lactam antibiotics in milk with different combinations of temperature and time. Increasing the temperature from 60 \u00b0 C to 100 \u00b0 C decreased the half-life of amoxicillin ( 372 to 50 min ) , ampicillin ( 741 to 26 min ) , cloxacillin ( 367 to 46 min ) , and penicillin G ( 382 to 43 min ) . These increases in temperature caused further degradation in cephalosporins, which was accompanied by a decrease in half-life times to reach very low values; for instance, 4, 5, and 6 min for cefoperazone, cephurexime, and cephapirin, respectively. Kinetic equations were applied to different heat treatments used in dairy processing. Heat treatments at high temperatures and long times (e.g., 120\u00b0C for 20 min) led to a further degradation of \u03b2-lactam antibiotics with percentages close to 100% for cefoperazone and cefuroxime. In contrast, when milk was subjected to heat treatments at lower temperatures and times (e.g., 72\u00b0C for 15s), the degradation of \u03b2-lactam in milk did not exceed 1% for the 10 antibiotics tested.", "source": "https://pubmed.ncbi.nlm.nih.gov/21338781/"}
{"doc_id": "381196cee26baefb6995f35a4de37b15", "sentence": "Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis .", "spans": [{"span_id": 0, "text": "moxifloxacin", "start": 16, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "levofloxacin", "start": 32, "end": 44, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "pyrazinamide", "start": 101, "end": 113, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Contribution of moxifloxacin or levofloxacin in second-line regimens with or without continuation of pyrazinamide in murine tuberculosis . High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown. ### objectives We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months. ### methods A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ. ### Measurements And Main Results After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log10 lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment. ### conclusions In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months in fluoroquinolone-containing second-line regimens, largely compensating for L's weaker activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/23593945/"}
{"doc_id": "31a108d057dc090881a6478c986ecb28", "sentence": "High-level resistance to quinolones was frequently observed ( 21 % ) , but resistance to erythromycin ( 3 % ) and tetracycline ( 5 % ) was rare .", "spans": [{"span_id": 0, "text": "erythromycin", "start": 89, "end": 101, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "tetracycline", "start": 114, "end": 126, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Campylobacter infections in HIV-infected patients: clinical and bacteriological features. To study the clinical and bacteriological features of Campylobacter infections in HIV-infected patients. ### design A retrospective analysis (1989-1992), followed by a prospective analysis (1992-1994). ### setting Hospital HIV inpatient unit. ### Patients And Methods All patients with Campylobacter spp. identified by the laboratory of microbiology at Saint-Louis Hospital, Paris were studied, and their clinical features as well as their response to therapy recorded. ### results During the study period, Campylobacter infection was documented in 38 HIV-infected patients, 76% of whom had AIDS. Campylobacter spp. was isolated from stools in 36 cases and from blood cultures in four cases. Species identification yielded C. jejuni (84%) and C. coli (16%). High-level resistance to quinolones was frequently observed ( 21 % ) , but resistance to erythromycin ( 3 % ) and tetracycline ( 5 % ) was rare . Diarrhoea, fever and abdominal pain were the main clinical features of infection. Other intestinal pathogens were found in 42% of patients. Most patients had an acute illness with rapid resolution under appropriate antimicrobial therapy. However, eight patients (21%), experienced chronic diarrhoea with persistent isolation of Campylobacter and in vivo selection of resistant strains, requiring multiple courses of antibiotics. ### conclusions Campylobacter usually cause acute diarrhoea in patients with HIV infection. Antimicrobial therapy should be guided on in vitro susceptibility testing because of the prevalence of antibiotic resistance. Despite appropriate therapy, some patients will present with prolonged diarrhoea and in vivo selection of multiresistant isolates.", "source": "https://pubmed.ncbi.nlm.nih.gov/7576322/"}
{"doc_id": "4c60c779d2cfef9da2574018640095c5", "sentence": "The addition of tamoxifen did not worsen the known side effects of gefitinib , or induce additional side effects .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 16, "end": 25, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "gefitinib", "start": 67, "end": 76, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum-taxane based therapy--a phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6). tamoxifen and gefitinib (IRESSA) combination therapy was studied in patients with ovarian cancer refractory or resistant to platinum- and taxane-based therapy. ### Patients And Methods In this phase II study, 56 patients with epithelial ovarian carcinoma or cancer of the fallopian tube or peritoneum received oral tamoxifen 40 mg/day and gefitinib 500 mg/day until progression or unacceptable toxicity. ### results Seventeen patients (mean age: 59.6 years) had previously received first-line platinum/taxane treatment only, while 39 had received 2-8 (median 2) prior chemotherapy regimens. gefitinib dose reduction to 250 mg/day was performed in 10 patients (14.9%), predominantly due to diarrhea (6 patients [10.7%]). Trial medication was discontinued in 6 patients (10.7%) due to adverse events (AEs). The most frequent drug-related AEs were diarrhea and acne-like skin rash. There were no tumor responses, but 16 patients had stable disease. Median time-to-progression was 58 days (95% CI, 55-71 days) and median survival was 253 days (95% CI, 137-355 days). ### conclusion gefitinib plus tamoxifen did not appear to be efficacious in the treatment of patients with refractory/resistant ovarian cancer. The addition of tamoxifen did not worsen the known side effects of gefitinib , or induce additional side effects .", "source": "https://pubmed.ncbi.nlm.nih.gov/17161453/"}
{"doc_id": "72fd0bfc3ea97cb4d9ed0ee4850e2bd3", "sentence": "A topical combination of 0.25 % finasteride and 3 % minoxidil may be a promising option in the treatment of FPHL with an additional benefit of increasing hair diameter .", "spans": [{"span_id": 0, "text": "finasteride", "start": 32, "end": 43, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "minoxidil", "start": 52, "end": 61, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Efficacy of Topical Combination of 0.25% Finasteride and 3% Minoxidil Versus 3% Minoxidil Solution in Female Pattern Hair Loss: A Randomized, Double-Blind, Controlled Study. The relationship between female pattern hair loss (FPHL) and androgenic hormones is not well established, but some evidence indicates oral finasteride may be efficacious in FPHL. Use of a topical formulation has been proposed to minimize unwanted effects. ### objectives Our objective was to compare the efficacy and safety of topical 0.25% finasteride combined with 3% minoxidil solution and 3% minoxidil solution as monotherapy in the treatment of FPHL. ### methods This was a prospective, randomized, double-blind study in 30 postmenopausal women with FPHL. Each participant was randomized to receive either topical 0.25% finasteride combined with topical 3% minoxidil or topical 3% minoxidil solution as monotherapy for 24\u00a0weeks. To determine efficacy, the hair density and diameter was measured and global photographic assessment was conducted at baseline and 8, 16, and 24\u00a0weeks. Side effects and serum dihydrotestosterone levels were also evaluated. ### results By 24\u00a0weeks, hair density and diameter had increased in both groups, and finasteride/minoxidil was significantly superior to minoxidil solution in terms of hair diameter (p\u2009=\u20090.039). No systemic side effects were reported. However, serum dihydrotestosterone levels in the finasteride/minoxidil group significantly decreased from baseline (p\u2009=\u20090.016). ### conclusion A topical combination of 0.25 % finasteride and 3 % minoxidil may be a promising option in the treatment of FPHL with an additional benefit of increasing hair diameter . Nevertheless, as it may be absorbed percutaneously, it should be reserved for postmenopausal women. ### Trial Registration clinicaltrials.in.th; identifier TCTR20160912002.", "source": "https://pubmed.ncbi.nlm.nih.gov/30206824/"}
{"doc_id": "4d71f06710452ec611d9616f759b359f", "sentence": "This report is the first about the long-term use of dasatinib in patients with Ph+ all and mrd elevation but hematologic remission during imatinib chemotherapy .", "spans": [{"span_id": 0, "text": "dasatinib", "start": 52, "end": 61, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "imatinib", "start": 138, "end": 146, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Dasatinib for a child with Philadelphia chromosome-positive acute lymphoblastic leukemia and persistently elevated minimal residual disease during imatinib therapy. imatinib has improved outcomes in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (all). Minimal residual disease (mrd) is a useful tool for predicting leukemia relapse. However, there is no consensus on how to treat children with elevation of BCR-ABL transcripts but no evidence of hematologic relapse during chemotherapy combined with imatinib. Here, we report the case of a child with Ph+ all who had persistent elevation of mrd, but no evidence of hematologic relapse while receiving imatinib plus intensive chemotherapy. dasatinib was substituted for imatinib because no suitable donor for allogeneic hematopoietic stem-cell transplantation (hsct) was available. Less-intensive chemotherapy with methotrexate and 6-mercaptopurine was administered concomitantly. No serious adverse events were encountered. With continuous dasatinib combined with chemotherapy, but no allogeneic hsct, our patient reached complete molecular remission and has been in complete molecular remission for more than 13 months. This report is the first about the long-term use of dasatinib in patients with Ph+ all and mrd elevation but hematologic remission during imatinib chemotherapy . In a similar situation, chemotherapy combined with dasatinib instead of allogeneic hsct could be considered to avoid hsct-related mortality and morbidity. Clinical trials are needed.", "source": "https://pubmed.ncbi.nlm.nih.gov/26300669/"}
{"doc_id": "7e0de118f601e9e5d0fca43b872b1a77", "sentence": "Acute verapamil toxicity in a patient with chronic toxicity : possible interaction with ceftriaxone and clindamycin .", "spans": [{"span_id": 0, "text": "verapamil", "start": 6, "end": 15, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "ceftriaxone", "start": 88, "end": 99, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "clindamycin", "start": 104, "end": 115, "token_start": 15, "token_end": 16}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Acute verapamil toxicity in a patient with chronic toxicity : possible interaction with ceftriaxone and clindamycin . To report a case of acute toxicity in a patient with chronic verapamil toxicity, possibly precipitated by intravenous administration of the highly protein-bound drugs ceftriaxone and clindamycin. ### Data Sources Case reports, review articles, and relevant laboratory and clinical studies identified by MEDLINE (1984-forward), and relevant cross references from those articles. ### Data Extraction Data were abstracted from pertinent sources by one author and reviewed by the remaining authors. ### Case Summary A 59-year-old man who had been receiving sustained-release verapamil 240 mg q12h for more than two years for hypertension, and phenytoin 300 mg/d for many years for prophylaxis against seizures, was noted to be in junctional rhythm when he presented to the emergency room with bilateral pneumonia. Administration of intravenous ceftriaxone 1 g and clindamycin 900 mg precipitated symptoms of acute verapamil toxicity in this patient. The toxicity led to complete heart block requiring cardiopulmonary resuscitation and insertion of a temporary pacemaker. He spontaneously reverted to normal sinus rhythm after 16 hours. Subsequent cardiac evaluation, including echocardiogram, 48-hour dynamic electrocardiographic recording (Holter), and exercise stress test were normal. The patient has remained in sinus rhythm for more than one year after this episode. ### conclusions We believe that junctional rhythm on admission was a result of chronic verapamil toxicity. This may have been because of increased bioavailability of the drug or increased sensitivity of the receptors. Administration of ceftriaxone, clindamycin, or both agents might have precipitated acute verapamil toxicity by displacing verapamil from its protein-binding sites. Extreme caution is necessary when a highly protein-bound drug is given to a patient already receiving verapamil.", "source": "https://pubmed.ncbi.nlm.nih.gov/8364267/"}
{"doc_id": "06dac7461e1acaebd6a082e3d469f6da", "sentence": "Eighty-three patients were treated with rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-CHOP ) , 7 with rituximab , etoposide , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-EPOCH ) , and 6 with R-CHOP with methotrexate , 3 g/m(2 ) .", "spans": [{"span_id": 0, "text": "rituximab", "start": 40, "end": 49, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "cyclophosphamide", "start": 52, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "doxorubicin", "start": 71, "end": 82, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "vincristine", "start": 85, "end": 96, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "prednisone", "start": 99, "end": 109, "token_start": 13, "token_end": 14}, {"span_id": 5, "text": "R-CHOP", "start": 112, "end": 118, "token_start": 15, "token_end": 16}, {"span_id": 6, "text": "rituximab", "start": 130, "end": 139, "token_start": 20, "token_end": 21}, {"span_id": 7, "text": "etoposide", "start": 142, "end": 151, "token_start": 22, "token_end": 23}, {"span_id": 8, "text": "cyclophosphamide", "start": 154, "end": 170, "token_start": 24, "token_end": 25}, {"span_id": 9, "text": "doxorubicin", "start": 173, "end": 184, "token_start": 26, "token_end": 27}, {"span_id": 10, "text": "vincristine", "start": 187, "end": 198, "token_start": 28, "token_end": 29}, {"span_id": 11, "text": "prednisone", "start": 201, "end": 211, "token_start": 30, "token_end": 31}, {"span_id": 12, "text": "methotrexate", "start": 249, "end": 261, "token_start": 40, "token_end": 41}, {"span_id": 13, "text": "R-CHOP", "start": 237, "end": 243, "token_start": 38, "token_end": 39}], "rels": [{"class": "NEG", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}, {"class": "NEG", "spans": [6, 7, 8, 9, 10, 11], "is_context_needed": true}, {"class": "NEG", "spans": [12, 13], "is_context_needed": true}], "paragraph": "De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort. De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-CHOP ) , 7 with rituximab , etoposide , cyclophosphamide , doxorubicin , vincristine , prednisone ( R-EPOCH ) , and 6 with R-CHOP with methotrexate , 3 g/m(2 ) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/26800311/"}
{"doc_id": "a48033035346a4791fd19c2ed770d582", "sentence": "More active therapies are needed for older and unfit patients with chronic lymphocytic leukemia ( CLL ) who are not eligible for chemoimmunotherapy with fludarabine , cyclophosphamide , and rituximab .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 153, "end": 164, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "cyclophosphamide", "start": 167, "end": 183, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "rituximab", "start": 190, "end": 199, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Outcomes of patients with chronic lymphocytic leukemia treated with first-line idelalisib plus rituximab after cessation of treatment for toxicity.  More active therapies are needed for older and unfit patients with chronic lymphocytic leukemia ( CLL ) who are not eligible for chemoimmunotherapy with fludarabine , cyclophosphamide , and rituximab . The phosphyotidylinositol-3-kinase \u03b4 inhibitor idelalisib is effective in patients with treatment-naive and relapsed/refractory CLL as monotherapy and in combination with rituximab, but it can be associated with treatment-limiting adverse events, particularly diarrhea/colitis. The outcomes for patients who cease treatment for adverse events have not been previously described. ### methods The authors analyzed long-term follow-up data from 40 treatment-na\u00efve patients aged \u226565 years who received treatment at The University of Texas MD Anderson Cancer Center on a phase 2 study of idelalisib plus rituximab for CLL. ### results In patients who permanently ceased treatment because of toxicity, the time to subsequent disease progression was analyzed according to baseline characteristics. Fifteen patients permanently ceased therapy (PCT) because of toxicity (PCTTOX ), most commonly diarrhea/colitis (n = 7), at a median of 11 months after commencing treatment. PCTTOX was associated with a higher risk of subsequent disease progression (hazard ratio, 6.61; 95% confidence interval, 1.77-16.15) relative to that observed in patients who remained on therapy. Ten patients subsequently progressed, and 7 required salvage therapy; 5 patients remained progression-free at a median of 23.3 months (range, 8.5-28.6 months). Patients who were positive for \u03b6-associated protein-70 had more rapid disease progression after treatment cessation (P = .048). There were no CLL-related deaths. ### conclusions PCTTOX is the major determinant of PFS in patients who receive first-line idelalisib-based treatment. However, a subgroup of patients with favorable biologic characteristics has prolonged PFS, even after PCTTOX . The absence of CLL-related deaths indicates that salvage treatment is generally successful after PCTTOX . Cancer 2016;122:2505-11. \u00a9 2016 American Cancer Society.", "source": "https://pubmed.ncbi.nlm.nih.gov/27182988/"}
{"doc_id": "5b7841090a61ffbb76316003d172ae52", "sentence": "Among them , 18 ( 85.7 % ) patients had disease control with gefitinib and 12 ( 57.1 % ) patients with salvage erlotinib .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 61, "end": 70, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "erlotinib", "start": 111, "end": 120, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer. Chemotherapy is the mainstay treatment for advanced non-small cell lung cancer (NSCLC). gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been recently shown to be effective as a first-line treatment in Asian patients with advanced NSCLC, especially for those with favourable clinical features such as female, non-smoker and adenocarcinoma. However, resistance to gefitinib ensues invariably and there is little evidence as for the effectiveness of subsequent salvage treatment. The purpose of this study is to evaluate the efficacy of erlotinib, another EGFR-TKI, after failed first-line use of gefitinib. ### method Retrospective review of NSCLC patients with favourable clinical features who received gefitinib as first-line treatment and subsequent salvage treatment with erlotinib. ### results A total of 21 patients with NSCLC were included in the study. Among them , 18 ( 85.7 % ) patients had disease control with gefitinib and 12 ( 57.1 % ) patients with salvage erlotinib . There was an association between the disease control with gefitinib and erlotinib (p = 0.031). The disease control rate of erlotinib was independent of the chemotherapy use between the two EGFR-TKIs. ### conclusion For NSCLC patients with favourable clinical features, erlotinib was effective in those who had prior disease control with first-line gefitinib.", "source": "https://pubmed.ncbi.nlm.nih.gov/19680652/"}
{"doc_id": "3f238468374dde345c8746618ac78e38", "sentence": "In addition to its reproductive function , kisspeptin signalling is also involved in extra-hypothalamic-pituitary-gonadal ( HPG ) axis systems , including oxytocin and arginine vasopressin ( AVP ) secretion .", "spans": [{"span_id": 0, "text": "oxytocin", "start": 155, "end": 163, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "vasopressin", "start": 177, "end": 188, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Mapping of Kisspeptin Receptor mRNA in the Whole Rat Brain and its Co-Localisation with Oxytocin in the Paraventricular Nucleus. The neuropeptide kisspeptin and its receptor play an essential role in reproduction as a potent modulator of the gonadotrophin-releasing hormone (GnRH) neurone. In addition to its reproductive function , kisspeptin signalling is also involved in extra-hypothalamic-pituitary-gonadal ( HPG ) axis systems , including oxytocin and arginine vasopressin ( AVP ) secretion . By contrast to the accumulating information for kisspeptin neurones and kisspeptin fibres, the histological distribution and function of the kisspeptin receptor in the rat brain remain poorly characterised. Using in\u00a0situ hybridisation combined with immunofluorescence, the present study aimed to determine the whole brain map of Kiss1r mRNA (encoding the kisspeptin receptor), and to examine whether oxytocin or AVP neurones express Kiss1r. Neurones with strong Kiss1r expression were observed in several rostral brain areas, including the olfactory bulb, medial septum, diagonal band of Broca and throughout the preoptic area, with the most concentrated population being around 0.5\u00a0mm rostral to the bregma. Co-immunofluorescence staining revealed that, in these rostral brain areas, the vast majority of the Kiss1r-expressing neurones co-expressed GnRH. Moderate levels of Kiss1r mRNA were also noted in the rostral periventricular area, paraventricular nucleus (PVN), and throughout the arcuate nucleus. Relatively weak Kiss1r expression was observed in the supraoptic nucleus and supramammillary nuclei. Moderate to weak expression of Kiss1r was also observed in several regions in the midbrain, including the periaqueductal gray and dorsal raphe nucleus. We also examined whether oxytocin and AVP neurones in the PVN co-express Kiss1r. Immunofluorescence revealed the co-expression of Kiss1r in a subset of the oxytocin neurones but not in the AVP neurones in the PVN. The present study provides a fundamental anatomical basis for further examination of the kisspeptin signalling system in the extra-HPG axis, as well as in reproductive function.", "source": "https://pubmed.ncbi.nlm.nih.gov/26709462/"}
{"doc_id": "e5a7cebcf893355e7a916810c41d4fd6", "sentence": "The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy .", "spans": [{"span_id": 0, "text": "volasertib", "start": 19, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "pemetrexed", "start": 35, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "pemetrexed", "start": 85, "end": 95, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer. Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy . ### introduction volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy. ### Patients And Methods A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), or pemetrexed (n = 47) administered on day 1 every 21 days. The primary end point was progression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics. ### results volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4 months with volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed. ### conclusion For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed.", "source": "https://pubmed.ncbi.nlm.nih.gov/26100229/"}
{"doc_id": "2203a64a832c5f247dd8231046b2e400", "sentence": "A phase I/II study was carried out to determine the maximum tolerated dose of paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) in combination with a fixed dose of carboplatin ( area under the concentration-time curve = 6 by Calvert method ) given on an every-3-week schedule to patients with non-small cell lung cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 78, "end": 88, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "carboplatin", "start": 183, "end": 194, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Preliminary results of a phase I/II clinical trial of paclitaxel and carboplatin in non-small cell lung cancer.  A phase I/II study was carried out to determine the maximum tolerated dose of paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) in combination with a fixed dose of carboplatin ( area under the concentration-time curve = 6 by Calvert method ) given on an every-3-week schedule to patients with non-small cell lung cancer ( NSCLC ) . Cohorts of patients were entered at increasing dose levels of paclitaxel: six at dose level I (paclitaxel 150 mg/m2), six at dose level 2 (paclitaxel 175 mg/m2), 11 at dose level 3 (paclitaxel 200 mg/ m2), 21 at dose level 4 (paclitaxel 225 mg/m2), and five at dose level 5 (paclitaxel 250 mg/m2). The patients comprised 31 men and 18 women with a median age of 62 years (age range, 46 to 81 years) and a median Southwest Oncology Group performance status of I (range, 0 to 2). Twenty-three patients had unresectable stage III NSCLC and 26 had stage IV NSCLC. Fortynine patients and 176 treatment courses are evaluable for toxicity. Grade 4 neutropenia or grade 3 arthralgias/ myalgias or sensory neuropathy were the most significant toxicities of therapy. In addition, two patients (dose levels 2 and 3) experienced acute chest pain, flushing, and hypotension, and had electrocardiogram changes during the paclitaxel infusion; one had mild creatine phosphokidnase MB elevation. Both recovered uneventfully, were not re-treated with paclitaxel, and account for two of only four hospitalizations for toxicity management in this trial. At this time, 42 patients with objectively measurable disease are evaluable for responses: two complete responses and 24 partial responses (62% objective response rate) have been observed. These data imply that the maximum tolerated dose of paclitaxel is 250 mg/m2 with dose-limiting toxicity consisting primarily of grade 3 osteo/arthralgias-myalgias or cumulative sensory neuropathy; paclitaxel at a dose of 225 mg/m2 given by 3-hour infusion combined with carboplatin at a calculated target area under the concentration-time curve of 6 is a well-tolerated outpatient treatment regimen and highly active in NSCLC; myelosuppression is mild and rarely dose limiting. Most notably, paclitaxel appears to decrease carboplatin's pharmacodynamic effects on thrombopoiesis.", "source": "https://pubmed.ncbi.nlm.nih.gov/8941402/"}
{"doc_id": "50f8baf7b85a4496d160a40dbd68f5f3", "sentence": "These results suggest that therapy with insulin plus dexamethasone but not therapy with leptin is beneficial for diabetics .", "spans": [{"span_id": 0, "text": "dexamethasone", "start": 53, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "leptin", "start": 88, "end": 94, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "insulin", "start": 40, "end": 47, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "The relationship between nitric oxide and leptin in the lung of rat with streptozotocin-induced diabetes. Lung structural changes and immunoreactivity of endothelial (eNOS)- and inducible nitric oxide synthase (iNOS) were investigated by light microscopy in lungs of treated and untreated diabetic rats. Diabetes was induced by a single intraperitoneal (i.p.) injection of 65 mg kg(-1) streptozotocin (STZ) in Wistar albino male rats. Diabetic rats received daily i.p. doses of dexamethasone (2 mg kg(-1)), leptin (0.5 microg kg(-1)) and intramuscular insulin (20 U kg(-1)) or a combination of these drugs for 1 week starting 4 weeks after the STZ injections. After treatment, the blood levels of glucose, leptin, insulin and nitrate/nitrite (NO(3) (-)/NO(2) (-)) were measured. Dilatation of alveoli and alveolar ducts, partial alveolar wall thickening and increased eNOS- and iNOS characterized the diabetic rat lungs. High blood glucose and nitrate/nitrite levels as well as low insulin and leptin levels were also present. Treatment with insulin, dexamethasone and a combination of these drugs resulted in improvement of the structural and immunohistochemical abnormalities. The most effective treatment was insulin therapy. leptin administration resulted in increased relative amounts of extracellular material, which led to noticeable respiratory efficiency in the diabetic rat lungs. All treatments except leptin lowered blood glucose levels. The combination of insulin and dexamethasone increased blood leptin and insulin, while the remaining diabetic rats had blood with low leptin and insulin concentrations. These results suggest that therapy with insulin plus dexamethasone but not therapy with leptin is beneficial for diabetics .", "source": "https://pubmed.ncbi.nlm.nih.gov/17542037/"}
{"doc_id": "cda1528c8e375d23ab4a92907786db43", "sentence": "After the first course of treatment , a statistically significant improvement ( p = 0.002 ) in the psychological subscale scores was observed after ondansetron compared with metoclopramide .", "spans": [{"span_id": 0, "text": "ondansetron", "start": 148, "end": 159, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "metoclopramide", "start": 174, "end": 188, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. This was a multicentre, randomised, double-blind, parallel-group study which included female breast cancer patients, receiving their first of 6 scheduled courses of chemotherapy (cyclophosphamide greater than or equal to 500 mg/m2). Patients received an intravenous dose of 16 mg dexamethasone with either 8 mg ondansetron or 60 mg metoclopramide before chemotherapy, followed by oral dosing with 8 mg ondansetron or 20 mg metoclopramide 3 times daily for 5 days. A total of 93 patients were treated with ondansetron and 94 patients with metoclopramide. On day 1 of their first course of treatment 91 and 60% of patients in the ondansetron and metoclopramide groups respectively were free of emesis (p less than 0.001). Over the 5-day treatment period, the corresponding figures were 81 and 48% (p less than 0.001). The results for nausea also revealed highly statistically significant treatment differences (p less than 0.001) in favour of ondansetron for both day 1 and day 1-5 analyses of the first treatment course. Over the series of courses, 67% of patients receiving ondansetron completed all 6 courses with a maximum of 2 emetic episodes on their worst day, compared with 28% of patients receiving metoclopramide (p less than 0.001). A similar analysis for nausea revealed that 49% of patients receiving ondansetron completed all 6 courses with 'none' or 'mild' nausea compared with 27% of patients receiving metoclopramide (p less than 0.001). These differences were reflected in quality of life data (Rotterdam Symptom Checklist). After the first course of treatment , a statistically significant improvement ( p = 0.002 ) in the psychological subscale scores was observed after ondansetron compared with metoclopramide . No differences were observed in the physical or functional activity subscales after the first course. However, the quality of life results over the series of courses revealed a more pronounced difference in favour of ondansetron in the psychological subscale scores (p less than 0.001) as well as trends in favour of ondansetron in the physical (p = 0.096) and functional activity (p = 0.056) subscales. Extrapyramidal symptoms were reported in 19% of patients in the metoclopramide group and resulted in 15% of patients withdrawing from their randomised anti-emetic schedule, either during or between treatment courses. Other adverse events were generally minor in nature and did not necessitate withdrawal from treatment. In conclusion, this study shows that ondansetron is significantly superior to metoclopramide (each with a single pre-treatment dose of dexamethasone) in the control of emesis over 6 courses of chemotherapy for breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/1387929/"}
{"doc_id": "8394cbf1a7ef9d49fdf46ec0121b08db", "sentence": "The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group , but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine .", "spans": [{"span_id": 0, "text": "venetoclax", "start": 222, "end": 232, "token_start": 37, "token_end": 38}, {"span_id": 1, "text": "bendamustine", "start": 243, "end": 255, "token_start": 40, "token_end": 41}], "rels": [], "paragraph": "Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. ### methods In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. ### results After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group , but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine . The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). ### conclusions Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).", "source": "https://pubmed.ncbi.nlm.nih.gov/29562156/"}
{"doc_id": "fb834baa1bb0f848711c6b8bd0faecd0", "sentence": "This study investigated the efficacy and toxicity associated with consolidation chemotherapy using paclitaxel and carboplatin after concurrent chemoradiation ( CCR ) in cervical cancer patients .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 99, "end": 109, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "carboplatin", "start": 114, "end": 125, "token_start": 14, "token_end": 15}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II Study of Consolidation Chemotherapy after Adjuvant or Primary Concurrent Chemoradiation Using Paclitaxel and Carboplatin to Treat High-Risk Early-Stage or Locally Advanced Cervical Cancer.  This study investigated the efficacy and toxicity associated with consolidation chemotherapy using paclitaxel and carboplatin after concurrent chemoradiation ( CCR ) in cervical cancer patients . ### Materials And Methods From a total of 37 patients, 19 with International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA cervical cancer (group 1) underwent surgery followed by consolidation chemotherapy after CCR, and 18 with stage IIB-IVA disease (group 2) received consolidation chemotherapy after primary CCR. Three cycles of chemotherapy using paclitaxel (135 mg/m(2)) and carboplatin (AUC 5.0) were administered every 3 weeks for CCR therapy, and three cycles of consolidation chemotherapy using paclitaxel (175 mg/m(2)) and carboplatin (AUC 5.0) were used every 3 weeks after CCR. ### results The complete and partial response rates were 77.8% and 22.2% in group 2. Moreover, the 3-year progression-free and overall survival rates were 62.7% and 90.9% in group 1, and 51.9% and 60% in group 2, respectively. The most common grade 3 or 4 hematologic toxicities observed were leukopenia (group 1, 10.5%; group 2, 13.0%) and neutropenia (group 1, 7.0%; group 2, 14.8%), and grade 3 or 4 diarrhea (group 1, 1.8%) and febrile illness (group 2, 1.9%) were the most frequently observed non-hematologic toxicities. When we compared these results with previous reports, consolidation chemotherapy after CCR using paclitaxel and carboplatin revealed a relatively lower complete response rate (77.8% vs. 87-100%, respectively) and shorter progression-free survival (51.9-62.7% vs. 81-86%, respectively) and overall survival (60-90.9% vs. 81-95%, respectively) in spite of similar toxicity findings. ### conclusion Due to low efficacy results, consolidation chemotherapy using paclitaxel and carboplatin after CCR is not a feasible treatment regimen for high-risk early-stage or locally advanced cervical cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/22802747/"}
{"doc_id": "b523382f44b1db749bb1508120a819b6", "sentence": "These secondary leukemias associated with topoisomerase II inhibitors ( most commonly teniposide , etoposide , or doxorubicin ) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors .", "spans": [{"span_id": 0, "text": "teniposide", "start": 86, "end": 96, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "etoposide", "start": 99, "end": 108, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "doxorubicin", "start": 114, "end": 125, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. The MLL gene located at 11q23 is frequently disrupted by chromosomal translocation in a wide spectrum of newly diagnosed acute leukemias. Recently, it has become apparent that the MLL gene is very frequently disrupted by chromosomal translocations in patients with secondary leukemias associated with chemotherapeutic regimens incorporating topoisomerase II inhibitors. These secondary leukemias associated with topoisomerase II inhibitors ( most commonly teniposide , etoposide , or doxorubicin ) have distinct clinical and biologic features which have led to the speculation that they are induced by treatment with topoisomerase II inhibitors . We have identified a site within the MLL breakpoint cluster region (bcr) that is highly sensitive to double-strand DNA cleavage induced by topoisomerase II inhibitors. This finding is quite specific and highly reproducible. Although it was initially discovered in malignant lymphoblasts isolated from a patient receiving multiagent chemotherapy, this site-specific double-strand DNA cleavage can be induced in tissue culture using malignant cell lines as well as peripheral blood from normal individuals. Site-specific cleavage occurs in a significant fraction of cells using a variety of model systems, is both time and dose dependent, and can be induced with either doxorubicin or etoposide. This site-specific cleavage maps to the same region as a consensus topoisomerase II cleavage site within the MLL bcr. These results suggest that site specific cleavage within the MLL bcr induced by topoisomerase II inhibitors may be an early step leading to MLL translocations and secondary leukemia.", "source": "https://pubmed.ncbi.nlm.nih.gov/8639880/"}
{"doc_id": "142b4a6fe75ee059396d3428fc9b4f40", "sentence": "In the intention to treat analysis , 14 patients receiving praziquantel were cured compared with none with mefloquine , one with artesunate ( odds ratio 0\u00b703 , 95 % CI 0\u00b7004 - 0\u00b729 ) , one with mefloquine-artesunate ( 0\u00b703 , 0\u00b7004 - 0\u00b729 ) , and 19 with tribendimidine ( 1\u00b787 , 0\u00b760 - 5\u00b785 ) .", "spans": [{"span_id": 0, "text": "praziquantel", "start": 59, "end": 71, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "mefloquine", "start": 107, "end": 117, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "artesunate", "start": 129, "end": 139, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, tribendimidine, and praziquantel in patients with Opisthorchis viverrini: a randomised, exploratory, open-label, phase 2 trial. praziquantel is the only drug available for treatment of Opisthorchis viverrini, although in-vivo studies point to activity of mefloquine, artesunate, and tribendimidine against this liver fluke. We aimed to assess the efficacy and safety of these drugs compared with that of praziquantel in patients with O viverrini infection. ### methods We did a randomised open-label trial between February and April, 2010, in the Saysetha district, Attapeu Province, Laos. Eligible patients were school children aged 10-15 years who had O viverrini infections. Patients were randomly assigned to one of five different treatment groups by use of a computer-generated randomisation code. We assessed efficacy as cure rate and egg reduction rate in intention-to-treat and per-protocol analyses. The trial was registered with Current Controlled Trials, ISRCTN23425032. ### results 125 children were randomly assigned: 25 received mefloquine, 24 artesunate, 24 mefloquine-artesunate, 27 tribendimidine, and 25 praziquantel. 19 patients were lost to follow-up. In the intention to treat analysis , 14 patients receiving praziquantel were cured compared with none with mefloquine , one with artesunate ( odds ratio 0\u00b703 , 95 % CI 0\u00b7004 - 0\u00b729 ) , one with mefloquine-artesunate ( 0\u00b703 , 0\u00b7004 - 0\u00b729 ) , and 19 with tribendimidine ( 1\u00b787 , 0\u00b760 - 5\u00b785 ) . Egg reduction rate was 98\u00b74% for praziquantel, 30\u00b72% for mefloquine (egg reduction-rate ratio 1\u00b761, 95% CI 0\u00b721-0\u00b772), 31\u00b75% for artesunate (0\u00b743, 0\u00b723-0\u00b780), 41\u00b73% for mefloquine-artesunate (0\u00b760, 0\u00b731-1\u00b710), and 99\u00b73% for tribendimidine (1\u00b700, 0\u00b744-2\u00b730). Most adverse events were mild or moderate and affected all treatment groups; serious adverse events--vertigo, nausea, vomiting, and anxiety--were reported only by patients taking mefloquine or mefloquine-artesunate. ### interpretation Tribendimidine seems to be at least as efficacious as the drug of choice, praziquantel, for the treatment of O viverrini infections; both drugs were well tolerated. mefloquine, artesunate, and mefloquine-artesunate did not show an effect. Tribendimidine should be further investigated with large clinical trials. ### funding Swiss National Science Foundation, University of Basel.", "source": "https://pubmed.ncbi.nlm.nih.gov/21111681/"}
{"doc_id": "530b2e275ea93cb02f8d259bdf63376b", "sentence": "Cladribine with Granulocyte Colony-Stimulating Factor , Cytarabine , and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia : A Phase II Multicenter Study .", "spans": [{"span_id": 0, "text": "Cladribine", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "Granulocyte Colony-Stimulating Factor", "start": 16, "end": 53, "token_start": 2, "token_end": 5}, {"span_id": 2, "text": "Cytarabine", "start": 56, "end": 66, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "Aclarubicin", "start": 73, "end": 84, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Cladribine with Granulocyte Colony-Stimulating Factor , Cytarabine , and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia : A Phase II Multicenter Study . Studies targeting cladribine in combination with granulocyte colony-stimulating factor, low-dose cytarabine, and aclarubicin (C-CAG) regimen in relapsed and refractory acute myeloid leukemia (R/R AML) are limited. The complete remission rate after two cycles of C-CAG regimen was 67.6%, and 1-year overall survival and disease-free survival rates were 59.7% and 72.9%, respectively. The C-CAG regimen is significantly effective against R/R AML with a low hematological toxicity and thus serves as an alternative treatment for R/R AML. ### background The optimal salvage chemotherapy regimen for relapsed and refractory acute myeloid leukemia (R/R AML) remains uncertain. Therefore, a phase II study was conducted for the prospective evaluation of the efficacy and safety of the purine analog cladribine in combination with granulocyte colony-stimulating factor (G-CSF), low-dose cytarabine, and aclarubicin (C-CAG) regimen for patients with R/R AML. ### methods A total of 34 patients received C-CAG regimen for salvage treatment as follows: cladribine 5 mg/m ### results All patients received at least two cycles of C-CAG regimen chemotherapy. After two cycles of C-CAG, 23 patients (67.6%) achieved CR, and 5 patients had partial remission (14.7%). At a median follow-up of 15 months (range, 3-38 months), the 1-year overall survival (OS) and disease-free survival (DFS) rates were 59.7% (95% confidence interval [CI], 42.6%-76.8%) and 72.9% (95% CI, 54.3%-91.5%), respectively. The most common adverse effect was myelosuppression. Nonhematological toxicities were mild, and no treatment-related deaths occurred. ### conclusion Preliminary data indicate that the C-CAG regimen chemotherapy is significantly effective against R/R AML with a high remission rate and a low hematological toxicity. Thus, it may serve as an alternative treatment for R/R AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/32845551/"}
{"doc_id": "ed8e174892bfa279bc6dff6ead1b951f", "sentence": "In guinea pig trachea and human bronchial smooth muscle , SALM was more potent than isoprenaline ( ISO ) , salbutamol ( SALB ) , and clenbuterol ( CLEN ) .", "spans": [{"span_id": 0, "text": "isoprenaline", "start": 84, "end": 96, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "salbutamol", "start": 107, "end": 117, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "The pharmacology of salmeterol. The pharmacology of salmeterol hydroxynaphthoate (SALM) has been investigated in respiratory tissues in vitro and in animal models in vivo. In guinea pig trachea and human bronchial smooth muscle , SALM was more potent than isoprenaline ( ISO ) , salbutamol ( SALB ) , and clenbuterol ( CLEN ) . The duration of action was greater than 7 h, whereas that for ISO, SALB, and CLEN was 2, 11, and 45 min, respectively. The sustained activity of SALM was reversed by sotalol, but was reestablished when the beta-blocker was removed. SALM was greater than 3000-fold weaker than ISO in cardiac tissues, indicating high beta 2-adrenoceptor selectivity. In the conscious guinea pig, aerosolized SALM, SALB, and CLEN caused dose-related bronchodilatation. The activity of SALM persisted for at least 6 h, compared with less than 2 h for SALB and CLEN. SALM is also a potent inhibitor of mediator release from human lung, this effect being sustained for up to 20 hours. In guinea pig airways in vivo, SALM inhibited histamine-induced plasma protein extravasation for approximately 8 h. salmeterol is a potent and selective beta 2-adrenoceptor agonist with a unique profile of action. It induces persistent bronchodilatation, sustained suppression of mediator release, and long-lasting inhibition of edema formation. This combination of properties may represent an important new advance in the treatment of bronchial asthma.", "source": "https://pubmed.ncbi.nlm.nih.gov/1974668/"}
{"doc_id": "7e4324b597ca970932933e012a25644d", "sentence": "Combining erlotinib with doxorubicin or docetaxel or SN-38 resulted in additive or even synergistic antiproliferative effects .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 10, "end": 19, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "doxorubicin", "start": 25, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "docetaxel", "start": 40, "end": 49, "token_start": 5, "token_end": 6}, {"span_id": 3, "text": "SN-38", "start": 53, "end": 58, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 3], "is_context_needed": false}], "paragraph": "Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5-year-survival new therapeutic approaches are urgently needed. Recently, evidence has been accumulated that the epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. Several reports indicate that EGFRs are expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors. ### methods erlotinib, an inhibitor of EGFR-tyrosine kinase, potently suppresses the growth of various tumors, but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of erlotinib in human HCC cells (Huh-7 and HepG2 cell lines). ### results We show that erlotinib inhibited HCC growth in a time- and dose-dependent manner. Moreover erlotinib treatment induced apoptosis and resulted in a dose-dependent arrest at the G1/S checkpoint of the cell cycle. Combining erlotinib with doxorubicin or docetaxel or SN-38 resulted in additive or even synergistic antiproliferative effects . ### conclusions Our data demonstrate that in human HCC cells the inhibition of EGFR-tyrosine kinase by erlotinib induces growth inhibition, apoptosis and cell cycle arrest. Additionally, erlotinib enhances the antineoplastic activity of conventional cytostatic drugs. Thus, inhibiting EGFR-tyrosine kinase appears to be a promising treatment strategy in HCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/16023762/"}
{"doc_id": "8f4e4e227dec85d45c10f67b403c5305", "sentence": "Importantly , the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children ( 45 % vs. 6 % ; p < .001 ) .", "spans": [{"span_id": 0, "text": "artesunate", "start": 81, "end": 91, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "amodiaquine", "start": 97, "end": 108, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. artemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)-infected populations. ### methods We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. ### results Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; p = .08). Importantly , the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children ( 45 % vs. 6 % ; p < .001 ) . The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, <750 cells/mm(3)). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; p < .001). ### conclusions artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals.", "source": "https://pubmed.ncbi.nlm.nih.gov/18444813/"}
{"doc_id": "c9295160c182a59fb221a758c0844948", "sentence": "During this period , blood pressure ( BP ) was monitored weekly , and daily rhythms of melatonin , corticosterone , leptin and testosterone were evaluated at the end of the experiment .", "spans": [{"span_id": 0, "text": "melatonin", "start": 87, "end": 96, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "corticosterone", "start": 99, "end": 113, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "leptin", "start": 116, "end": 122, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "testosterone", "start": 127, "end": 139, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Endocrine and cardiovascular rhythms differentially adapt to chronic phase-delay shifts in rats. Disturbances in regular circadian oscillations can have negative effects on cardiovascular function, but epidemiological data are inconclusive and new data from animal experiments elucidating critical biological mechanisms are needed. To evaluate the consequences of chronic phase shifts of the light/dark (LD) cycle on hormonal and cardiovascular rhythms, two experiments were performed. In Experiment 1, male rats were exposed to either a regular 12:12 LD cycle (CONT) or rotating 8-h phase-delay shifts of LD every second day (SHIFT) for 10 weeks. During this period , blood pressure ( BP ) was monitored weekly , and daily rhythms of melatonin , corticosterone , leptin and testosterone were evaluated at the end of the experiment . In Experiment 2, female rats were exposed to the identical shifted LD schedule for 12 weeks, and daily rhythms of BP, heart rate (HR) and locomotor activity were recorded using telemetry. Preserved melatonin rhythms were found in the pineal gland, plasma, heart and kidney of SHIFT rats with damped amplitude in the plasma and heart, suggesting that the central oscillator can adapt to chronic phase-delay shifts. In contrast, daily rhythms of corticosterone, testosterone and leptin were eliminated in SHIFT rats. Exposure to phase shifts did not lead to increased body weight and elevated BP. However, a shifted LD schedule substantially decreased the amplitude and suppressed the circadian power of the daily rhythms of BP and HR, implying weakened circadian control of physiological and behavioural processes. The results demonstrate that endocrine and cardiovascular rhythms can differentially adapt to chronic phase-delay shifts, promoting internal desynchronization between central and peripheral oscillators, which in combination with other negative environmental stimuli may result in negative health effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/27459109/"}
{"doc_id": "e6ef2ab4a8014182fc22a771b631cf26", "sentence": "Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed : chloroquine , hydroxychloroquine , losartan , azithromycin , naproxen , dexamethasone and prednisone .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 152, "end": 163, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "hydroxychloroquine", "start": 166, "end": 184, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "losartan", "start": 187, "end": 195, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "azithromycin", "start": 198, "end": 210, "token_start": 28, "token_end": 29}, {"span_id": 4, "text": "naproxen", "start": 213, "end": 221, "token_start": 30, "token_end": 31}, {"span_id": 5, "text": "dexamethasone", "start": 224, "end": 237, "token_start": 32, "token_end": 33}, {"span_id": 6, "text": "prednisone", "start": 242, "end": 252, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception. With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed : chloroquine , hydroxychloroquine , losartan , azithromycin , naproxen , dexamethasone and prednisone . ### results For azithromycin and naproxen, large numbers of offspring were exposed (>\u20091800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~\u2009900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (<\u2009300 offspring). There is strong evidence that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. With some caution, the other drugs investigated can be considered safe.", "source": "https://pubmed.ncbi.nlm.nih.gov/32869015/"}
{"doc_id": "a61de2c1b9288243838027e81390bf89", "sentence": "The present work is concerned with simultaneous determination of cefepime ( CEF ) and the co-administered drug , levofloxacin ( LEV ) , in spiked human plasma by applying a new approach , Savitzky-Golay differentiation filters , and combined trigonometric Fourier functions to their ratio spectra .", "spans": [{"span_id": 0, "text": "cefepime", "start": 65, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "levofloxacin", "start": 113, "end": 125, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Application of Savitzky-Golay differentiation filters and Fourier functions to simultaneous determination of cefepime and the co-administered drug, levofloxacin, in spiked human plasma.  The present work is concerned with simultaneous determination of cefepime ( CEF ) and the co-administered drug , levofloxacin ( LEV ) , in spiked human plasma by applying a new approach , Savitzky-Golay differentiation filters , and combined trigonometric Fourier functions to their ratio spectra . The different parameters associated with the calculation of Savitzky-Golay and Fourier coefficients were optimized. The proposed methods were validated and applied for determination of the two drugs in laboratory prepared mixtures and spiked human plasma. The results were statistically compared with reported HPLC methods and were found accurate and precise.", "source": "https://pubmed.ncbi.nlm.nih.gov/25576942/"}
{"doc_id": "b78111ab8e6346e4897ac7fb177d87c0", "sentence": "Forthcoming data from phase 3 placebo-controlled trials of everolimus , one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome , will provide insight into its future place in NET therapy .", "spans": [{"span_id": 0, "text": "everolimus", "start": 59, "end": 69, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "octreotide", "start": 156, "end": 166, "token_start": 24, "token_end": 25}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors. Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for \"REnal Cell cancer treatment with Oral RAD001 given Daily\"), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus , one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome , will provide insight into its future place in NET therapy . The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.", "source": "https://pubmed.ncbi.nlm.nih.gov/20623346/"}
{"doc_id": "2139b0194d74f7931e11395298f4b7b7", "sentence": "The effects of prednisone and azathioprine on circulating immunoglobulin levels and lymphocyte subpopulations in normal dogs .", "spans": [{"span_id": 0, "text": "prednisone", "start": 15, "end": 25, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "azathioprine", "start": 30, "end": 42, "token_start": 5, "token_end": 6}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The effects of prednisone and azathioprine on circulating immunoglobulin levels and lymphocyte subpopulations in normal dogs . This study investigates serum immunoglobulin (SIg) levels and lymphocyte subpopulations in normal dogs in response to putative immunosuppressive doses of prednisone and/or azathioprine. The objectives were to quantify SIg levels and lymphocyte subpopulations, including Thy-1+, CD4+, CD8+ and B cells, in normal dogs both before and after the administration of prednisone and/or azathioprine at 2 mg/kg, PO, each. Eighteen beagles were divided into 3 groups of 6 dogs each. Blood samples for radial immunodiffusion assay of IgG, IgM and IgA, complete blood count (CBC)and flow cytometry were collected prior to the administration of any drugs and again after 14 d of azathioprine, prednisone or azathioprine and prednisone. Peripheral blood mononuclear cells were isolated using density centrifugation and were incubated with monoclonal antibodies reacting with CD4+, CD8+, Thy-1+ and membrane immunoglobulin. Lymphocyte subsets were quantified using flow cytometry. azathioprine-treated dogs had no significant changes in SIg levels or lymphocyte subpopulations. prednisone-treated dogs had significant (P < 0.05) decreases in all SIg levels, all lymphocyte subpopulations and erythrocyte numbers, and had an increase in neutrophil counts. prednisone and azathioprine-treated dogs had significant (P < 0.05) decreases in serum IgG levels and Thy-1+ and CD8+ lymphocyte subpopulations, with an increase in the CD4:CD8. These dogs also had a significant decrease in erythrocyte number and a significant increase in the monocyte count. These findings suggest that azathioprine and prednisone in combination or prednisone alone may be useful for the treatment of T cell-mediated diseases since decreased circulating T cell levels were demonstrated following treatment. The combination of drugs or azathioprine alone may not be appropriate for treatment of acute or autoantibody-mediated immune disease, because SIg levels were minimally affected by treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/9918329/"}
{"doc_id": "f879c21487b13e35c833840fda58d3a7", "sentence": "The analytical range for dihydroartemisinin , dihydroartemisinin-glucuronide and artesunate was 10 - 1000 ng/ml and for artemether 90 - 3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml , respectively .", "spans": [{"span_id": 0, "text": "dihydroartemisinin", "start": 25, "end": 43, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "dihydroartemisinin-glucuronide", "start": 46, "end": 76, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "artesunate", "start": 81, "end": 91, "token_start": 8, "token_end": 9}, {"span_id": 3, "text": "artemether", "start": 120, "end": 130, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Development and validation of a liquid chromatography and ion spray tandem mass spectrometry method for the quantification of artesunate, artemether and their major metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Recently, promising fasciocidal activities of artesunate and artemether were described in rats and sheep. Therefore, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify artesunate, artemether and their metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Protein precipitation with methanol was used for sample workup. Reversed-phase high-performance liquid chromatography (HPLC) was performed using an Atlantis C18 analytical column with a mobile phase gradient system of ammonium formate and acetonitrile. The analytes were detected by MS/MS using selected reaction monitoring (SRM) with electrospray ionisation in the positive mode (transition m/z 267.4 \u2192 163.0). The analytical range for dihydroartemisinin , dihydroartemisinin-glucuronide and artesunate was 10 - 1000 ng/ml and for artemether 90 - 3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml , respectively . Inter- and intra-day accuracy and precision deviations were < 10%. Consistent relative recoveries (60-80%) were observed over the investigated calibration range for all analytes. All analytes were stable in the autosampler for at least 30 h (6 \u00b0C) and after three freeze and thaw cycles. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be used for the determination of the artemisinins in sheep plasma. The method was applied successfully to determine the pharmacokinetic parameters of artesunate and its metabolites in plasma of intramuscularly treated sheep.", "source": "https://pubmed.ncbi.nlm.nih.gov/21259399/"}
{"doc_id": "2e2b58482bca022994e3931d9f553e16", "sentence": "Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 microg/ml to a mean of 0.16 microg/ml against Aspergillus , and from a mean of 0.97 microg/ml to a mean of 0.39 microLg/ml against Fusarium ( P < 0.000001 for both ) .", "spans": [{"span_id": 0, "text": "Amphotericin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "rifabutin", "start": 55, "end": 64, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Inhibition of RNA synthesis as a therapeutic strategy against Aspergillus and Fusarium: demonstration of in vitro synergy between rifabutin and amphotericin B. We investigated the in vitro antifungal activity of amphotericin B, alone and in combination with rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates of Aspergillus and 25 clinical isolates of Fusarium. Synergy or additivism between these drugs was demonstrated against all isolates tested. Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 microg/ml to a mean of 0.16 microg/ml against Aspergillus , and from a mean of 0.97 microg/ml to a mean of 0.39 microLg/ml against Fusarium ( P < 0.000001 for both ) . Similarly, the MICs of rifabutin were reduced upon combination with amphotericin B from a mean of >32 microg/ml to a mean of 1.1 microg/ml against both fungi (P < 0.000001 for both). These positive interactions were corroborated by a colony count study with two Fusarium isolates, for which treatment with the combination of subinhibitory concentrations of amphotericin B (at concentrations 2- and 4-fold less than the MIC) and rifabutin (at concentrations ranging from 4- to 64-fold less than the MIC) resulted in 3.2-log reductions in colony counts compared to those after treatment with either drug alone. Inhibition of RNA synthesis was shown to be the mechanism of antifungal activity. These results suggest that inhibition of fungal RNA synthesis might be a potential target for antifungal therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/9517924/"}
{"doc_id": "616bc5c68d16fb4ffb21ea45bb72e4a4", "sentence": "Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 25, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxorubicin", "start": 42, "end": 53, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report. The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity . Semin Oncol 28 (suppl 10):57-61.", "source": "https://pubmed.ncbi.nlm.nih.gov/11510035/"}
{"doc_id": "cc9932640d9be5ec55eb2675d707e52e", "sentence": "Treatment of invasive sphenoidal aspergillosis is surgical , followed by antifungal therapy , mostly amphotericin B. To optimize the adjuvant antifungal treatment , which is often limited by severe side effects , the new triazole antifungal agent voriconazole with broad coverage of fungal pathogens including Aspergillus was investigated in a study of 4 patients with clinical , radiological and histological signs of invasive sphenoidal aspergillosis .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 101, "end": 113, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "voriconazole", "start": 247, "end": 259, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Invasive sphenoidal aspergillosis: successful treatment with sphenoidotomy and voriconazole.  Treatment of invasive sphenoidal aspergillosis is surgical , followed by antifungal therapy , mostly amphotericin B. To optimize the adjuvant antifungal treatment , which is often limited by severe side effects , the new triazole antifungal agent voriconazole with broad coverage of fungal pathogens including Aspergillus was investigated in a study of 4 patients with clinical , radiological and histological signs of invasive sphenoidal aspergillosis . They first underwent endoscopic sphenoidotomy with drainage and extraction of the fungal mass. Postoperatively, 2 patients were immediately treated with voriconazole. Two patients initially received amphotericin B; but this treatment had to be stopped because of acute renal toxicity. Finally, all patients were treated orally with 200 mg voriconazole twice a day for 12-14 weeks. After this combined treatment all patients were asymptomatic and there were no endoscopic or radiological signs of residual fungal disease. The only side effects were nausea in one and transient visual disturbances in 2 other patients. In the 4 patients presented and treated, voriconazole was shown to be effective and less toxic than amphotericin B in adjuvant treatment of invasive sphenoidal aspergillosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/17159376/"}
{"doc_id": "af6d0095cfd9cc4170dc875f6c8ad4d1", "sentence": "At cross over the ORR was 0 % and 18 % on cross over to vinorelbine and docetaxel respectively with a median TTP of 17.3 weeks ( 95 % CI , 16.3 - 18.1 ) and 18.7 weeks ( 95 % CI , 13.9 - 23.4 ) for those receiving vinorebine and docetaxel at cross over respectively .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 56, "end": 67, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "docetaxel", "start": 72, "end": 81, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "docetaxel", "start": 229, "end": 238, "token_start": 52, "token_end": 53}], "rels": [], "paragraph": "A randomized feasibility study of docetaxel versus vinorelbine in advanced breast cancer. docetaxel and vinorelbine have demonstrated efficacy in the treatment of metastatic breast cancer (MBC). This prospective feasibility study compared the efficacy of these two treatments in MBC. ### methods Patients with MBC progressing following anthracycline treatment were randomly assigned to either docetaxel (100 mg/m(2)day 1 q3W) or vinorelbine (25mg/m(2) day 1 q2W). Patients were eligible to cross over at progression. Objective response rates (ORR), time to progression (TTP) and overall survival (OS) were measured. ### results 37 patients were randomised. 2 patients were excluded due to protocol violations. Of 35 remaining patients 17 received docetaxel and 18 received vinorelbine per protocol. ORR was 12.5% and 6.0% respectively for docetaxel and vinorelbine. The median time to progression was 10.4 weeks (range 6-14 weeks) in docetaxel arm and 7.6 weeks (range 4-11 weeks) in vinorelbine arm (p = .82). The clinical benefit rate (defined as complete response, partial response plus stable disease) was 44% in the docetaxel arm and 12% in the vinorelbine arm. Based on intent to treat the median OS in the docetaxel arm was 34 weeks (95% CI, 20.7-48) and 21.2 weeks (95% CI, 17-25.4) in vinorelbine arm (p = .388). 16 patients crossed over, 5 from docetaxel to vinorelbine and 11 from vinorelbine to docetaxel. At cross over the ORR was 0 % and 18 % on cross over to vinorelbine and docetaxel respectively with a median TTP of 17.3 weeks ( 95 % CI , 16.3 - 18.1 ) and 18.7 weeks ( 95 % CI , 13.9 - 23.4 ) for those receiving vinorebine and docetaxel at cross over respectively . vinorelbine however was much better tolerated with fewer grade 3-4 toxicity events (n = 4) than docetaxel (n = 27). ### discussion While docetaxel resulted in a longer TTP and OS in this study it did not reach statistical significance. TTP duration for those patients who crossed over was similar, but overwhelmingly vinorelbine had fewer significant grade 3-4 toxicities than docetaxel. Only two previous randomized studies have compared the efficacy of single agent docetaxel and vinorelbine following prior anthracycline exposure, one in an unselected population [16], and the other, HERNATA, in HER2 positive disease with trastuzumab used in both arms [17]. The patients randomized in this study were relatively heavily pretreated with the majority having received 2-3 lines of prior treatment for their metastatic disease. The lower response rates with vinorelbine as compared to docetaxel in this study concur with results reported in other studies [16]. However, the numbers in both this study and the other unselected study [16] are small and need to be interpreted with caution. With regard to toxicity, in the present study, grade 3-4 hematological adverse events and infection were tenfold greater with docetaxel as compared with vinorelbine, consistent with results in HERNATA [17]. While others have reported a significantly higher number of overall grade 3-4 toxicities with vinorelbine [16], the fact that, as in HERNATA, discontinuations due to toxicities in that study [16] were significantly greater with docetaxel as compared to vinorelbine suggests either the toxicity data collected did not reflect the true toxicities on treatment or that docetaxel toxicities were in some way more severe or protracted leading to more numerous discontinuations [16]. Larger randomized studies are needed to determine (1) the efficacy of docetaxel versus vinorelbine in anthracycline pretreated disease and (2) the efficacy of vinorelbine after prior taxane exposure, and particularly how it may compares both with regard to efficacy and tolerability with other possible regimens that may utilized such as carboplatin-gemcitabine [20] or eribulin [21]. The longer as well as comparable TTP at cross over for both agents compared to that upfront suggests there may be enrichment at cross over of a group of patients who are not only fit for further treatment but are more likely to a derive continued benefit from additional treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/23002126/"}
{"doc_id": "8af357219cf885cb867e13a5fdf0022e", "sentence": "The drugs approved in Europe for the systemic treatment of herpes zoster are aciclovir , valaciclovir , famciclovir and brivudine .", "spans": [{"span_id": 0, "text": "aciclovir", "start": 77, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "valaciclovir", "start": 89, "end": 101, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "famciclovir", "start": 104, "end": 115, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "brivudine", "start": 120, "end": 129, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "[Update in the treatment of herpes zoster]. The systemic treatment of herpes zoster shortens the healing process, and prevents or alleviates pain and other acute or chronic complications, especially when it is administered in the first 72 hours after symptoms appear. This treatment is especially indicated in patients over the age of 50 and in those who, regardless of age, have head and neck involvement, especially in herpes zoster ophthalmicus. The drugs approved in Europe for the systemic treatment of herpes zoster are aciclovir , valaciclovir , famciclovir and brivudine . brivudine shows greater effectiveness against the varicella-zoster virus than aciclovir and its derivatives, and can be given just once a day for seven days, compared to multiple doses of the latter. As opposed to the others, brivudine is a non-nephrotoxic drug that should not be administered to immunodepressed patients or to those being treated with 5-fluorouracil. The treatment of herpes zoster to reduce pain should be combined with analgesics and neuroactive agents (amitriptyline, gabapentin, etc). While corticosteroids are of dubious efficacy in the treatment of post-herpes neuralgia, the intensity and duration of the pain can be reduced with some topical treatments (capsaicin, lidocaine patches, etc). Finally, this review discusses treatment guidelines for special locations (cranial nerves) and different subpopulations (children, pregnant women, immunodepressed patients, etc).", "source": "https://pubmed.ncbi.nlm.nih.gov/16595111/"}
{"doc_id": "e2fbcabdf6187dc1681261af1681670e", "sentence": "In this parallel group , randomized , double-blind study , 301 PD patients , the majority with motor fluctuations , received entacapone ( 200 mg ) or placebo with each daily dose of standard or controlled-release ( CR ) levodopa .", "spans": [{"span_id": 0, "text": "entacapone", "start": 125, "end": 135, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "levodopa", "start": 220, "end": 228, "token_start": 39, "token_end": 40}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. ### Patients And Methods In this parallel group , randomized , double-blind study , 301 PD patients , the majority with motor fluctuations , received entacapone ( 200 mg ) or placebo with each daily dose of standard or controlled-release ( CR ) levodopa . The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. ### results In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). entacapone benefit was lost on withdrawal. entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. ### conclusion entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.", "source": "https://pubmed.ncbi.nlm.nih.gov/11939936/"}
{"doc_id": "7bd40e2672dafd76efef54ff7abc63aa", "sentence": "Importance of adding neomycin to metronidazole for bowel preparation .", "spans": [{"span_id": 0, "text": "neomycin", "start": 21, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "metronidazole", "start": 33, "end": 46, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Importance of adding neomycin to metronidazole for bowel preparation . A prospective randomized trial has investigated whether it is necessary to add oral neomycin to oral metronidazole as a means of preventing sepsis in elective colonic resection. Seventy-three patients completed the study; 41 received metronidazole and placebo neomycin and 32 received metronidazole and active neomycin. There was a significant reduction in the incidence of wound infection in patients receiving neomycin and metronidazole (22%) compared with metronidazole alone (51%, P<0.02). There was also a significant reduction in anaerobic infections in the group receiving metronidazole and neomycin compared with metronidazole alone (P<0.05). These results indicate that oral metronidazole alone is of no benefit for patients requiring elective colonic operations and that if oral metronidazole is advised it should always be given in combination with oral neomycin.", "source": "https://pubmed.ncbi.nlm.nih.gov/7017122/"}
{"doc_id": "ada8d4f1718084cd5e05de0a435a0497", "sentence": "The effects of metformin ( MET ) and curcumin ( CUR ) single treatments have been tested against breast cancer ; however , their combination has not been explored .", "spans": [{"span_id": 0, "text": "metformin", "start": 15, "end": 24, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "curcumin", "start": 37, "end": 45, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis.  The effects of metformin ( MET ) and curcumin ( CUR ) single treatments have been tested against breast cancer ; however , their combination has not been explored . Here, we evaluated the antitumor activity of MET and CUR combination against breast cancer in mice. ### Materials And Methods The antiproliferative activity of single and combined treatments against breast cancer cell lines was determined. Vascular endothelial growth factor (VEGF) and ### results The combination treatment exhibited the highest effects against tumor proliferation and growth. It significantly reduced VEGF expression, induced ### conclusion The combination can be a potential therapeutic option to treat breast cancer. However, further testing is needed to measure the exact serum levels of MET and CUR and to further explain the obtained results.", "source": "https://pubmed.ncbi.nlm.nih.gov/28491145/"}
{"doc_id": "feacfbaedd37f2a268494690707ec2ed", "sentence": "Warfarin was associated with a significantly higher risk of MB ( HR = 1.52 , 95 % CI = 1.14 - 2.04 ) , CRNM bleeding ( HR = 1.27 , 95 % CI = 1017.15 - 1.40 ) , and recurrent VTE ( HR = 1.50 , 95 % CI = 1.24 - 1.82 ) compared with apixaban .", "spans": [{"span_id": 0, "text": "Warfarin", "start": 0, "end": 8, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "apixaban", "start": 230, "end": 238, "token_start": 58, "token_end": 59}], "rels": [], "paragraph": "Comparative Clinical and Economic Outcomes Associated with Warfarin Versus Apixaban in the Treatment of Patients with Venous Thromboembolism in a Large U.S. Commercial Claims Database. Venous thromboembolism (VTE), constituting deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common cause of vascular-related morbidity and mortality, resulting in a significant clinical and economic burden in the United States each year. Clinical guidelines recommend that patients with DVT and PE without cancer should be initiated on anticoagulation therapy with a direct oral anticoagulant over a vitamin K antagonist. Yet there is limited real-world evidence comparing the economic burden of warfarin and apixaban in treating VTE patients in a large commercially insured population. ### objective To compare safety and effectiveness of warfarin and apixaban and evaluate associated economic burden in treating VTE patients in a large U.S. commercial health care claims database. ### methods The PharMetrics Plus database was used to identify oral anticoagulant (OAC)-naive patients aged \u2265 18 years who initiated apixaban or warfarin within 30 days of a qualifying VTE encounter and had continuous health plan enrollment with medical and pharmacy benefits for 6 months before treatment initiation. apixaban initiators and warfarin initiators were matched using the propensity score matching (PSM) technique. Cox proportional hazard models were used to assess and compare the risk of major bleeding (MB), clinically relevant nonmajor (CRNM) bleeding, and recurrent VTE. Generalized linear models were used to assess and compare the all-cause health care costs. A 2-part model with bootstrapping was used to evaluate MB- and recurrent VTE-related medical costs. ### results Among 25,193 prematched patients, 13,421 (53.3%) were prescribed warfarin and 11,772 (46.7%) were prescribed apixaban. After 1:1 PSM, 8,858 matched warfarin-apixaban pairs were selected with a mean follow-up of 109 days and 103 days, respectively. Warfarin was associated with a significantly higher risk of MB ( HR = 1.52 , 95 % CI = 1.14 - 2.04 ) , CRNM bleeding ( HR = 1.27 , 95 % CI = 1017.15 - 1.40 ) , and recurrent VTE ( HR = 1.50 , 95 % CI = 1.24 - 1.82 ) compared with apixaban . warfarin patients had significantly higher all-cause medical costs per patient per month (PPPM; $2,333 vs. $1,992; ### conclusions warfarin use was associated with a higher risk of MB, CRNM bleeding, and recurrent VTE compared with apixaban. warfarin use was also associated with higher all-cause medical costs, MB-related medical costs, and recurrent VTE-related costs PPPM compared with apixaban.", "source": "https://pubmed.ncbi.nlm.nih.gov/32452277/"}
{"doc_id": "17cd6451aee625142a75f18fe3653670", "sentence": "A combination chemotherapy regimen containing mitomycin-C ( 10 mg/m2 , day 2 ) , vincristine ( 0.5 mg/m2 , days 1 and 4 ) , bleomycin ( 30 U QD , days 1 - -4 as a continuous intravenous infusion during courses one and two only ) , and cis-platinum ( 50 mg/m2 , days 1 and 22 ) was administered every 6 weeks to 14 evaluable patients with advanced ( i.e. , Stage IVB ) and/or recurrent squamous cell carcinoma of the cervix .", "spans": [{"span_id": 0, "text": "mitomycin-C", "start": 46, "end": 57, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "vincristine", "start": 81, "end": 92, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "bleomycin", "start": 124, "end": 133, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "cis-platinum", "start": 235, "end": 247, "token_start": 49, "token_end": 50}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Mitomycin-C, bleomycin, vincristine, and cis-platinum in the treatment of advanced, recurrent squamous cell carcinoma of the cervix.  A combination chemotherapy regimen containing mitomycin-C ( 10 mg/m2 , day 2 ) , vincristine ( 0.5 mg/m2 , days 1 and 4 ) , bleomycin ( 30 U QD , days 1 - -4 as a continuous intravenous infusion during courses one and two only ) , and cis-platinum ( 50 mg/m2 , days 1 and 22 ) was administered every 6 weeks to 14 evaluable patients with advanced ( i.e. , Stage IVB ) and/or recurrent squamous cell carcinoma of the cervix . Four patients (29%) achieved a complete response, lasting 8, 9.5+, 17+, and 21+ months. Three of these patients have had complete disappearance of their pulmonary metastases and one has had resolution of a large left-sided pelvic wall mass. Two additional patients (14%) had a partial response to therapy, each lasting 1.5 months. The median survival for these 14 patients was 9.0 months. The chemotherapy regimen was well tolerated. There were no drug-related deaths and no instances of severe or irreversible renal dysfunction or peripheral neuropathy. The mean lowest white blood cell and platelet counts were 4540 and 205,000 per mm3, respectively. Although severe or life-threatening thrombocytopenia occurred in only 36% patients, it appeared to be the dose-limiting toxicity of this drug combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/6169465/"}
{"doc_id": "3f692f14fd1dc7ff15258ac63e7d03a7", "sentence": "Co-injection of the lowest doses of levobupivacaine and lidocaine dramatically increased the paw withdrawal latency .", "spans": [{"span_id": 0, "text": "levobupivacaine", "start": 36, "end": 51, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "lidocaine", "start": 56, "end": 65, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Modification of local anesthetic-induced antinociception by fentanyl in rats. In clinical practice, using the lowest doses of drugs for anesthesia or analgesia is the main goal. Opioid combinations with local anesthetics can be preferable for achieving adequate anesthesia or analgesia. The primary purpose of this study was to examine possible thermal antinociceptive effects of the opioid -fentanyl and the amide local anesthetics levobupivacaine and lidocaine when locally administered alone or in combination. The paw withdrawal latencies to noxious thermal stimuli in rats were measured to assess the antinociceptive actions of drugs after subcutaneous intraplantar injection into the hind paw. All drugs examined in this study produced dose- and time-dependent increases in the paw withdrawal latencies. Fentanyl is approximately 125 and 500 times more potent than levobupivacaine and lidocaine, respectively. At the same dose, the antinociceptive potency of levobupivacaine was 3.6-fold higher than that of lidocaine. Co-injection of the lowest doses of levobupivacaine and lidocaine dramatically increased the paw withdrawal latency . However, in the presence of fentanyl, the effects of levobupivacaine and lidocaine were different. Although co-injection of levobupivacaine with fentanyl both enhanced and prolonged antinociceptive action, the lidocaine-fentanyl combination did not significantly change the paw withdrawal latency. These results suggest that intraplantar co-administration of fentanyl with levobupivacaine, but not lidocaine, may provide more effective antinociception without increasing the dose requirements.", "source": "https://pubmed.ncbi.nlm.nih.gov/22358090/"}
{"doc_id": "cc67bf6e7bbf69b13b54908cf76fe9d7", "sentence": "Inflammatory breast cancer ( IBC ) is a rare , aggressive form of breast cancer associated with HER2 amplification , with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label , single-arm phase II clinical trial ( ClinicalTrials.gov NCT01325428 ) to investigate the efficacy and safety of afatinib , an irreversible ErbB family inhibitor , alone and in combination with vinorelbine in patients with HER2-positive IBC .", "spans": [{"span_id": 0, "text": "afatinib", "start": 330, "end": 338, "token_start": 54, "token_end": 55}, {"span_id": 1, "text": "vinorelbine", "start": 411, "end": 422, "token_start": 67, "token_end": 68}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine.  Inflammatory breast cancer ( IBC ) is a rare , aggressive form of breast cancer associated with HER2 amplification , with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label , single-arm phase II clinical trial ( ClinicalTrials.gov NCT01325428 ) to investigate the efficacy and safety of afatinib , an irreversible ErbB family inhibitor , alone and in combination with vinorelbine in patients with HER2-positive IBC . This trial included prospectively planned exome analysis before and after afatinib monotherapy. ### Methods And Findings HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-na\u00efve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-na\u00efve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-na\u00efve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies. ### conclusions afatinib, with or without vinorelbine, showed activity in trastuzumab-na\u00efve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease. ### Trial Registration ClinicalTrials.gov NCT01325428.", "source": "https://pubmed.ncbi.nlm.nih.gov/27923043/"}
{"doc_id": "bce7b05d7aeb7352b707222c1976fbdf", "sentence": "Carboplatin and paclitaxel versus cisplatin , paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer : a Hellenic Cooperative Oncology Group ( HeCOG ) study .", "spans": [{"span_id": 0, "text": "Carboplatin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 16, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "cisplatin", "start": 34, "end": 43, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "paclitaxel", "start": 46, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "doxorubicin", "start": 61, "end": 72, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3, 4], "is_context_needed": true}], "paragraph": "Carboplatin and paclitaxel versus cisplatin , paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer : a Hellenic Cooperative Oncology Group ( HeCOG ) study . The combination of carboplatin and paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of cisplatin, paclitaxel and doxorubicin. ### Patients And Methods Patients with AOC were randomised to either six courses of paclitaxel 175mg/m(2) plus carboplatin 7AUC or paclitaxel at the same dose plus cisplatin 75mg/m(2) plus doxorubicin 40mg/m(2). ### results Analysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm. ### conclusion The combination of cisplatin, paclitaxel and doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard carboplatin/paclitaxel regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/18691879/"}
{"doc_id": "513c3d2bb7d335b2cb1527a1775af10c", "sentence": "For susceptibility testing , DS-8587 exhibited more effective antibacterial activity when compared with ciprofloxacin and levofloxacin .", "spans": [{"span_id": 0, "text": "ciprofloxacin", "start": 104, "end": 117, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "levofloxacin", "start": 122, "end": 134, "token_start": 15, "token_end": 16}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Characteristics of antibiotic resistance and sequence type of Acinetobacter baumannii clinical isolates in Japan and the antibacterial activity of DS-8587. DS-8587 is a novel broad-spectrum fluoroquinolone with extended antimicrobial activity against both Gram-positive and Gram-negative pathogens. In this study, we evaluated the antibacterial activity and mechanism of DS-8587 in 31 quinolone-resistant Acinetobacter baumannii clinical isolates. Efflux pump and qnr genes, mutations in quinolone resistance-determining regions of target enzymes, and sequence types determined by multilocus sequence typing were analyzed. Forty-two quinolone-susceptible clinical isolates were analyzed for comparison. For susceptibility testing , DS-8587 exhibited more effective antibacterial activity when compared with ciprofloxacin and levofloxacin . When combined with the efflux pump inhibitor 1-(1-napthylmethyl)-piperazine, the MIC of DS-8587 was less affected when compared with the MIC exhibited by combined ciprofloxacin and 1-(1-napthylmethyl)-piperazine. The efflux pump genes adeA/adeB/adeC and regulatory elements adeR/adeS were detected in 23 of 31 quinolone-resistant isolates. The qnrA/qnrB/qnrS genes were not detected in any A.\u00a0baumannii isolates analyzed. Mutations in quinolone resistance-determining regions were observed in all 31 quinolone-resistant isolates. Multilocus sequence typing analyses revealed that 22 of 31 quinolone-resistant isolates belonged to ST-2, corresponding to international clonal lineage II. In conclusion, DS-8587 exhibits potent antibacterial activity against quinolone-resistant A.\u00a0baumannii isolates that harbor mutations in quinolone resistance-determining regions. In the presence of the efflux pump inhibitor 1-(1-napthylmethyl)-piperazine, no significant changes were observed in the MIC for DS-8587. DS-8587 should be considered as a treatment option for A.\u00a0baumannii including ST-2 strains that are predominant among the quinolone-resistant A.\u00a0baumannii isolates found in Japan.", "source": "https://pubmed.ncbi.nlm.nih.gov/24709045/"}
{"doc_id": "43b1b9a41604d7aa5ad660cb80fe319a", "sentence": "Since 1987 , we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer ( NSCLC ) who had not received prior chemotherapy .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 31, "end": 42, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "etoposide", "start": 72, "end": 81, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase II studies with carboplatin in non-small cell lung cancer.  Since 1987 , we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer ( NSCLC ) who had not received prior chemotherapy . Single-agent carboplatin produced a 20% response rate in 51 patients treated with 390 mg/m2 intravenously every 4 weeks. A 3-day schedule of etoposide 140 mg/m2 on days 2, 3, and 4, and carboplatin 150 mg/m2 on days 1 and 5 also resulted in a 26.7% response rate in 46 patients. Myelosuppressive toxicity associated with carboplatin/etoposide was substantially greater than that seen with carboplatin alone. carboplatin as a single agent is active in previously untreated patients with advanced NSCLC. The two-drug combination of carboplatin and etoposide also shows activity in NSCLC similar to other combination chemotherapeutic regimens based on comparable prognostic factors in untreated patients. Further evaluation of carboplatin as part of combination chemotherapy in NSCLC is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/2154856/"}
{"doc_id": "f3ca6904190590488d651122c505034a", "sentence": "Oral formulations of paclitaxel and docetaxel are of great interest , but have yet to receive regulatory approval in this disease .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 21, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "docetaxel", "start": 36, "end": 45, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Taxanes, past, present, and future impact on non-small cell lung cancer. Taxanes are novel microtubule-stabilizing agents and have shown efficacy in non-small cell lung cancer (NSCLC) since the 1990s. paclitaxel and docetaxel have been used either as single agents or in combination with a platinum compound. The newer generation albumin-bound taxane, nab-paclitaxel, has also shown similar efficacy in advanced NSCLC, both as a single agent and in combination with a platinum compound. Nab-paclitaxel, being Cremophor EL free, appears to have a better toxicity profile than paclitaxel. Taxane/platinum combinations still remain the foundation of treatment for advanced or metastatic NSCLC. docetaxel and paclitaxel as single agents have also shown efficacy in the second-line setting in advanced/metastatic NSCLC. Oral formulations of paclitaxel and docetaxel are of great interest , but have yet to receive regulatory approval in this disease . The phase I-II trials have shown that these formulations are feasible in the clinical setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/24463482/"}
{"doc_id": "02baf8db20b9dcdda7efc4ece6762c6d", "sentence": "FLAIE ( fludarabine , cytarabine , idarubicin , and etoposide ) , a four drug induction chemotherapy for adult acute myeloid leukemia : A single center experience .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 8, "end": 19, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "cytarabine", "start": 22, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "idarubicin", "start": 35, "end": 45, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "etoposide", "start": 52, "end": 61, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "FLAIE ( fludarabine , cytarabine , idarubicin , and etoposide ) , a four drug induction chemotherapy for adult acute myeloid leukemia : A single center experience . ", "source": "https://pubmed.ncbi.nlm.nih.gov/19731308/"}
{"doc_id": "0d77af88b5d27b2a2a55fbdc6b44750e", "sentence": "Overall , our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells .", "spans": [{"span_id": 0, "text": "dabrafenib", "start": 50, "end": 60, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "cetuximab", "start": 65, "end": 74, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "BRAF and EGFR inhibitors synergize to increase cytotoxic effects and decrease stem cell capacities in BRAF(V600E)-mutant colorectal cancer cells. Mutations in the oncogene BRAF(V600E) are found in ~10% of colorectal cancers (CRCs) and are associated with poor prognosis. However, BRAF(V600E) has a limited response to the small-molecule drug, vemurafenib, a BRAF inhibitor, and BRAF inhibition is thought to cause a feedback activation of EGFR signaling that supports continued proliferation. In this study, we explored the effect of combined use of dabrafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, on BRAF(V600E)-mutant CRC stem cells and its possible mechanisms. Through cell viability analysis, flow cytometry, sphere forming, and western blot analysis, we found that the dabrafenib can synergize with cetuximab to reduce cell viability, induce enhanced apoptotic rates and cell cycle arrest in BRAF(V600E)-mutant HT-29 cells and inhibits stem cell capacities. Further, western blot analysis revealed that PTEN/Src/c-Myc pathway is possibly involved in the synergism between dabrafenib and cetuximab. Overall , our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells .", "source": "https://pubmed.ncbi.nlm.nih.gov/29534162/"}
{"doc_id": "35f40d091be6cc1509c9e9ac25d22237", "sentence": "Forty-seven patients with previously untreated metastatic or unresectable colorectal adenocarcinoma received capecitabine 1000 mg/m2 twice daily on days 2 - 15 and intravenous irinotecan 100 mg/m2 on days 1 and 8 , every 21 days .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 109, "end": 121, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "irinotecan", "start": 176, "end": 186, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Multicenter phase II study of oral capecitabine plus irinotecan as first-line chemotherapy in advanced colorectal cancer: a Korean Cancer Study Group trial. A phase II study was conducted to assess the efficacy and tolerability of capecitabine in combination with irinotecan (CAPIRI) in advanced colorectal cancer. Forty-seven patients with previously untreated metastatic or unresectable colorectal adenocarcinoma received capecitabine 1000 mg/m2 twice daily on days 2 - 15 and intravenous irinotecan 100 mg/m2 on days 1 and 8 , every 21 days . A total of 268 cycles of chemotherapy (median 6: range 1-11) were administered. According to an intent-to-treat analysis, the overall response rate was 49% (95% CI, 35-63%). Median time to progression and overall survival were 7.5 months (95% CI, 4.8-10.2) and 19.5 months (95% CI, 15.7-23.8), respectively. The most common grade 3/4 adverse events were diarrhea (24%) and neutropenia (11%). There were no treatment-related deaths. These results indicate that CAPIRI has comparable activity and tolerability to FOLFIRI as first-line treatment for advanced colorectal cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/16076694/"}
{"doc_id": "905b604d62ba8d7f64c81a504648e942", "sentence": "Amphotericin B plus flucytosine were initially given to 4 patients , all of them developed liver and renal abnormalities to some degree after therapy .", "spans": [{"span_id": 0, "text": "Amphotericin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "flucytosine", "start": 20, "end": 31, "token_start": 3, "token_end": 4}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[Retrospective analysis of seven cases of pulmonary cryptococcosis]. To understand the diagnosis and treatment of pulmonary cryptococcosis. ### methods Patients diagnosed as having pulmonary cryptococcosis in the past 15 years were retrospectively studied. Their demographic data, respiratory symptoms, diagnostic methods, chest radiograph, immune state, antifungal therapy and follow-up results were analyzed. ### results Thirty cases of cryptococcosis were diagnosed, of which 7 were diagnosed as having pulmonary cryptococcosis, one of them presented with concomitant meningitis. Of the 7 patients, 4 were male and 3 were female, with a median age of 41.8. All were HIV negative; one case was immunocompromised with a history of colon cancer and glucocorticoid therapy for 8 months, while others were immunocompetent. Three patients complained of low fever or cough and sputum, while 4 others presented no symptoms. The X-ray and chest CT showed unilateral or bilateral patches, nodules or cavities. The diagnosis was made by pathology and bacterial culture of sputum or bronchoalveolar lavage fluid. Amphotericin B plus flucytosine were initially given to 4 patients , all of them developed liver and renal abnormalities to some degree after therapy . Three patients were given fluconazole or itraconazole initially. All the 7 patients with pulmonary cryptococcosis responded favorably to antifungal therapy and the prognosis was good. ### conclusions Clinically pulmonary cryptococcosis was less common than cryptococcal meningitis. Pathology and cryptococcal culture were essential to the diagnosis. For immunocompetent patients with pulmonary cryptococcosis, the prognosis was good.", "source": "https://pubmed.ncbi.nlm.nih.gov/12490129/"}
{"doc_id": "cd7f36f8e535377e9822cc17ee70ab0a", "sentence": "Liposomes were surface modified with transferrin ( Tf ) for receptor targeting , and cell penetrating peptide PFVYLI ( PFV ) to increase translocation of doxorubicin ( Dox ) and Erlotinib ( Erlo ) across the BBB into glioblastoma ( U87 ) tumor cells .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 154, "end": 165, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "Erlotinib", "start": 178, "end": 187, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Co-delivery of doxorubicin and erlotinib through liposomal nanoparticles for glioblastoma tumor regression using an in vitro brain tumor model. Glioma is a highly malignant tumor that starts in the glial cells of brain. Tumor cells reproduce quickly and infiltrate rapidly in high grade glioma. Permeability of chemotherapeutic agents into brain is restricted owing to the presence of blood brain barrier (BBB). In this study, we developed a dual functionalized liposomal delivery system for efficient transport of chemotherapeutics across BBB for the treatment of glioma. Liposomes were surface modified with transferrin ( Tf ) for receptor targeting , and cell penetrating peptide PFVYLI ( PFV ) to increase translocation of doxorubicin ( Dox ) and Erlotinib ( Erlo ) across the BBB into glioblastoma ( U87 ) tumor cells . In vitro cytotoxicity and hemolysis studies were performed to assess biocompatibility of liposomal nanoparticles. Cellular uptake studies demonstrated efficient internalization of Dox and Erlo in U87, brain endothelial (bEnd.3), and glial cells. In addition, dual functionalized liposomes showed significantly (p\u2009<\u20090.05) higher apoptosis in U87 cells. Significantly (p\u2009<\u20090.05) higher translocation of dual functionalized liposomes across the BBB and delivering chemotherapeutic drugs to the glioblastoma tumor cells inside PLGA-Chitosan scaffold resulted in approximately 52% tumor cell death, using in vitro brain tumor model.", "source": "https://pubmed.ncbi.nlm.nih.gov/30261346/"}
{"doc_id": "41bf69e0eca5a16659fc722436c1365d", "sentence": "Endpoints were determination of maximum tolerated dose of doxorubicin and etoposide , treatment tolerability , and survival .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 58, "end": 69, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 74, "end": 83, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A prospective, non-randomised phase 1-2 trial of VACOP-B with filgrastim support for HIV-related non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma (NHL) remains an important complication of associated HIV infection despite advances in antiretroviral therapy (ART), and the optimum chemotherapy regimen for this disease remains to be defined. A dose-escalation trial was performed to determine the maximum tolerated doses of etoposide and doxorubicin as part of the 12-week VACOP-B regimen, supported by filgrastim (r-metHuG-CSF). Patients with aggressive histology HIV-related NHL who were previously untreated with chemotherapy, and who had no active opportunistic infection were eligible for the study. Chemotherapy consisted of cyclophosphamide 350 mg/m2, vincristine 2 mg, bleomycin 10 U/m2; and prednisone 100 mg q2 days x 12 weeks, with increasing doses of doxorubicin 25-50 mg/m2 and etoposide 25-50 mg/m2 intravenously and 50-100 mg/m2 orally. Central nervous system prophylaxis (intrathecal cytarabine 50 mg x 4 doses), antifungal, and Pneumocystis carinii prophylaxis were used, and filgrastim was administered to prevent neutropenic complications. One dose level was expanded to permit the concomitant use of ART. Endpoints were determination of maximum tolerated dose of doxorubicin and etoposide , treatment tolerability , and survival . Forty-seven patients were enrolled, most with diffuse large-cell or immunoblastic NHL. Protocol-defined maximum tolerated dose was not reached and the limits of dose-limiting toxicity were not exceeded, even in patients receiving ART. Thirty-two cycles (4.9%) were delayed >6 days because of toxicity; 30 patients (64%) completed all 12 weeks of treatment. After completion of therapy, 14 patients had a complete response (30%), and 4 had a partial response (8%). Median time to progression was 9 months. At 42 months, progression-free survival was 25% and overall survival was 28%.", "source": "https://pubmed.ncbi.nlm.nih.gov/16216784/"}
{"doc_id": "546f5069e5a5df509d89decc6fa0ab10", "sentence": "Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC ( pembrolizumab , combination pembrolizumab and relacorilant , nivolumab , combination nivolumab and ipilimumab ) .", "spans": [{"span_id": 0, "text": "pembrolizumab", "start": 108, "end": 121, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "pembrolizumab", "start": 136, "end": 149, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "relacorilant", "start": 154, "end": 166, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "nivolumab", "start": 169, "end": 178, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "nivolumab", "start": 193, "end": 202, "token_start": 26, "token_end": 27}, {"span_id": 5, "text": "ipilimumab", "start": 207, "end": 217, "token_start": 28, "token_end": 29}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [4, 5], "is_context_needed": true}], "paragraph": "The Role of Immunotherapy in the Treatment of Adrenocortical Carcinoma. Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC ( pembrolizumab , combination pembrolizumab and relacorilant , nivolumab , combination nivolumab and ipilimumab ) . The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders.", "source": "https://pubmed.ncbi.nlm.nih.gov/33498467/"}
{"doc_id": "801965c4cbde0556f5d76bb35ff1c9e0", "sentence": "Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 \u20ac ( FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases ) , of \u20ac 15,822 ( FOLFOX with panitumumab in KRAS wild type ) , and of 13,383 \u20ac ( FOLFOX with bevacizumab ) .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 110, "end": 119, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "panitumumab", "start": 203, "end": 214, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "bevacizumab", "start": 267, "end": 278, "token_start": 49, "token_end": 50}], "rels": [], "paragraph": "First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs. In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC). ### methods Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs. ### results Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 \u20ac per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 \u20ac per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 \u20ac ( FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases ) , of \u20ac 15,822 ( FOLFOX with panitumumab in KRAS wild type ) , and of 13,383 \u20ac ( FOLFOX with bevacizumab ) . According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3. ### conclusions Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.", "source": "https://pubmed.ncbi.nlm.nih.gov/30196427/"}
{"doc_id": "bfd9d42e3f083e5d336c1c3786cac47d", "sentence": "Several liposomal anthracyclines have been extensively studied in humans with a variety of cancer types , including TLC D-99 ( Myocet ; The Liposome Company , Elan Corporation , Princeton , NJ ) , liposomal daunorubicin ( Daunoxome ; NeXstar Pharmaceuticals , Inc , San Dimas , CA ) , and pegylated liposomal doxorubicin ( Doxil ; Alza Pharmaceuticals , Palo Alto , CA , Caelyx ; Schering Corporation , Kenilworth , NJ ) .", "spans": [{"span_id": 0, "text": "daunorubicin", "start": 207, "end": 219, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "doxorubicin", "start": 309, "end": 320, "token_start": 53, "token_end": 54}], "rels": [], "paragraph": "Liposomal anthracyclines for breast cancer. doxorubicin and other anthracyclines are an important class of agents for the treatment of early and advanced stage breast cancer, but produce substantial acute and chronic toxicities. One strategy for reducing anthracycline-associated toxicity is packaging them in liposomes. Liposomes are closed vesicular structures that envelop water-soluble molecules. They may serve as vehicles for delivering cytotoxic agents more specifically to tumor, and limit exposure of normal tissues to the drug. Liposomal anthracyclines are more effective and less toxic in a number of preclinical models compared with conventional anthracyclines. Several liposomal anthracyclines have been extensively studied in humans with a variety of cancer types , including TLC D-99 ( Myocet ; The Liposome Company , Elan Corporation , Princeton , NJ ) , liposomal daunorubicin ( Daunoxome ; NeXstar Pharmaceuticals , Inc , San Dimas , CA ) , and pegylated liposomal doxorubicin ( Doxil ; Alza Pharmaceuticals , Palo Alto , CA , Caelyx ; Schering Corporation , Kenilworth , NJ ) . Although none of these agents are currently approved for the treatment of breast cancer in the United States, the liposomal doxorubicin preparations seem to have comparable activity and less cardiac toxicity than conventional doxorubicin. Furthermore, they have been safely combined with other cytotoxic agents, including cyclophosphamide, 5-fluorouracil, vinorelbine, paclitaxel, and docetaxel. Further studies will be required do determine their role in the treatment of breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/11552228/"}
{"doc_id": "4a2f57276f745307d489ba43f622a866", "sentence": "In this study , combined drug action from the combination of Oxa with the phytochemicals andrographolide ( Andro ) , epigallocatechin-3-gallate ( EGCG ) , chlorophyllin ( Chl ) , colchicines ( Col ) , curcumin ( Cur ) and paclitaxel ( Tax ) was evaluated in the human ovarian cancer cell lines A2780 and A2780(cisR ) .", "spans": [{"span_id": 0, "text": "curcumin", "start": 201, "end": 209, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "paclitaxel", "start": 222, "end": 232, "token_start": 40, "token_end": 41}], "rels": [], "paragraph": "Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines. oxaliplatin (Oxa) is a third generation platinum drug currently in clinical use for the treatment against colorectal cancer. Although it has a somewhat different spectrum of activity than cisplatin (Cis), it too has two major limitations, namely problems of side-effects and drug resistance. In this study , combined drug action from the combination of Oxa with the phytochemicals andrographolide ( Andro ) , epigallocatechin-3-gallate ( EGCG ) , chlorophyllin ( Chl ) , colchicines ( Col ) , curcumin ( Cur ) and paclitaxel ( Tax ) was evaluated in the human ovarian cancer cell lines A2780 and A2780(cisR ) . The combination index (CI) was used as a measure of synergism (CI<1), addictiveness (CI=1) and antagonism (CI>1). Generally, all the combinations showed greater synergism at a lower concentration (ED(50)) than at higher concentrations (ED(75) and ED(90)). Oxa in binary combination with Col and Tax showed the highest synergism in both the cancer cell lines, when administered 4 h after the phytochemical, with CI at ED(50) ranging from 0.004 to 0.1. The combination of Oxa with the other phytochemicals generally showed greater synergism when Oxa was administered 4 h before the phytochemical. Appropriately sequenced combination of Oxa with tumor active phytochemicals produces marked synergistic effects in cisplatin resistant as well as non-resistant ovarian cancer cell lines and may offer the means of overcoming drug resistance in ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/22199293/"}
{"doc_id": "9ef762a2a01d3569685f5e98013ae2a6", "sentence": "Bevacizumab and intetumumab can be administered safely in combination .", "spans": [{"span_id": 0, "text": "Bevacizumab", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "intetumumab", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors. Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks \u03b1v integrins when complexed with \u03b2 integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. ### methods Patients with refractory solid tumors, Karnofsky performance status \u226570%, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. ### results Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. ### conclusions Bevacizumab and intetumumab can be administered safely in combination . bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.", "source": "https://pubmed.ncbi.nlm.nih.gov/25527204/"}
{"doc_id": "7768631e00096b41ac8aa6992665bf23", "sentence": "The key findings were that amsacrine produced comparable levels of cell killing with both alpha and beta , whilst etoposide , doxorubicin and mitoxantrone produced higher degrees of cell killing with alpha than with beta or yeast topoisomerase II .", "spans": [{"span_id": 0, "text": "amsacrine", "start": 27, "end": 36, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "etoposide", "start": 114, "end": 123, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "doxorubicin", "start": 126, "end": 137, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "mitoxantrone", "start": 142, "end": 154, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Complementation of temperature-sensitive topoisomerase II mutations in Saccharomyces cerevisiae by a human TOP2 beta construct allows the study of topoisomerase II beta inhibitors in yeast. We show herein that human DNA topoisomerase II beta is functional in yeast. It can complement a yeast temperature-sensitive mutation in topoisomerase II. The effect on human topoisomerase II beta of a number of topoisomerase II inhibitors was analysed in a yeast in vivo system and compared with that of human topoisomerase II alpha and wild-type yeast topoisomerase II. A drug permeable yeast strain (JN394 top2-4) was used to analyse the in vivo effects of known anti-topoisomerase II agents on human topoisomerase II beta transformants. A parallel analysis on human topoisomerase II alpha transformants provides the first in vivo analysis of the responses of yeast bearing the individual isoforms to these drugs. The strain was analysed at 35 degrees C, a non-permissive temperature at which only plasmid-borne topoisomerase II is active. A shuttle vector with either human topoisomerase II beta, human topoisomerase II alpha or yeast topoisomerase II under the control of a GAL1 promoter was used. The key findings were that amsacrine produced comparable levels of cell killing with both alpha and beta , whilst etoposide , doxorubicin and mitoxantrone produced higher degrees of cell killing with alpha than with beta or yeast topoisomerase II . Merbarone had the greatest effect on the yeast strain bearing plasmid-borne yeast topoisomerase II. Suramin, quercetin and genistein showed little cell killing in this system. This yeast in vivo system provides a powerful way to analyse the effects of anti-topoisomerase II agents on transformants bearing the individual human isoforms. This system also provides a means of analysing putative drug-resistance mutations in human topoisomerase II beta or to select for drug-resistance mutations in human topoisomerase II beta.", "source": "https://pubmed.ncbi.nlm.nih.gov/9025779/"}
{"doc_id": "3bd47c43bdafcc2ae400aa4d28b3022a", "sentence": "In the full study population , there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival ( hazard ratio [ HR ] 0\u00b791 , 95 % CI 0\u00b783 - 0\u00b799 ; p=0\u00b704 ) , time to recurrence ( 0\u00b784 , 0\u00b775 - 0\u00b793 ; p=0\u00b7001 ) , and time to distant recurrence ( 0\u00b787 , 0\u00b777 - 0\u00b799 ; p=0\u00b703 ) .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 74, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "tamoxifen", "start": 110, "end": 119, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. The Arimidex, tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months. ### methods We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. ### findings Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population , there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival ( hazard ratio [ HR ] 0\u00b791 , 95 % CI 0\u00b783 - 0\u00b799 ; p=0\u00b704 ) , time to recurrence ( 0\u00b784 , 0\u00b775 - 0\u00b793 ; p=0\u00b7001 ) , and time to distant recurrence ( 0\u00b787 , 0\u00b777 - 0\u00b799 ; p=0\u00b703 ) . For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0\u00b786, 95% CI 0\u00b778-0\u00b795; p=0\u00b7003), time to recurrence (0\u00b779, 0\u00b770-0\u00b789; p=0\u00b70002), and time to distant recurrence (0\u00b785, 0\u00b773-0\u00b798; p=0\u00b702). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2\u00b77% at 5 years and 4\u00b73% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0\u00b781, 95% CI 0\u00b767-0\u00b798; p=0\u00b703), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0\u00b787, 95% CI 0\u00b774-1\u00b702; p=0\u00b709), but there was little difference in overall mortality (0\u00b795, 95% CI 0\u00b784-1\u00b706; p=0\u00b74). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1\u00b733, 95% CI 1\u00b715-1\u00b755; p<0\u00b70001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0\u00b798, 95% CI 0\u00b774-1\u00b730; p=0\u00b79). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0\u00b757, 95% CI 0\u00b748-0\u00b769; p<0\u00b70001), but were similar after treatment completion (66 vs 78; OR 0\u00b784, 95% CI 0\u00b760-1\u00b719; p=0\u00b73). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported. ### interpretation These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/21087898/"}
{"doc_id": "74cc59748549558a9b00fd53720fdd4a", "sentence": "The optimal correlation coefficients for norfloxacin , enrofloxacin , and ofloxacin in the prediction set were obtained with multiple linear regression that combined absorption peaks with wavelengths selected by stepwise regression , which were 0.867 , 0.828 , and 0.964 , respectively .", "spans": [{"span_id": 0, "text": "norfloxacin", "start": 41, "end": 52, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "enrofloxacin", "start": 55, "end": 67, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "ofloxacin", "start": 74, "end": 83, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Analysis of fluoroquinolones antibiotic residue in feed matrices using terahertz spectroscopy. As antibiotic residue becomes more and more serious all over the world, a rapid and effective detection method is needed to evaluate the antibiotic residue in feed matrices to ensure food safety for consumers. In this study, three different kinds of fluoroquinolones (norfloxacin, enrofloxacin, and ofloxacin) in feed matrices were analyzed using terahertz (THz) spectroscopy, respectively. Meanwhile, pure fluoroquinolones and pure feed matrices were also measured in the same way. Then, the absorption spectra of all of the samples were extracted in the transmission mode. Pure norfloxacin has two absorption peaks at 0.825 and 1.187\u00a0THz, and they could still be observed when mixing norfloxacin with feed matrices. Also, there was an obvious and strong absorption peak for ofloxacin at 1.044\u00a0THz. However, no obvious absorption peak for enrofloxacin was observed, and only a weak absorption peak was located at 0.8\u00a0THz. Then, the different models were established with different chemometrics to identify the fluoroquinolones in feed matrices and determined the fluoroquinolones content in the feed matrices. The least squares support vector machines, Naive Bayes, Mahalanobis distance, and back propagation neural network (BPNN) were used to build the identification model with a Savitzky-Golay filter and standardized normal variate pretreatments. The results show that the excellent classification model was acquired with the BPNN combined with no pretreatment. The optimal classification accuracy was 80.56% in the testing set. After that, multiple linear regression and stepwise regression were used to establish the quantitative detection model for different kinds of fluoroquinolones in feed matrices. The optimal correlation coefficients for norfloxacin , enrofloxacin , and ofloxacin in the prediction set were obtained with multiple linear regression that combined absorption peaks with wavelengths selected by stepwise regression , which were 0.867 , 0.828 , and 0.964 , respectively . Overall, this research explored the potential of identifying the fluoroquinolones in feed matrices using THz spectroscopy without a complex pretreatment process and then quantitatively detecting the fluoroquinolones content in feed matrices. The results demonstrate that THz spectra could be used to identify fluoroquinolones in feed matrices and also detect their content quantitatively, which has great significance for the food safety industry.", "source": "https://pubmed.ncbi.nlm.nih.gov/29400779/"}
{"doc_id": "333bbd0b71066c038075b72815a68105", "sentence": "The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m(2 ) on days 1 , 15 , and 29 , and RT ( 50.4 Gy in 28 1.8-Gy fractions ) .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 31, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "oxaliplatin", "start": 82, "end": 93, "token_start": 14, "token_end": 15}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pilot study of gefitinib, oxaliplatin, and radiotherapy for esophageal adenocarcinoma: tissue effect predicts clinical response. Overexpression of epidermal growth factor receptor (EGFR) in esophageal cancer is associated with poor prognosis. Preclinical studies indicate synergism between the EGFR inhibitor gefitinib and oxaliplatin or radiotherapy (RT). We report here early results of a planned phase I/II study of gefitinib, oxaliplatin, and RT for locally advanced, unresectable esophageal cancer. ### Methods And Materials The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m(2 ) on days 1 , 15 , and 29 , and RT ( 50.4 Gy in 28 1.8-Gy fractions ) . Four-quadrant biopsies were obtained at 1-cm intervals along the length of the tumor before and after treatment and the specimens were immunostained for EGFR, Erk, Akt, and their phosphorylated (activated) forms. ### results Enrollment was halted at 6 evaluable cases [all male; median age, 72.5 years (range, 51-75); and all with Eastern Cooperative Oncology Group performance status of 1]. All 6 tumors were adenocarcinomas; 5 were stage III and 1 stage IVA. oxaliplatin was given at 85 mg/m(2) in 3 cases and at 100 mg/m(2) in 3 cases. gefitinib therapy lasted a median 24 weeks; the median number of oxaliplatin doses was 6.5. Best responses were mucosal complete response (n = 1), partial response (n = 1), stable disease (n = 1), and progressive disease (n = 3). EGFR was expressed by tumor in 5 cases and Erk and Akt in 6 cases before treatment; no changes were noted after treatment. EGFR expression did not correlate with survival or response. No grade 4 toxicities were noted; grade 3 toxicities were diarrhea (n = 1), vomiting (n = 1), fatigue (n = 1), and constipation (n = 2). Median overall and disease-free survival times were 10.8 months and 8.4 months. ### conclusions gefitinib in combination with oxaliplatin and RT was tolerable, but had limited clinical activity and did not down-regulate total or activated EGFR, Akt, or Erk in esophageal tumor samples.", "source": "https://pubmed.ncbi.nlm.nih.gov/18845990/"}
{"doc_id": "63a2b77527a0d3a6b7af107f664cf52b", "sentence": "The efflux curves observed for both verapamil and prochlorperazine could be mathematically modeled by assuming", "spans": [{"span_id": 0, "text": "verapamil", "start": 36, "end": 45, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "prochlorperazine", "start": 50, "end": 66, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "The cationic lipid stearylamine reduces the permeability of the cationic drugs verapamil and prochlorperazine to lipid bilayers: implications for drug delivery. The therapeutic activity of a wide variety of drugs is significantly improved when their longevity in the circulation is extended by encapsulation in liposomes. To improve the retention of cationic drugs in liposomes, we have investigated the effect of the cationic lipid stearylamine on the permeability of the calcium channel blocker verapamil and the antipsychotic drug prochlorperazine, both of which are also multidrug resistance modulators. Both drugs were efficiently incorporated into liposomes composed of DSPC/cholesterol that possessed a transmembrane pH gradient (inside acidic). However, the efflux of the loaded drugs was relatively rapid (i.e., 50% of the encapsulated verapamil was released after 4 h at 37 degrees C), despite the presence of a 3 unit pH gradient (pHi = 4.0, pHo = 7.5). Drug retention within the liposomes was improved by increasing the magnitude of the transmembrane pH gradient to approx. 5 units (pHi = 2.0, pHo = 7.5). Further improvements in drug retention were achieved by the addition of 10 mol% of the cationic lipid stearylamine in the DSPC/cholesterol liposomes. The combination of the 5 unit pH gradient and stearylamine resulted in increases of the retention of verapamil and prochlorperazine by approx. 20- and 5-fold, respectively. Calculation of the permeability coefficients for the charged (cationic) and neutral forms of the drugs indicated that the neutral forms of both drugs were approx. 10(4)-fold more permeable than were the cationic forms of the drugs. Further, the presence of stearylamine reduced the permeability coefficient for the cationic species of the drugs by approximately an order of magnitude, but had no effect on the neutral species of the drugs. The efflux curves observed for both verapamil and prochlorperazine could be mathematically modeled by assuming that the primary influence of stearylamine was on the development of a positive surface charge density on the inner monolayer of the liposome. Taken in sum, these results indicate that stearylamine is effective at decreasing the leakage of cationic drugs from liposomes, and may prove to be a valuable component of liposomal drug formulations.", "source": "https://pubmed.ncbi.nlm.nih.gov/7548129/"}
{"doc_id": "1f087a954b04aab5fc7970966aca70cd", "sentence": "The in vitro concentration-effect relationships for , chloroquine , mefloquine , lumefantrine and artesunate , were derived from clinical isolates obtained from patients on the western border of Thailand .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 54, "end": 65, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "mefloquine", "start": 68, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "lumefantrine", "start": 81, "end": 93, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "artesunate", "start": 98, "end": 108, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Nonlinear mixed-effects modelling of in vitro drug susceptibility and molecular correlates of multidrug resistant Plasmodium falciparum. The analysis of in vitro anti-malarial drug susceptibility testing is vulnerable to the effects of different statistical approaches and selection biases. These confounding factors were assessed with respect to pfmdr1 gene mutation and amplification in 490 clinical isolates. Two statistical approaches for estimating the drug concentration associated with 50% effect (EC50 ) were compared: the commonly used standard two-stage (STS) method, and nonlinear mixed-effects modelling. The in vitro concentration-effect relationships for , chloroquine , mefloquine , lumefantrine and artesunate , were derived from clinical isolates obtained from patients on the western border of Thailand . All isolates were genotyped for polymorphisms in the pfmdr1 gene. The EC50 estimates were similar for the two statistical approaches but 15-28% of isolates in the STS method had a high coefficient of variation (>15%) for individual estimates of EC50 and these isolates had EC50 values that were 32 to 66% higher than isolates derived with more precision. In total 41% (202/490) of isolates had amplification of pfmdr1 and single nucleotide polymorphisms were found in 50 (10%). Pfmdr1 amplification was associated with an increase in EC50 for mefloquine (139% relative increase in EC50 for 2 copies, 188% for 3+ copies), lumefantrine (82% and 75% for 2 and 3+ copies respectively) and artesunate (63% and 127% for 2 and 3+ copies respectively). In contrast pfmdr1 mutation at codons 86 or 1042 were associated with an increase in chloroquine EC50 (44-48%). Sample size calculations showed that to demonstrate an EC50 shift of 50% or more with 80% power if the prevalence was 10% would require 430 isolates and 245 isolates if the prevalence was 20%. In conclusion, although nonlinear mixed-effects modelling did not demonstrate any major advantage for determining estimates of anti-malarial drug susceptibility, the method includes all isolates, thereby, potentially improving confirmation of candidate molecular markers of anti-malarial drug susceptibility.", "source": "https://pubmed.ncbi.nlm.nih.gov/23894496/"}
{"doc_id": "6621bb3ae6f16fa28ac7aea66b0ff743", "sentence": "Forty-eight patients were treated with mitoxantrone alone , 40 with mitoxantrone plus beta-interferon , 11 with fluorouracil plus folinic acid and the remaining four with adriamycin .", "spans": [{"span_id": 0, "text": "mitoxantrone", "start": 39, "end": 51, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "mitoxantrone", "start": 68, "end": 80, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "fluorouracil", "start": 112, "end": 124, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "folinic acid", "start": 130, "end": 142, "token_start": 18, "token_end": 20}, {"span_id": 4, "text": "beta-interferon", "start": 86, "end": 101, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [1, 4], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Prognostic factors in patients affected by hepatocellular carcinoma treated with systemic chemotherapy: the experience of the National Cancer Institute of Milan. Survival times and overall response rates are generally poor in patients with unresectable hepatocellular carcinoma submitted to systemic chemotherapy. Limited data are reported in the literature concerning the factors influencing survival among this subset of patients but the distribution of these variables may affect the results of clinical trials. ### Patients And Methods The data on 103 patients undergoing systemic chemotherapy at the Istituto Nazionale Tumori from January 1988 through July 1991 have been analyzed using univariate and Cox multivariate analysis. Forty-eight patients were treated with mitoxantrone alone , 40 with mitoxantrone plus beta-interferon , 11 with fluorouracil plus folinic acid and the remaining four with adriamycin . ### results Median survival time, and 6-month and 12-month survival rates, were 7.1, 55% and 29%, respectively. Lactate dehydrogenase value (P = 0.0009), TNM stage (P = 0.001), vascular invasion (P = 0.001), bilirubin (P = 0.008), Child status (P = 0.01), aspartate amino-transferase (P = 0.02), extent of liver involvement (P = 0.02) and performance status (P = 0.03) were the most significant factors influencing survival in univariate analysis. In the multivariate analysis, aspartate amino-transferase (P = 0.02) and, particularly, TNM stage (p = 0.0009) were confirmed as independent variables correlating with survival. A prognostic index was calculated on the basis of these factors and high- and low-risk groups were identified. Median survival time and 12-month survival were 11.1 months and 43% for the low-risk group, and 4.0 months and 9% for the high-risk group (p = 0.0005). ### conclusion The results of this analysis may provide guidance for the design of future therapeutic trials in unresectable hepatocellular carcinoma. In particular, patient stratification should be considered for further clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/8394736/"}
{"doc_id": "6556ed7ec43351f47276edd66fb4a943", "sentence": "Fifty-one HIV-negative patients with an average age of 50.3 years were treated with chemotherapy regimen included 2500 mg/m(2 ) MTX with Leucovorin rescue and 1.4 mg/m(2 ) vincristine ( day two ) , which was administered every other week for 6 weeks .", "spans": [{"span_id": 0, "text": "Leucovorin", "start": 137, "end": 147, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "vincristine", "start": 172, "end": 183, "token_start": 27, "token_end": 28}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Treatment of Primary Central Nervous System Lymphoma with High-dose Methotrexate and Radiotherapy in HIV-negative Patients. We assessed the outcome of high-dose methotrexate (HD-MTX) chemotherapy with or without radiotherapy (RT) in primary central nervous system lymphoma (PCNSL) patients. ### methods Fifty-one HIV-negative patients with an average age of 50.3 years were treated with chemotherapy regimen included 2500 mg/m(2 ) MTX with Leucovorin rescue and 1.4 mg/m(2 ) vincristine ( day two ) , which was administered every other week for 6 weeks . Only the patients who were younger than 60 years received RT. All patients received two cycles of 3000 mg/m(2) cytarabine at the end of the treatment for two successive days. ### results Diffuse large B-cell lymphoma was the most common histologic subtype (90.2%), and twenty-six (51.0%)patients had multiple brain lesions. The median survival of patients who were younger than 60 years was 37 months. For patients who were older than 60 years, the median survival was 20 months. The median survival of men and women were 30 and 34 months, respectively. There was no significant difference in survival of patients in terms of age and sex. Overall, sixteen patients (31%) out of fifty-one patients died, five of them were older than 60 years and eleven were younger than 60 years. Twenty-five (49%) of all patients experienced relapse, and 10 (40%) of them died after rechemotherapy. ### conclusions The base of our chemotherapy regimen was HD-MTX as the regular doses of MTX cannot penetrate the blood brain barrier (BBB). Our results indicated that the combination of HD-MTX with RT may not influence the outcome of PCNSL; thus, RT cannot be the first line therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/26317598/"}
{"doc_id": "aa64cc4e50f7476207f460edbe742bba", "sentence": "Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors : a Children 's Oncology Group study .", "spans": [{"span_id": 0, "text": "decitabine", "start": 17, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxorubicin", "start": 33, "end": 44, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "cyclophosphamide", "start": 49, "end": 65, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}, {"class": "NEG", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors : a Children 's Oncology Group study . Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. ### procedure Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m(2)) and cyclophosphamide (1 g/m(2)) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. ### results The maximum-tolerated dose of decitabine was 5 mg/m(2)/day for 7 days. Dose-limiting toxicities at 10 mg/m(2)/day were neutropenia and thrombocytopenia. decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for > or = 4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. ### conclusion Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deacetylase inhibitors should be explored.", "source": "https://pubmed.ncbi.nlm.nih.gov/20589651/"}
{"doc_id": "13876a1ea5fd417c7bfb9f3330b8c313", "sentence": "Tail-flick test showed that tramadol produced better antinociceptive effect than gabapentin .", "spans": [{"span_id": 0, "text": "tramadol", "start": 28, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "gabapentin", "start": 81, "end": 91, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "The antinociceptive effects of systemic administration of tramadol, gabapentin and their combination on mice model of acute pain. The aim of the present study was to investigate the possible antinociceptive effects of systemic administration of tramadol and gabapentin either alone or in combination on acute pain models in mice. ### methods After obtaining the approval of Animal Ethics Committee; 96 BALB/c albino male mice were divided into 12 groups: (I) control without injection, (II) control treated with saline, (III)-(IV) mice treated with tramadol 10 mg/kg or 30 mg/kg, (V)-(VIII) mice treated with gabapentin; 30, 100, 200, 300 mg/kg respectively. In order to determine possible interactions between tramadol gabapentin and; mice received four different combinations of tramadol + gabapentin (30+30, 30+100, 30+200 and 30+300 mg/kg) (Groups IX-XII respectively). Mice received 0.1 ml solution for every 10 g of their weight. The drug was injected into peritonea. Thirty minutes after the drug injection, tail-flick and hot-plate tests were conducted. ### results Ten and 30 mg/kg tramadol produced dose dependent antinociceptive effect in tail-flick and hot plate tests. gabapentin had no antinociceptive effect in the tail flick test except 300 mg/kg dose, and had dose dependent antinociceptive effect in hot-plate test. In both tests, various combinations of tramadol and gabapentin produced an antinociceptive effect that is greater than that produced by tramadol and gabapentin alone. But, just 30 mg/kg tramadol + 300 mg/kg gabapentin combination caused statistically significant increase in both tests (p<0.05). ### conclusion When gabapentin and tramadol were used in combination, gabapentin had no additive antinociceptive effect except for 300 mg/kg in tail-flick and hot-plate tests. Tail-flick test showed that tramadol produced better antinociceptive effect than gabapentin .", "source": "https://pubmed.ncbi.nlm.nih.gov/22865488/"}
{"doc_id": "84db443a60cee772007ee38cd9fe366f", "sentence": "Our study involves a preliminary phase II trial , which evaluates the activity , feasibility and tolerability of a sequential combination of docetaxel and gemcitabine followed by docetaxel and carboplatin , as first-line treatment for inoperable NSCLC .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 141, "end": 150, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "gemcitabine", "start": 155, "end": 166, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "docetaxel", "start": 179, "end": 188, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "carboplatin", "start": 193, "end": 204, "token_start": 29, "token_end": 30}], "rels": [{"class": "POS", "spans": [0, 1, 3], "is_context_needed": true}], "paragraph": "A phase II study of sequential docetaxel and gemcitabine followed by docetaxel and carboplatin as first-line therapy for non-small cell lung cancer.  Our study involves a preliminary phase II trial , which evaluates the activity , feasibility and tolerability of a sequential combination of docetaxel and gemcitabine followed by docetaxel and carboplatin , as first-line treatment for inoperable NSCLC . Twenty-six chemo-na\u00efve patients aged less than 75 years with histologically or cytologically confirmed unresectable stage IIIB, IV or relapsed post-operative metastatic NSCLC were included in the study. gemcitabine 1,250 mg/m(2) was administered and was followed by docetaxel 65 mg/m(2). Treatment was administered on days 1 and 14 in a 28-day cycle for three consecutive cycles. If patients had no progressive disease after three cycles of chemotherapy, they received another three cycles of docetaxel 65 mg/m(2) followed by carboplatin AUC5 on day 1 in a 21-day cycle. Recombinant human granocyte colony-stimulating factor (rhG-CSF) was given prophylactically. In addition, all patients received standard pre- and post- treatment with oral dexamethasone. Response rates at three cycles were: 19% achieved a partial response (PR), 46% had stable disease (SD) and 23% had progressive disease. At six cycles, 8% of the patients maintained PR, 19% showed SD and 35% had progressive disease. The median time-to-disease progression was 6 months. The median survival time of patients was 10 months while, at the end of the first year, the patients who managed to get through the complete therapy (20 patients) had a survival rate of 38%. This detailed analysis of 20 patients showed that 80% of the patients survived for up to 6 months, 38% up to 12 months and 19% for more than a year. The only risk factor associated with the hazard of death among the factors studied was the performance status of the patients. Patients with PS=0 presented a median survival time of 13 months and those with PS=1, it was only 9 months. Non-haematological and haematological toxic effects were generally mild to moderate and entirely manageable.", "source": "https://pubmed.ncbi.nlm.nih.gov/18204976/"}
{"doc_id": "72f38214c809afe54fa6dec8941d6ce8", "sentence": "The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome .", "spans": [{"span_id": 0, "text": "galunisertib", "start": 19, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "sorafenib", "start": 36, "end": 45, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Phase 2 Study of Galunisertib (TGF-\u03b21 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma. Inhibition of tumor growth factor-\u03b2 (TGF-\u03b2) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). galunisertib is a small-molecule selective inhibitor of TGF-\u03b21 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. ### methods The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-\u03b21, safety, overall survival (OS), response rate, and pharmacokinetics (PK). ### results Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-\u03b21 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). ### discussion The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome .", "source": "https://pubmed.ncbi.nlm.nih.gov/31295152/"}
{"doc_id": "e011193be897784c42a549400738bd35", "sentence": "All the patients were conditioned with busulfan ( BU ) 12 mg.kg-1 and cyclophosphamide ( CY ) 3.6 g.m-2 , of whom 4 were conditioned with additioned antithymocyte globulin(ATG ) .", "spans": [{"span_id": 0, "text": "busulfan", "start": 39, "end": 47, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "cyclophosphamide", "start": 70, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "antithymocyte globulin(ATG", "start": 149, "end": 175, "token_start": 27, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Human leukocyte antigen mismatched hemopietic stem cell transplants for the treatment of leukemia]. To explore the feasibility of HLA mismatched hemopietic stem cell transplants for the treatment of leukemia. ### methods Between July 2000 and December 2001, seven patients received hemopietic stem cell transplants(HSCT) with HLA mismatched family donors, including 3 chronic myelocytic leukemia (CML), 3 acute nonlymphocytic leukemia (ANLL), and 1 acute lymphocytic leukemia (ALL). Stem cell sources were bone marrow(n = 1) or G-CSF mobilized peripheral blood (n = 6). All the patients were conditioned with busulfan ( BU ) 12 mg.kg-1 and cyclophosphamide ( CY ) 3.6 g.m-2 , of whom 4 were conditioned with additioned antithymocyte globulin(ATG ) . Graft versus host disease (GVHD) prophylaxis regimen consisted of cyclosporin-A (CSA), methotrexate (MTX) and mycophenolate mofetil(MMF). ### results One patients received 3.41 x 10(8) kg-1 mononuclear cells(MNC) from bone marrow; six patients received a mean number of 8.46 x 10(8) kg-1 (4.3 x 10(8)-15.4 x 10(8) kg-1) MNC from peripheral blood. The mean time of ANC > 0.5 x 10(9) L-1 was day 13 (11-16), and BPC > 20.0 x 10(9) L-1 was day 16 (11-23). All the patients got engraftment successfully and attained CR. Acute I-II GVHD occurred in 3(42.9%) patients, no acute III-IV GVHD occurred and extensive chronic GVHD did in 2(28.6%) patients. All the patients were alive and well after 6-24 months' follow-up. ### conclusion (1) BU/CY plus ATG appears to be an effective conditioning regimen for HLA mismatched allogenic stem cell transplants. (2) G-CSF mobilized peripheral blood stem cells may be the source of stem cells even for HLA mismatched hemopietic stem cell transplants.", "source": "https://pubmed.ncbi.nlm.nih.gov/12920822/"}
{"doc_id": "9a1b4790ee47a73210561eb4db593e83", "sentence": "Phase II study of an intensive combination chemotherapy with cisplatin , adriamycin , etoposide and cyclophosphamide ( CAVE ) in small cell lung cancer .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 61, "end": 70, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "adriamycin", "start": 73, "end": 83, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "etoposide", "start": 86, "end": 95, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "cyclophosphamide", "start": 100, "end": 116, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Phase II study of an intensive combination chemotherapy with cisplatin , adriamycin , etoposide and cyclophosphamide ( CAVE ) in small cell lung cancer . One hundred and twelve patients with small cell lung cancer (SCLC) were treated with a combination (CAVE) of cisplatin (60 mg/m2 day 1), adriamycin (45 mg/m2 day 1), etoposide (80 mg/m2 days 1-2-3) and cyclophosphamide (1 g/m2 day 1) given every 4 weeks. A total of 10 courses were given. Response evaluation was initially evaluated after the first two courses of CAVE and repeated at least after treatment completion. This regimen was associated with severe hematological toxicity, mainly leucopenia; five toxic deaths related to sepsis were observed. One hundred and one patients were evaluable for response: 63 with limited disease and 49 with extensive disease. Overall complete and partial response rates after the first two courses of chemotherapy were 16% and 63% respectively but 14 late complete responses were documented, leading to a 30% total complete response rate; 38% in patients with limited disease and 19% in those with disseminated disease. Median overall survival was 46 weeks with a 17% 2 year survival. The only significant prognostic factor for survival was the type of response. There was no survival difference between 'early' and 'late' complete responders. Complete responders had a 75 week median survival time with a 34% 2 year survival. CAVE is thus an effective regimen for SCLC, but with a considerable toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/2838289/"}
{"doc_id": "e75884e8d96c3040a948221a74fcc92f", "sentence": "These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF : amiodarone , sotalol and class 1c agents ( flecainide and propafenone ) .", "spans": [{"span_id": 0, "text": "amiodarone", "start": 107, "end": 117, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "sotalol", "start": 120, "end": 127, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "flecainide", "start": 150, "end": 160, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "propafenone", "start": 165, "end": 176, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Dronedarone for the treatment of atrial fibrillation: a NICE single technology appraisal. The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq\u00ae, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF : amiodarone , sotalol and class 1c agents ( flecainide and propafenone ) . The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below \u00a320,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around \u00a319,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.", "source": "https://pubmed.ncbi.nlm.nih.gov/22136303/"}
{"doc_id": "e83777d937c0c9e8b04aebf93acb357b", "sentence": "First-line PFS for sorafenib , sunitinib , temsirolimus , everolimus , and \" other \" was 6.9 , 8.9 , 4.2 , not analyzed ( too few patients ) , and 10.8 months , respectively .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "sunitinib", "start": 31, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "temsirolimus", "start": 43, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "everolimus", "start": 58, "end": 68, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "\"Real world\" treatment of metastatic renal cell carcinoma in a joint community-academic cohort: progression-free survival over three lines of therapy. New targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies. ### Patients And Methods Drawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and \"other\") for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses. ### results PFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib , sunitinib , temsirolimus , everolimus , and \" other \" was 6.9 , 8.9 , 4.2 , not analyzed ( too few patients ) , and 10.8 months , respectively . Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy. ### conclusion Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident.", "source": "https://pubmed.ncbi.nlm.nih.gov/23856102/"}
{"doc_id": "dcf22d47d862a9e7ca895b583d3061dc", "sentence": "Simultaneous treatment with gefitinib and pemetrexed enhanced cell growth inhibition and cell death and prevented the appearance of gefitinib resistance mediated by T790 M mutation or epithelial-to-mesenchymal transition ( EMT ) in PC9 and HCC827 cells , respectively .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 28, "end": 37, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "pemetrexed", "start": 42, "end": 52, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "gefitinib", "start": 132, "end": 141, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination of Gefitinib and Pemetrexed Prevents the Acquisition of TKI Resistance in NSCLC Cell Lines Carrying EGFR-Activating Mutation. Development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is a clinical issue in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC). The aim of this study was to investigate the potential of combining gefitinib and pemetrexed in preventing the acquisition of resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines harboring EGFR exon 19 deletion. ### methods The effect of different combinatorial schedules of gefitinib and pemetrexed on cell proliferation, cell cycle, apoptosis, and acquisition of gefitinib resistance in PC9 and HCC827 NSCLC cell lines and in PC9 xenograft models was investigated. ### results Simultaneous treatment with gefitinib and pemetrexed enhanced cell growth inhibition and cell death and prevented the appearance of gefitinib resistance mediated by T790 M mutation or epithelial-to-mesenchymal transition ( EMT ) in PC9 and HCC827 cells , respectively . In PC9 cells and in PC9 xenografts the combination of gefitinib and pemetrexed, with different schedules, prevented gefitinib resistance only when pemetrexed was the first treatment, given alone or together with gefitinib. Conversely, when gefitinib alone was administered first and pemetrexed sequentially alternated, a negative interaction was observed and no prevention of gefitinib resistance was documented. The mechanisms of resistance that developed in\u00a0vivo included T790M mutation and EMT. The induction of EMT was a feature of tumors treated with gefitinib when given before pemetrexed, whereas T790M was recorded only in tumors treated with gefitinib alone. ### conclusions The combination of gefitinib and pemetrexed is effective in preventing gefitinib resistance; the application of intermittent treatments requires that gefitinib not be administered before pemetrexed.", "source": "https://pubmed.ncbi.nlm.nih.gov/27006151/"}
{"doc_id": "f23c04d1cfa9c526da88afe28383d0e8", "sentence": "Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin ( 500 and 800 mg/m(2 ) per course , respectively ) were administered after surgery .", "spans": [{"span_id": 0, "text": "etoposide", "start": 63, "end": 72, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "carboplatin", "start": 78, "end": 89, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. ### Patients And Methods Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin ( 500 and 800 mg/m(2 ) per course , respectively ) were administered after surgery . Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. ### results Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. ### conclusion Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.", "source": "https://pubmed.ncbi.nlm.nih.gov/16034048/"}
{"doc_id": "060d0d773e51ed4d195d2697f39b9d90", "sentence": "Azithromycin , doxycycline , and moxifloxacin hydrochloride were shown to relieve symptoms but were not as effective after continuous usage .", "spans": [{"span_id": 0, "text": "Azithromycin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxycycline", "start": 15, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "moxifloxacin", "start": 33, "end": 45, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "A case of human infection with a novel Babesia species in China. Babesiosis is an uncommon but emerging tick-borne disease caused by the genus Babesia. In this case study, we report a case of human infection with a novel Babesia sp. in China. ### findings The patient in question had been suffering from repetitive occurrences of mild fever of unknown origin and fatigue for 10 years. Ring forms, tetrads, and one or two dots of chromatin or trophozoite-like organisms were observed in the patient's thin blood smears and bone marrow smears. Using a confocal laser-scanning microscope, it was observed that the patient's serum had reactivity with the surface proteins of the B. microti strain. Electron microscopy revealed oval red blood cells with 1\u2009~\u20092 \u03bcm of knob protrusions in the cellular membrane. The results of the Babesia-specific nested PCR assay for 18S rRNA confirmed the presence of Babesia infection. The construction of a phylogenetic relationship showed clustering with B. microti and B. duncani, which was identified as a novel Babesia species and named as Babesia sp. XXB/HangZhou. Azithromycin , doxycycline , and moxifloxacin hydrochloride were shown to relieve symptoms but were not as effective after continuous usage . After atovaquone (Mepron\u00ae) administration, the patient recovered from fever and tested negative for detection of Babesia-specific genes. ### conclusion Babesia sp. XXB/HangZhou is a novel Babesia species, which causes mild babesiosis in an immunocompetent patient.", "source": "https://pubmed.ncbi.nlm.nih.gov/27025290/"}
{"doc_id": "0222ad5a8d7b268dfac452940ab10aae", "sentence": "Travellers used doxycycline ( 15 % ) for malaria prophylaxis , 11 % took an antibiotic for travellers ' diarrhoea ( TD ) treatment ( fluoroquinolone 7 % , azithromycin 4 % ) .", "spans": [{"span_id": 0, "text": "doxycycline", "start": 16, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "azithromycin", "start": 155, "end": 167, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Travel-associated multidrug-resistant organism acquisition and risk factors among US military personnel. International travel is a risk factor for incident colonization with extended spectrum beta-lactamase (ESBL)-producing organisms. These and other multidrug-resistant (MDR) bacteria are major pathogens in combat casualties. We evaluated risk factors for colonization with MDR bacteria in US military personnel travelling internationally for official duty. ### methods TravMil is a prospective observational study enrolling subjects presenting to military travel clinics. We analysed surveys, antimicrobial use data, and pre- and post-travel perirectal swabs in military travellers to regions outside the continental USA, Canada, Western or Northern Europe, or New Zealand, presenting to one clinic from 12/2015 to 12/2017. Recovered Gram-negative isolates underwent identification and susceptibility testing (BD Phoenix). Characteristics of trip and traveller were analysed to determine risk factors for MDR organism colonization. ### results 110 trips were planned by 99 travellers (74% male, median age 38\u00a0years [IQR 31, 47.25]); 72 trips with returned pre- and post-travel swabs were completed by 64 travellers. Median duration was 21\u00a0days (IQR 12.75, 79.5). 17% travelled to Mexico/Caribbean/Central America, 15% to Asia, 57% to Africa and 10% to South America; 56% stayed in hotels and 50% in dormitories/barracks. Travellers used doxycycline ( 15 % ) for malaria prophylaxis , 11 % took an antibiotic for travellers ' diarrhoea ( TD ) treatment ( fluoroquinolone 7 % , azithromycin 4 % ) . Incident MDR organism colonization occurred in 8 travellers (incidence density 3.5/1000 travel days; cumulative incidence 11% of trips [95% CI: 4-19%]), all ESBL-producing Escherichia coli. A higher incidence of ESBL-producing E. coli acquisition was associated with travel to Asia (36% vs 7%, P\u2009=\u20090.02) but not with travel to other regions, TD or use of antimicrobials. No relationship was seen between fluoroquinolone or doxycycline exposure and resistance to those antimicrobials. ### conclusions Incident colonization with MDR organisms occurs at a lower rate in this military population compared with civilian travellers, with no identified modifiable risk factors, with highest incidence of ESBL acquisition observed after South Asia travel.", "source": "https://pubmed.ncbi.nlm.nih.gov/33675647/"}
{"doc_id": "2b93901ec2000c5b67bd9da8cb04762d", "sentence": "3 . When timolol was administered concomitantly with hydrochlorothiazide , plasma renin activity was suppressed and blood pressure was significantly lowered .", "spans": [{"span_id": 0, "text": "timolol", "start": 9, "end": 16, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "hydrochlorothiazide", "start": 53, "end": 72, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Enhancement of the antihypertensive effect of hydrochlorothiazide in dogs after suppression of renin release by beta-adrenergic blockade. 1. Renal hypertensive dogs were treated with hydrochlorothiazide (8-2 mumol/kg or 33 mumol/kg daily for 7 days), or timolol (4-6 mumol/kg daily for 4 days), a potent beta-adrenergic blocking agent, or combinations of these drugs). Changes in mean arterial blood pressure and plasma renin activity were measured over the treatment period. 2. Neither drug significantly lowered arterial blood pressure when administered alone. Plasma renin activity, which did not change during treatment with timolol, was substantially elevated during treatment with hydrochlorothiazide. 3 . When timolol was administered concomitantly with hydrochlorothiazide , plasma renin activity was suppressed and blood pressure was significantly lowered . 4. These observations suggest that compensatory activation of the renin-angiotensin system limits the antihypertensive activity of hydrochlorothiazide in renal hypertensive dogs and suppression of diuretic-induced renin release by timolol unmasks the antihypertensive effect of the diuretic.", "source": "https://pubmed.ncbi.nlm.nih.gov/234821/"}
{"doc_id": "33dd0f530003bdb85acc6415460c70ba", "sentence": "Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma .", "spans": [{"span_id": 0, "text": "temsirolimus", "start": 39, "end": 51, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "sunitinib", "start": 56, "end": 65, "token_start": 8, "token_end": 9}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma . Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC. ### Patients And Methods Eligibility included advanced RCC and <or= 2 previous systemic regimens. At the starting dose, temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period. ### results In the first cohort, dose-limiting toxicities (grade 3 treatment-related toxicities that lasted >or= 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/microL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/microL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents. ### conclusion Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.", "source": "https://pubmed.ncbi.nlm.nih.gov/19213664/"}
{"doc_id": "50a955738574e2180ca53947a32832d7", "sentence": "Both anastrozole ( 1.0 mg/d ) and letrozole ( 2.5 mg/d ) have now been approved as second-line treatment for hormone-dependent breast cancer in postmenopausal women in whom disease has progressed following tamoxifen treatment .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 5, "end": 16, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "letrozole", "start": 34, "end": 43, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "tamoxifen", "start": 206, "end": 215, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Emerging role of aromatase inhibitors in the treatment of breast cancer. The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme aromatase act by decreasing estrogen production throughout the body in postmenopausal women. The most potent of these agents may also inhibit estrogen synthesis within metastatic breast cancer tissue. The newly developed, orally administered, nonsteroidal competitive inhibitors, such as anastrozole (Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times more potent inhibitors of aromatase than is aminoglutethimide. Furthermore, these agents are highly selective. In several large randomized trials, the new inhibitors produced similar response rates as megestrol acetate (160 mg/d) in postmenopausal women with hormone-dependent breast cancer, but showed a trend toward improved response duration and survival. They also produced less weight gain and fewer cardiovascular and thromboembolic side effects. In addition, letrozole proved superior to aminoglutethimide in another randomized trial. Both anastrozole ( 1.0 mg/d ) and letrozole ( 2.5 mg/d ) have now been approved as second-line treatment for hormone-dependent breast cancer in postmenopausal women in whom disease has progressed following tamoxifen treatment . Either drug should replace the routine use of megestrol acetate in this setting. Ongoing clinical studies are comparing anastrozole and letrozole to antiestrogens as first-line endocrine therapy for metastatic breast cancer. Other trials will study the possible roles of these compounds as adjuvant therapy and chemoprevention for breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/9556789/"}
{"doc_id": "435964f6f8ee59908d3297556750e0bd", "sentence": "P-glycoprotein effluxes a variety of anticancer drugs , such as doxorubicin , vinca alkaloids , etoposide and taxol , and thereby allows cancer cells to show resistance to these drugs .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 64, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "etoposide", "start": 96, "end": 105, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Therapeutic approach to drug resistant tumors. Drug resistance is a major problem in cancer chemotherapy. P-glycoprotein plays a major role in multidrug resistance in cancer cells. P-glycoprotein is expressed in some normal tissues and has physiological functions. These include protecting the brain against toxic substances at the blood-brain barrier site, excreting toxic substances from the liver, kidney, and gastrointestinal tracts, and transporting steroidal hormones in the adrenal grand. Once expressed in cancer cells. P-glycoprotein effluxes a variety of anticancer drugs , such as doxorubicin , vinca alkaloids , etoposide and taxol , and thereby allows cancer cells to show resistance to these drugs .", "source": "https://pubmed.ncbi.nlm.nih.gov/9780138/"}
{"doc_id": "897f9a3302265c3ceed1ad42cae9f915", "sentence": "The H2-receptor antagonists dose-dependently inhibited the histamine-stimulated acid production ( IC50 for cimetidine = 10(-5 ) M and 10(-6 ) M and for ranitidine = 10(-5 ) M and 2 X 10(-7 ) M for high and low concentrations of histamine , respectively ) .", "spans": [{"span_id": 0, "text": "cimetidine", "start": 107, "end": 117, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "ranitidine", "start": 152, "end": 162, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Omeprazole, cimetidine, and ranitidine: inhibition of acid production in isolated human parietal cells. The antisecretory properties of omeprazole, cimetidine, and ranitidine were studied in vitro, using human gastric mucosal cells, which were obtained by sequential pronase and collagenase incubation of small tissue specimens obtained by endoscopic biopsy. Acid production was measured as the accumulation of radioactive aminopyrine in the acid compartments of the parietal cells. Acid production was stimulated via H2-receptors by histamine (10(-4) M or 5 X 10(-6) M) and via intracellular mechanisms by db-cAMP (10(-3) M). omeprazole induced a dose-dependent inhibition of acid production for all stimulators (IC50 = 2 X 10(-7) M and 3 X 10(-8) M with high and low concentrations of histamine, respectively, and 5 X 10(-6) M with db-cAMP). The H2-receptor antagonists dose-dependently inhibited the histamine-stimulated acid production ( IC50 for cimetidine = 10(-5 ) M and 10(-6 ) M and for ranitidine = 10(-5 ) M and 2 X 10(-7 ) M for high and low concentrations of histamine , respectively ) . Neither cimetidine nor ranitidine inhibited acid production after intracellular stimulation with db-cAMP. omeprazole reduced the aminopyrine accumulation stimulated by histamine (10(-4) M) already within 5-10 min, whereas cimetidine (10(-3) M and ranitidine (10(-4) M) required 20-30 min. The unstimulated level of acid production was also inhibited by omeprazole but not by the H2-receptor antagonists.", "source": "https://pubmed.ncbi.nlm.nih.gov/4081628/"}
{"doc_id": "c16e11de09ac91bbdcce0ab321ac08d2", "sentence": "To examine the cost-effectiveness of aripiprazole , quetiapine , and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy .", "spans": [{"span_id": 0, "text": "aripiprazole", "start": 37, "end": 49, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "quetiapine", "start": 52, "end": 62, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder. While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown. ### objective To examine the cost-effectiveness of aripiprazole , quetiapine , and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy . ### methods Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy alone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources. ### results With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine. ### conclusions Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.", "source": "https://pubmed.ncbi.nlm.nih.gov/22550279/"}
{"doc_id": "438212a88b4990ac96ee4e56a46dd644", "sentence": "2 . The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone , but the high dose nifedipine combination was no more effective than the low dose nifedipine combination .", "spans": [{"span_id": 0, "text": "atenolol", "start": 110, "end": 118, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "nifedipine", "start": 145, "end": 155, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "nifedipine", "start": 208, "end": 218, "token_start": 35, "token_end": 36}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability. 1. In a double-blind, randomised, three-way-crossover study, 25 patients with sitting diastolic blood pressure between 95 and 120 mm Hg (Phase V) after 4 weeks' run-in on atenolol 50 mg twice daily, received atenolol 50 mg twice daily alone, atenolol 50 mg plus nifedipine 20 mg each twice daily and atenolol 50 mg plus nifedipine 40 mg each twice daily in three treatment periods each lasting 4 weeks. 'Washout' periods were not included. 2 . The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone , but the high dose nifedipine combination was no more effective than the low dose nifedipine combination . Sitting systolic BP (+/- s.e. mean) at the end of each period was 174 +/- 5 mm Hg after the atenolol run-in, 170 +/- 5 mm Hg with atenolol alone, 156 +/- 5 mm Hg with the low dose combination and 158 +/- 4 mm Hg with the high dose combination. Corresponding diastolic BP readings were 106 +/- 2 mm Hg, 106 +/- 2 mm Hg, 97 +/- 2 mm Hg and 99 +/- 2 mm Hg respectively. 3. Side-effects tended to occur less commonly with the low dose of the fixed combination than with atenolol alone. An increased number of side-effects occurred with the 40 mg twice daily doses of nifedipine, particularly flushing/erythema, oedema of the ankles/feet, and a hot feeling in the legs. These differences did not reach significance. 4. Overall compliance was good (98 +/- 0.7 s.e. mean %) and was similar within the different treatment regimes.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/3289598/"}
{"doc_id": "27cd3f43b9cbb557253aeb707e8c59ce", "sentence": "In addition , a variety of systemic chemotherapeutic agents have been tested in HCC , including various combinations of 5-fluorouracil , doxorubicin , epirubicin , etoposide , cisplatin , and mitoxantrone , as well as interferon , tamoxifen , capecitabine , thalidomide , and octreotide .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 137, "end": 148, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "epirubicin", "start": 151, "end": 161, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "etoposide", "start": 164, "end": 173, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "cisplatin", "start": 176, "end": 185, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "mitoxantrone", "start": 192, "end": 204, "token_start": 30, "token_end": 31}, {"span_id": 5, "text": "tamoxifen", "start": 231, "end": 240, "token_start": 37, "token_end": 38}, {"span_id": 6, "text": "capecitabine", "start": 243, "end": 255, "token_start": 39, "token_end": 40}, {"span_id": 7, "text": "thalidomide", "start": 258, "end": 269, "token_start": 41, "token_end": 42}, {"span_id": 8, "text": "octreotide", "start": 276, "end": 286, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Nonsurgical treatment of hepatocellular carcinoma. While surgical resection and tumor ablation are the preferred therapies for hepatocellular carcinoma (HCC), these are available or appropriate in only a minority of patients. This reflects the usual comorbidity of severe underlying liver disease that either precludes surgery or makes the surgical approach extremely dangerous. Nonetheless, regional control of HCC is highly relevant and many regional strategies have been explored, including hepatic intra-arterial chemotherapy transarterial chemoembolization, lipiodol chemoembolization, radiation therapy, cryosurgery, percutaneous ethanol injection, and radiofrequency ablation. In addition , a variety of systemic chemotherapeutic agents have been tested in HCC , including various combinations of 5-fluorouracil , doxorubicin , epirubicin , etoposide , cisplatin , and mitoxantrone , as well as interferon , tamoxifen , capecitabine , thalidomide , and octreotide . Published data regarding these regional and systemic therapies will be discussed in this review.", "source": "https://pubmed.ncbi.nlm.nih.gov/11685743/"}
{"doc_id": "1841564f5c327bd81bb7274a6552a054", "sentence": "A very reasonable first-choice antidepressant is either sertraline or paroxetine .", "spans": [{"span_id": 0, "text": "sertraline", "start": 56, "end": 66, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "paroxetine", "start": 70, "end": 80, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Depression in Parkinson's Disease. Depression is very common in Parkinson's disease (PD), but its severity and particular symptoms vary. It can often be difficult to diagnose because many of the symptoms typically associated with depression (eg, sleep difficulties, fatigue) can be seen in nondepressed patients with PD, and signs thought to represent depression (eg, lack of facial expression, slowness) can be produced by PD itself. Apathy, although a possible feature of depression, can exist apart from depression and is often associated with cognitive impairment. Therefore, when evaluating patients with PD for possible depression, one should concentrate on the psychological or ideational aspects of the illness. One must determine whether the patient feels sad or hopeless or has a marked inability to enjoy life. Once it has been determined that the patient has clinically significant depressive symptoms, it is important to let him or her know that depression is an aspect of PD requiring treatment, just like the motor manifestations of the disease. The idea of adding antidepressant medications and the possibility of psychotherapy should be introduced. A very reasonable first-choice antidepressant is either sertraline or paroxetine . Because of isolated case reports of worsening motor function associated with institution of a selective serotonin reuptake inhibitor (SSRI), one should keep track of when the medication was started so that the patient can be seen again within a month. It is important from a psychological perspective to have regular follow-up visits when treating depression. If the SSRIs are ineffective or not tolerated, nortriptyline is a good next choice. It has fewer anticholinergic effects and is less likely to cause or worsen orthostatic hypotension than other tricyclic antidepressants. amitriptyline, although an old favorite of neurologists, is very sedating and has too much anticholinergic activity to be well tolerated in the higher doses needed to treat depression. If a patient could benefit from a dopamine agonist from a motor standpoint and his or her depressive symptoms are mild, consider using pramipexole, which may improve mood and motivation (although this has not yet been proven in a well-controlled trial). It is a good idea to keep patients on antidepressant therapy at least 6 months; many patients require long-term treatment. If a patient is severely depressed, he or she should be referred to a psychiatrist, who may consider admission to the hospital and possible electroconvulsive therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/11096753/"}
{"doc_id": "33a31447659a13473eb60f58152b458e", "sentence": "It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI ( fenofibrate , ciprofibrate ) or both apo E and A-I ( gemfibrozil ) .", "spans": [{"span_id": 0, "text": "fenofibrate", "start": 158, "end": 169, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "ciprofibrate", "start": 172, "end": 184, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "gemfibrozil", "start": 211, "end": 222, "token_start": 38, "token_end": 39}], "rels": [], "paragraph": "Gemfibrozil increases both apo A-I and apo E concentrations. Comparison to other lipid regulators in cholesterol-fed rats. HDL cholesterol (HDL-C) was increased by gemfibrozil (+3.6-fold), fenofibrate (+1.3-fold) and ciprofibrate (+1.2-fold) but not clofibrate or bezafibrate when dosed PO at 50 mg/kg for 2 weeks in cholesterol-fed rats. Cholesterol in apo B-containing lipoproteins decreased with gemfibrozil (-76%), clofibrate (-12%) and ciprofibrate (-12%). Plasma apo B decreased to the greatest extent with gemfibrozil (-86%) followed by ciprofibrate (-47%), fenofibrate (-40%), clofibrate (-24%) and bezafibrate (-20%). Only gemfibrozil increased plasma apo E levels which are characteristically low in this rat model. gemfibrozil, fenofibrate and ciprofibrate increased apo A-I concentrations. It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI ( fenofibrate , ciprofibrate ) or both apo E and A-I ( gemfibrozil ) . It is hypothesized that drugs which alter the metabolism of both HDL peptides result in the greatest HDL-C elevation in the rat.", "source": "https://pubmed.ncbi.nlm.nih.gov/3081014/"}
{"doc_id": "6ba484620193fedfad6ddb775e6184f3", "sentence": "To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor ( VEGF ) therapy for choroidal neovascularisation ( CNV ) .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 39, "end": 50, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ranibizumab", "start": 54, "end": 65, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation.  To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor ( VEGF ) therapy for choroidal neovascularisation ( CNV ) . ### methods The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subretinal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). ### results 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. ### conclusions Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/21791509/"}
{"doc_id": "18c6d31cc386a2c4a4842f2ba9325548", "sentence": "Low-risk patients received three cycles of modified CODOX-M ( cyclophosphamide , doxorubicin , adriamycin , vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate , regimen A ) .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 62, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "doxorubicin", "start": 81, "end": 92, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "vincristine", "start": 108, "end": 119, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "methotrexate", "start": 137, "end": 149, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "cytarabine", "start": 154, "end": 164, "token_start": 20, "token_end": 21}, {"span_id": 5, "text": "methotrexate", "start": 196, "end": 208, "token_start": 25, "token_end": 26}, {"span_id": 6, "text": "adriamycin", "start": 95, "end": 105, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 6], "is_context_needed": true}], "paragraph": "Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Burkitt and Burkitt-like lymphomas are rapidly growing tumors which require specialized therapy. Although intensive, multi-agent regimens have been effective in children, results are more variable in adults. Magrath et al. previously described a regimen that was highly effective in children and young adults. This phase II study of a modified Magrath regimen was designed to assess its efficacy in older adults and reduce treatment-related toxicity. Fourteen patients with Burkitt/Burkitt-like lymphoma and median age of 47 years were stratified into two categories: low-risk (normal LDH and a single focus of disease measuring less than 10 cm, 3 patients) and high risk (all other, 11 patients). Low-risk patients received three cycles of modified CODOX-M ( cyclophosphamide , doxorubicin , adriamycin , vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate , regimen A ) . High-risk patients received four alternating cycles of regimens A and B (A-B-A-B). Regimen B consisted of ifosfamide, cytarabine, etoposide and intrathecal methotrexate (IVAC). The modified treatment regimen was associated with no grade 3/4 neuropathy and only one episode of grade 3/4 mucositis. All patients completed protocol therapy and there were no treatment-related deaths. Twelve patients (86%, 90% CI: 61 97%) achieved a complete response; 1 patient achieved a PR and 1 patient died of progressive disease. Nine patients (64%) are alive and disease free at a median follow-up of 29 months. This modified Magrath regimen is effective and well-tolerated in a representative group of older adult patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/15160953/"}
{"doc_id": "2ab0adbbe0f3976d64dcdaa3e633966e", "sentence": "Background The National Wilms Tumor Study ( NWTS ) approach to treating stage III favorable-histology Wilms tumor ( FHWT ) is Regimen DD4A ( vincristine , dactinomycin , and doxorubicin ) and radiation therapy .", "spans": [{"span_id": 0, "text": "vincristine", "start": 141, "end": 152, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "doxorubicin", "start": 174, "end": 185, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "dactinomycin", "start": 155, "end": 167, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group Study AREN0532.  Background The National Wilms Tumor Study ( NWTS ) approach to treating stage III favorable-histology Wilms tumor ( FHWT ) is Regimen DD4A ( vincristine , dactinomycin , and doxorubicin ) and radiation therapy . Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/29211618/"}
{"doc_id": "ee13fff13e99f5f1f6204552cc001ecc", "sentence": "The role of serotonergic neurons in foot shock-induced jumping behavior was evaluated by studying the effects of serotonin agonists and depletors under conditions of increasing activity of catecholaminergic neurons by combining different shock intensities with methamphetamine or clonidine pretreatment .", "spans": [{"span_id": 0, "text": "methamphetamine", "start": 261, "end": 276, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "clonidine", "start": 280, "end": 289, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Serotonergic-catecholaminergic interactions and foot shock-induced jumping behavior in rats.  The role of serotonergic neurons in foot shock-induced jumping behavior was evaluated by studying the effects of serotonin agonists and depletors under conditions of increasing activity of catecholaminergic neurons by combining different shock intensities with methamphetamine or clonidine pretreatment . Low shock (40 V) jumping was suppressed by three different kinds of serotonergic agonists: 5-hydroxytryptophan (50 and 100 mg/kg), 5-methoxydimethyltryptamine (1 and 5 mg/kg) and clomipramine (5 mg/kg) but these drugs did not suppress high shock (60 V) jumping. A depletor of brain serotonin, p-chlorophenylalanine (200 mg/kg), failed to affect the jumping induced by both shock intensities. The inhibitory effect of serotonergic agonists on low shock jumping was abolished by pretreatment with methamphetamine (1 mg/kg) or clonidine (100 micrograms/kg). Furthermore, 5-methoxydimethyltryptamine (5 mg/kg), a serotonergic postsynaptic receptor stimulant, potentiated high shock jumping in rats pretreated with methamphetamine (3 and 5 mg/kg). The results indicated that activation of serotonergic neurons has a differential effect on jumping behavior ranging from inhibitory to facilitatory, depending upon the increasing activity of catecholaminergic neurons.", "source": "https://pubmed.ncbi.nlm.nih.gov/6653659/"}
{"doc_id": "efaf3b6f6b5f664849d17e9c57112c6a", "sentence": "Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy .", "spans": [{"span_id": 0, "text": "leuprolide", "start": 46, "end": 56, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "bicalutamide", "start": 91, "end": 103, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer. Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation. ### methods Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy . Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received. ### results Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %). ### conclusions The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.", "source": "https://pubmed.ncbi.nlm.nih.gov/23604530/"}
{"doc_id": "310fe5ed4e6b2d907d28ff5f621520b5", "sentence": "Clinical studies have indicated the following relative potency differences : fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide .", "spans": [{"span_id": 0, "text": "fluticasone", "start": 77, "end": 88, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "budesonide", "start": 102, "end": 112, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "beclomethasone", "start": 115, "end": 129, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "triamcinolone", "start": 145, "end": 158, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Establishing a therapeutic index for the inhaled corticosteroids: part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. The inhaled corticosteroids contain physicochemical differences that alter both glucocorticoid receptor-binding characteristics and the pharmacokinetic variables of these drugs. Differences in receptor-binding affinity translate into differences in potency for different drugs. Differences in pharmacokinetics, however, determine the topical effect to systemic effect ratio, or the \"pulmonary targeting\" of the drug. Beneficial pharmacokinetic properties that may improve pulmonary targeting include low oral bioavailability, rapid systemic clearance, and slow absorption from the lung. Delivery devices can produce clinically significant differences in topical activity by altering the dose deposited in the lung and, for orally absorbed drugs, the amount deposited in the oropharynx and swallowed. Clinical trials have confirmed that differences in potency or drug delivery of 2-fold or more can be detected in patients with asthma. However, because of the relatively flat nature of the dose-response curve for morning peak expiratory flow and forced expiratory volume in 1 second, the trials must be adequately powered and well controlled. The use of bronchial provocation measures are problematic because of the prolonged lag time for response. Study design flaws can lead to misinterpretation of results. Clinical studies have indicated the following relative potency differences : fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide . Current evidence suggests that potency differences can be overcome by giving larger doses of the less potent drug. However, because of these potency differences, studies of systemic effects should not be done in isolation of adequate topical activity studies to define the pulmonary targeting of the drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/9798722/"}
{"doc_id": "92547edbc8aa1ee6250ed5d19f1b04cf", "sentence": "To evaluate the efficacy and safety of lapatinib ( L ) and trastuzumab ( T ) combination in HER2-positive metastatic breast cancer ( MBC ) patients previously treated with T and/or L.", "spans": [{"span_id": 0, "text": "lapatinib", "start": 39, "end": 48, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "trastuzumab", "start": 59, "end": 70, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study.  To evaluate the efficacy and safety of lapatinib ( L ) and trastuzumab ( T ) combination in HER2-positive metastatic breast cancer ( MBC ) patients previously treated with T and/or L. ### Materials And Methods We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. ### results One hundred and fifteen patients from 14 institutions were included. The median age was 59.8\u00a0years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6\u00a0months, respectively. Heavily pretreated and\u2009\u2265\u20093 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and\u2009<\u20093 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-na\u00efve patients (31.5% versus 40.5% for L-pretreated versus L-na\u00efve). Grade 3/4 adverse events were reported in 19 patients (16.5%). ### conclusion The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.", "source": "https://pubmed.ncbi.nlm.nih.gov/31203575/"}
{"doc_id": "49701c7a424eb30b64f745b9d5bdf83e", "sentence": "Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis .", "spans": [{"span_id": 0, "text": "Meloxicam", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "sorafenib", "start": 24, "end": 33, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis . sorafenib (SOR) is a promising treatment for advanced hepatocellular carcinoma (HCC). However, the precise mechanisms of toxicity and drug resistance have not been fully explored and new strategies are urgently needed for HCC therapy. meloxicam (MEL) is a selective cyclooxygenase-2 (COX-2) inhibitor which elicits antitumor effects in human HCC cells. In the present study, we investigated the interaction between MEL and SOR in human SMMC\u20117721\u00a0cells and the role endoplasmic reticulum (ER) stress exerts in the combination of SOR with MEL treatment-induced cytotoxicity. Our results revealed that the combination treatment synergistically inhibited cell proliferation and enhanced apoptosis. Furthermore, the combination treatment enhanced ER stress-related molecules which involved in SMMC-7721 cell apoptosis. GRP78 knockdown by siRNA or co-treatment with MG132 significantly increased this combination treatment-induced apoptosis. In addition, we found that the combination treatment suppressed tumor growth by way of activation of ER stress in in\u00a0vivo models. We concluded that the combination of SOR with MEL treatment-induced ER stress, and eventually apoptosis in human SMMC-7721\u00a0cells. Knockdown of GRP78 using siRNA or proteosome inhibitor enhanced the cytotoxicity of the combination of SOR with MEL-treatment in SMMC-7721\u00a0cells. These findings provided a new potential treatment strategy against HCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/26252057/"}
{"doc_id": "9509f8edbe454f9760ad599d91515702", "sentence": "We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy ( E2997 ) .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 109, "end": 120, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "cyclophosphamide", "start": 171, "end": 187, "token_start": 25, "token_end": 26}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia. The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy ( E2997 ) . High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.", "source": "https://pubmed.ncbi.nlm.nih.gov/28412730/"}
{"doc_id": "aecf217b9cc205de69a52ac110a4aa53", "sentence": "The antiviral agents ganciclovir and foscarnet are effective against CMV retinitis and gastrointestinal diseases , although dose-limiting adverse effects and the need for long-term maintenance therapy may hinder their use in many patients .", "spans": [{"span_id": 0, "text": "ganciclovir", "start": 21, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "foscarnet", "start": 37, "end": 46, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Treatment and prophylaxis of cytomegalovirus disease. The diseases caused by cytomegalovirus (CMV) may threaten the life or sight of immunocompromised individuals such as patients undergoing transplantation and those with the acquired immunodeficiency syndrome. The management of CMV disease can be difficult. The antiviral agents ganciclovir and foscarnet are effective against CMV retinitis and gastrointestinal diseases , although dose-limiting adverse effects and the need for long-term maintenance therapy may hinder their use in many patients . When used to treat CMV pneumonitis in bone marrow transplant recipients, ganciclovir alone is not as effective as when it is combined with immune globulin. Since CMV disease can be fatal, several protocols have been developed for the transplant patient population, including administration of acyclovir, ganciclovir, screened blood products, and immune globulins.", "source": "https://pubmed.ncbi.nlm.nih.gov/1325636/"}
{"doc_id": "42fcd1c1fa5ccff740b1a69412b2de1f", "sentence": "Switching between metronidazole and clarithromycin seems to be a sensible strategy as these two are the most effective anti-Helicobacter agents .", "spans": [{"span_id": 0, "text": "metronidazole", "start": 18, "end": 31, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "clarithromycin", "start": 36, "end": 50, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Where are We with current therapy? Despite intensive research and widely publicized recommendations from consensus meetings in different continents, the public and primary care physicians are relatively slow in picking up the impact of Helicobacter pylori infection and identifying optimal therapies. The treatment of H. pylori infection has evolved from bismuth-containing regimens, 2-week proton pump inhibitor (PPI)-dual therapies, and now, the widely accepted PPI/ranitidine bismuth citrate (RBC) single week triple therapies. There is a wealth of evidence showing that these regimens are highly efficacious and well tolerated by patients. The MACH-2 studies have confirmed that the addition of a PPI to two antimicrobials has significantly improved the cure rate of H. pylori infection and reduced the impact of antimicrobial resistance. Attempts to use shorter regimens ranging from 1 to 3 days should be resisted because of their unacceptably low therapeutic efficacy. In the United States, there are some indications that 10-14 days of treatment may be required. While the first-line therapies for H. pylori infection is well established, we are still struggling with the choice of optimal regimen in retreatment after the first attempt fails. Quadruple therapy combining PPI with bismuth, metronidazole and tetracycline has achieved a respectable success of around 85%. Switching between metronidazole and clarithromycin seems to be a sensible strategy as these two are the most effective anti-Helicobacter agents . Changing between PPI and RBC in the triple therapy would not make much difference without replacing some of the antimicrobials. rifabutin-containing regimens and high-dose PPI-amoxicillin dual therapy deserve more studies with large-scale studies. Data on anti-Helicobacter therapy for children are few. Most studies based on bismuth derivatives in combination with amoxicillin or tinidazole and were limited by the small number of cases. Recent studies showed 1-week bismuth-based triple therapy and 2-week PPI-based triple therapy are highly efficacious. Reinfection in children > 5 years of age after successful cure is rare. It is worthwhile to refine the optimal therapy for children as the treatment of this group would, theoretically, prevent the development gastric cancer in the long term.", "source": "https://pubmed.ncbi.nlm.nih.gov/10828750/"}
{"doc_id": "caec1f330b4ff88064928cbdfe2d04ae", "sentence": "Therefore , downregulation of bcl-2 or xIAP by RNAi enhances the effects of etoposide and doxorubicin .", "spans": [{"span_id": 0, "text": "etoposide", "start": 76, "end": 85, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "doxorubicin", "start": 90, "end": 101, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Antiapoptotic genes such as bcl-2 or xIAP may be responsible for resistance to apoptosis induced by cytotoxic drugs. The aim of this study was to investigate if downregulation of bcl-2 or xIAP by RNA interference (RNAi) would sensitize MCF-7 cells to etoposide and doxorubicin. FITC-siRNAs uptake was verified by fluorescence microscopy and downregulation of Bcl-2 or XIAP was confirmed by Western Blotting. Both siRNAs reduced the number of viable cells and increased cellular apoptosis. Treatment with siRNAs followed by treatment with etoposide or doxorubicin further reduced the number of viable cells, when compared to either of the treatments alone. Therefore , downregulation of bcl-2 or xIAP by RNAi enhances the effects of etoposide and doxorubicin .", "source": "https://pubmed.ncbi.nlm.nih.gov/15031723/"}
{"doc_id": "e64a65a04bf8a854d6a211efc8068c61", "sentence": "Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan .", "spans": [{"span_id": 0, "text": "Cetuximab", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "irinotecan", "start": 88, "end": 98, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "N0436 (Alliance): A Phase II Trial of Irinotecan With Cetuximab in Patients With Metastatic Breast Cancer Previously Exposed to Anthracycline and/or Taxane-Containing Therapy. irinotecan has a 20% to 25% response rate (RR) in patients with previously treated metastatic breast cancer (MBC). Epidermal growth factor receptor (EGFR) is overexpressed in some MBC, especially in triple-negative breast cancer (TNBC). Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan . ### Patients And Methods We report a 1-stage phase II study on MBC, measurable disease, and previous anthracycline and/or taxane therapy. Patients received cetuximab 400 mg/m(2) on day 1 cycle 1 then 250 mg/m(2) weekly thereafter and irinotecan 80 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall RR (ORR) according to Response Evaluation Criteria in Solid Tumors criteria (version 1.1). ### results Of 19 eligible patients enrolled from February to September 2006, 14 patients (74%) had visceral disease, seven patients (37%) were hormone receptor-positive, two patients (11%) HER2-positive, and 11 patients (58%) were triple-negative. Patients received a median of 2 cycles (range, 1-37). Confirmed ORR was 11% (95% confidence interval [CI], 1%-33%), with 1 partial response and 1 complete response. One patient had stable disease for 8 months. RR for TNBC versus non-TNBC was 18% versus 0% (P = .49). Median time to progression was 1.4 months (95% CI, 1.0-2.2) and median overall survival was 9.4 months (95% CI, 2.8-16.1). Twelve patients had disease progression within 2 cycles during therapy. Because of a low RR and rapid disease progression, the study leadership decided to close the trial early. ### conclusion The tolerability of the combination of cetuximab and irinotecan is acceptable but demonstrated low overall activity. Potentially promising results were noted in patients with TNBC and further studies of these patients might be considered.", "source": "https://pubmed.ncbi.nlm.nih.gov/26381420/"}
{"doc_id": "650a70ac002563b1aea29279e3f6a48a", "sentence": "A non-specific inhibitor of 5-HT reuptake , imipramine , did not produce this amnesic effect , nor did the combination of fenfluramine with the MAOI tranylcypromine , although it produced , as expected , the \" serotonergic syndrome . \" Results for the metabolic precursor of 5-HT , 5-HTP , also administered peripherally , were inconsistent , with amnesic effects seen at 5 and 20 mg/kg but none at 10 mg/kg .", "spans": [{"span_id": 0, "text": "imipramine", "start": 44, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "fenfluramine", "start": 122, "end": 134, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "tranylcypromine", "start": 149, "end": 164, "token_start": 25, "token_end": 26}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Manipulations of 5-HT activity and memory in the rat. The activity of 5-HT was manipulated by means of the peripheral injection of 5-HT reuptake inhibitors, fenfluramine and fluoxetine. These drug treatments, at doses higher than 1 mg/kg, produced retrograde amnesia in a one-trial appetitive learning task in rats. A non-specific inhibitor of 5-HT reuptake , imipramine , did not produce this amnesic effect , nor did the combination of fenfluramine with the MAOI tranylcypromine , although it produced , as expected , the \" serotonergic syndrome . \" Results for the metabolic precursor of 5-HT , 5-HTP , also administered peripherally , were inconsistent , with amnesic effects seen at 5 and 20 mg/kg but none at 10 mg/kg .", "source": "https://pubmed.ncbi.nlm.nih.gov/3873076/"}
{"doc_id": "db1c10486c4e7c99ceaac0fc14a353cf", "sentence": "Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 12, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "temozolomide", "start": 27, "end": 39, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models . The combination of temozolomide (TMZ) and irinotecan is a regimen used in neuroblastoma patients with recurrent disease. O(6)-methylguanine-DNA methyltransferase (MGMT) may have a function in resistance to TMZ. Using neuroblastoma pre-clinical models, we determined whether the inhibition of MGMT by O(6)-benzylguanine (O6-BG) could enhance the anti-tumour activity of TMZ and irinotecan. ### methods The cytotoxicity of TMZ and irinotecan, either alone or in combination, was measured in five neuroblastoma cell lines in the presence or absence of O6-BG with a fluorescence-based cell viability assay (DIMSCAN). Anti-tumour activity was measured in three neuroblastoma xenograft models. ### results MGMT mRNA and protein were expressed in 9 out of 10 examined cell lines. Pretreatment of cells with 25 \u03bcM O6-BG decreased MGMT protein expression and enhanced The TMZ cytotoxicity by up to 0.3-1.4 logs in four out of five tested cell lines. TMZ (25 mg\u2009kg(-1) per day for 5 days every 3 weeks for four cycles) did not significantly improve mice survival, whereas the same schedule of irinotecan (7.5\u2009mg\u2009kg(-1) per day) significantly improved survival (P<0.0001) in all three xenograft models. Combining O6-BG and/or TMZ with irinotecan further enhanced survival. ### conclusion Our in vitro and in vivo findings suggest that irinotecan drives the activity of irinotecan and TMZ in recurrent neuroblastoma. Inhibitors of MGMT warrant further investigation for enhancing the activity of regimens that include TMZ.", "source": "https://pubmed.ncbi.nlm.nih.gov/20924375/"}
{"doc_id": "c5b1038c47002a14dda922096cd0be58", "sentence": "This is a phase II study of etoposide , vincristine , and doxorubicin , administered as a 96-hour continuous infusion , with intravenous ( IV ) bolus cyclophosphamide and oral prednisone ( EPOCH ) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule .", "spans": [{"span_id": 0, "text": "etoposide", "start": 28, "end": 37, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "vincristine", "start": 40, "end": 51, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "doxorubicin", "start": 58, "end": 69, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "cyclophosphamide", "start": 150, "end": 166, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "prednisone", "start": 176, "end": 186, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. ### Patients And Methods This is a phase II study of etoposide , vincristine , and doxorubicin , administered as a 96-hour continuous infusion , with intravenous ( IV ) bolus cyclophosphamide and oral prednisone ( EPOCH ) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule . Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. ### results Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. ### conclusion EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.", "source": "https://pubmed.ncbi.nlm.nih.gov/7687667/"}
{"doc_id": "525796501d9304f57265c5bab837ebe3", "sentence": "Based on the FIRM-ACT trial , mitotane plus etoposide , doxorubicin , and cisplatin is now the established first-line cytotoxic therapy .", "spans": [{"span_id": 0, "text": "mitotane", "start": 30, "end": 38, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "etoposide", "start": 44, "end": 53, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "doxorubicin", "start": 56, "end": 67, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "cisplatin", "start": 74, "end": 83, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Update in adrenocortical carcinoma. Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/\u03b2-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial , mitotane plus etoposide , doxorubicin , and cisplatin is now the established first-line cytotoxic therapy . However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive \"-omic approaches\" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.", "source": "https://pubmed.ncbi.nlm.nih.gov/24081734/"}
{"doc_id": "b419ddb50eed7610d1d9c4e619f1b6bb", "sentence": "Additionally , thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose , length of exposure , trimester of use , and deleterious patient or fetal outcomes can be concluded .", "spans": [{"span_id": 0, "text": "dasatinib", "start": 94, "end": 103, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "nilotinib", "start": 108, "end": 117, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Experience with dasatinib and nilotinib use in pregnancy. Pregnancy in a patient with chronic myeloid leukemia presents a therapeutic challenge. Both dasatinib and nilotinib are indicated for first-line treatment as well as for treatment-resistant chronic myeloid leukemia. Animal studies with dasatinib or nilotinib demonstrate fetal skeletal malformations as well as significant mortality during organogenesis. The goal of this article is to review the experience to date of dasatinib and nilotinib in human pregnancy, specifically dasatinib and nilotinib dose, length of exposure, trimester of use, as well as patient and fetal outcomes. Based on the limited data, both dasatinib and nilotinib may cause fetal harm. Additionally , thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose , length of exposure , trimester of use , and deleterious patient or fetal outcomes can be concluded . Therefore, health care professionals need to regularly counsel women of child bearing potential with chronic myeloid leukemia regarding the risks of taking dasatinib or nilotinib during pregnancy. The safest potential therapeutic options for the management of chronic myeloid leukemia in pregnancy include temporary discontinuation of the tyrosine kinase inhibitor followed by observation or intervention with interferon alfa and/or leukapheresis.", "source": "https://pubmed.ncbi.nlm.nih.gov/29284357/"}
{"doc_id": "93ead62c1d4c59ac6ea81f118b1343b5", "sentence": "The principal toxicity was myelosuppression ; grade 4 neutropenia was more frequent with topotecan ( 81.4 % of patients ) than with paclitaxel ( 22.9 % of patients ) .", "spans": [{"span_id": 0, "text": "topotecan", "start": 89, "end": 98, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "paclitaxel", "start": 132, "end": 142, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer. A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. ### Patients And Methods Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. ### results Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression ; grade 4 neutropenia was more frequent with topotecan ( 81.4 % of patients ) than with paclitaxel ( 22.9 % of patients ) . ### conclusion topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/11283120/"}
{"doc_id": "e18f53a72ef354dc4bf0992f2d580682", "sentence": "Consistent with previous reports , genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells , and genistein reduced the chemoresistance of these cells .", "spans": [{"span_id": 0, "text": "genistein", "start": 35, "end": 44, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "doxorubicin", "start": 59, "end": 70, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "genistein", "start": 121, "end": 130, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Synergistic cytotoxic effect of genistein and doxorubicin on drug-resistant human breast cancer MCF-7/Adr cells. The molecular mechanisms underlying genistein-mediated reversal of chemoresistance remains unknown. In the present study, we investigated the molecular mechanisms by which genistein overcomes chemoresistance and its effect on doxorubicin-induced cytotoxicity. Consistent with previous reports , genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells , and genistein reduced the chemoresistance of these cells . genistein treatment increased the intracellular accumulation of doxorubicin but did not influence P-gp function. The combination of genistein and doxorubicin significantly induced cell cycle arrest and apoptosis. genistein treatment strongly inhibited HER2/neu but not MDR-1 expression at both the mRNA and protein levels. Therefore, our results demonstrated that genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells, and the mechanisms likely involve an increase in the intracellular accumulation of doxorubicin and suppression of HER2/neu expression.", "source": "https://pubmed.ncbi.nlm.nih.gov/25109508/"}
{"doc_id": "400902e0b2c154edcc0b488ee004fddb", "sentence": "This historical cohort study evaluated the association of efavirenz ( EFV ) compared to nevirapine ( NVP ) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large , urban HIV clinic in Uganda .", "spans": [{"span_id": 0, "text": "efavirenz", "start": 58, "end": 67, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "nevirapine", "start": 88, "end": 98, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Risk of tuberculosis after antiretroviral treatment initiation: a comparison between efavirenz and nevirapine using inverse probability weighting. There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz ( EFV ) compared to nevirapine ( NVP ) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large , urban HIV clinic in Uganda . ### methods Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multivariable logistic regression model), stratifying by baseline CD4+ T-cell count. Adjustment for time-updated CD4+ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. ### results ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (SD 9) and a median baseline CD4+ T-cell count of 117 cells/mm3 (IQR 43-182). Overall, 60% (n = 3,484) were initiated on NVP and 40% (n = 2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4+ T-cell count < 100 cells/mm3 (HR 2.05 [95% CI 1.29, 3.27]; P = 0.003), but not at higher CD4+ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P = 0.428). These estimates were robust to all sensitivity analyses. ### conclusions There was a higher incidence of TB in patients with baseline CD4+ T-cell counts < 100 cells/mm3 initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.", "source": "https://pubmed.ncbi.nlm.nih.gov/23423604/"}
{"doc_id": "04b4d94b76cbe96ab4d75a4e83e53da1", "sentence": "Combination of ibrutinib and ublituximab ( n = 64 ) had an ORR of 78 % ( CR 7 % ) in a phase 3 study .", "spans": [{"span_id": 0, "text": "ibrutinib", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "ublituximab", "start": 29, "end": 40, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of Ibrutinib-Based Regimen in Chronic Lymphocytic Leukemia: A Systematic Review. ibrutinib has shown to have better efficacy than standard chemoimmunotherapy in del17 positive chronic lymphocytic leukemia (CLL) patients; however its role in del17 negative patients is less clear. We aim to evaluate the efficacy of ibrutinib-based regimens in CLL. Seven databases were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI-32765. Data from only prospective clinical trials was included. In a phase 3 trial (n = 136), the overall response rate (ORR) with ibrutinib was 92% whereas 18% patients had a complete response (CR). Progression free survival (PFS) and overall survival (OS) at 2 years were 89% and 95% respectively. Phase 3 trial (n = 195) with single agent ibrutinib showed ORR of 63%. PFS at 6 months and OS at 12 months were 88% and 90% respectively. In a phase 2 trial of relapsed and/or refractory (R/R) or high risk treatment naive (TN) patients, combination of ibrutinib and rituximab (n = 104) achieved an ORR of 100% (CR 28%) as compared to ORR 98% (CR 21%) with ibrutinib monotherapy (n = 102) with no significant difference in PFS. Combination of ibrutinib and ublituximab ( n = 64 ) had an ORR of 78 % ( CR 7 % ) in a phase 3 study . In del17p negative R/R patients, combination of bendamustine/rituximab (BR) and ibrutinib (n = 289) achieved an ORR of 83% (CR/CRi 10%) and the 18 month PFS was 79%. In a phase 2 trial treated with ibrutinib (n = 145), patients with del17p R/R disease achieved an ORR of 64% and the 24 month PFS and OS was 63% and 75% respectively. In TN del17p patients (n = 35), ORR was 97% (CR-0) and the 24 month PFS and OS were 82% and 84% respectively with single agent ibrutinib. ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/32300434/"}
{"doc_id": "0db914a1836322dc765a2945b4cfb1c9", "sentence": "Overall median effective concentration ( EC50 ) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism ( EC50 values for 16-h growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine , respectively ) , followed by duckweed Lemna minor ( 7-d growth inhibition , EC50 2.1 and 3.0 mg/L ) and green alga Pseudokirchneriella subcapitata ( 4-d growth inhibition , EC50 3.1 and 2.6 mg/L ) .", "spans": [{"span_id": 0, "text": "oxytetracycline", "start": 209, "end": 224, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "flumequine", "start": 229, "end": 239, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Complex evaluation of ecotoxicity and genotoxicity of antimicrobials oxytetracycline and flumequine used in aquaculture. Ecotoxicity and genotoxicity of widely used veterinary antimicrobials oxytetracycline and flumequine was studied with six model organisms (Vibrio fischeri, Pseudomonas putida, Pseudokirchneriella subcapitata, Lemna minor, Daphnia magna, Escherichia coli). Overall median effective concentration ( EC50 ) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism ( EC50 values for 16-h growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine , respectively ) , followed by duckweed Lemna minor ( 7-d growth inhibition , EC50 2.1 and 3.0 mg/L ) and green alga Pseudokirchneriella subcapitata ( 4-d growth inhibition , EC50 3.1 and 2.6 mg/L ) . The least sensitive organism was Daphnia magna (48-h immobilization, lowest-observed-effect concentration [LOEC] of oxytetracycline of 400 mg/L). oxytetracycline showed limited genotoxicity (SOS-chromotest with Escherichia coli, minimal genotoxic concentration of 500 mg/L), and flumequine was genotoxic at 0.25 mg/L. Based on the reported measured concentrations (MECs) and predicted no-effect concentrations (PNECs), oxytetracycline may be concluded to be of ecotoxicological concern (calculated risk quotient = 8), whereas flumequine seems to represent lower risk.", "source": "https://pubmed.ncbi.nlm.nih.gov/21312248/"}
{"doc_id": "958cbca38ea92887cc70337ca7273e47", "sentence": "This review therefore aims to overview the prognostic value of MRD eradication in CLL , the role of post-remission intervention with \" passive \" immunotherapy ( alemtuzumab or rituximab ) so as to eliminate persistent MRD or prevent MRD relapse , the impact of these strategies on disease-free survival and their possible adverse consequences .", "spans": [{"span_id": 0, "text": "alemtuzumab", "start": 161, "end": 172, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "rituximab", "start": 176, "end": 185, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Post-remission intervention with alemtuzumab or rituximab to eradicate minimal residual disease in chronic lymphocytic leukemia: where do we stand? The introduction of purine nucleoside analogs, later in combination with alkylating moieties and anti-CD20 immunotherapy, has profoundly improved the response rate and response duration in patients with chronic lymphocytic leukemia (CLL). The quality of clinical response following treatment may be improved to a level where residual leukemic cells become undetectable. As patients with this type of response appear to have extended survival rates, minimal residual disease (MRD) eradication is considered a new objective in CLL treatment with the aim of improving progression-free survival (PFS) and potentially overall survival (OS). This review therefore aims to overview the prognostic value of MRD eradication in CLL , the role of post-remission intervention with \" passive \" immunotherapy ( alemtuzumab or rituximab ) so as to eliminate persistent MRD or prevent MRD relapse , the impact of these strategies on disease-free survival and their possible adverse consequences . The data indicate a potential for post-remission alemtuzumab or rituximab to prolong PFS in CLL, although more investigations and longer follow-up are required before MRD-guided strategies can be recommended outside of clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/21854093/"}
{"doc_id": "6b0c167b3ee8a9f88fdb82ebaff2c407", "sentence": "Paclitaxel , 5-fluorouracil , hydroxyurea , and concomitant radiation therapy for poor-prognosis head and neck cancer .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "5-fluorouracil", "start": 13, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "hydroxyurea", "start": 30, "end": 41, "token_start": 4, "token_end": 5}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Paclitaxel , 5-fluorouracil , hydroxyurea , and concomitant radiation therapy for poor-prognosis head and neck cancer . A series of phase I and phase II studies investigating multiagent concomitant chemoradiotherapy in patients with poor-prognosis head and neck cancer have been conducted at the University of Chicago. Drug combinations initially included 5-fluorouracil (5-FU) and hydroxyurea, with the more recent addition of cisplatin; in the most recent trial, paclitaxel was substituted for cisplatin. The primary end point of these trials was definition of maximum tolerated doses in combination with radiation therapy. All radiation therapy was given concomitantly with chemotherapy on an every-other-week schedule (total dose, hydroxyurea and 5-FU were defined at 1 g given orally twice daily for a total of 11 doses and 800 mg/m2/d for 5 days (by continuous intravenous infusion), respectively. When cisplatin was added to this regimen, the observed myelosuppression necessitated the addition of granulocyte colony-stimulating factor. The recommended phase II doses for the three-drug combination were cisplatin 100 mg/m2 every 28 days, 5-FU 800 mg/m2/d for 5 days, and hydroxyurea 1 g orally twice daily for 11 doses. The feasibility of administering radiation at 1.5 Gy twice daily with chemotherapy was also established, which allowed the administration of 75 Gy over 5 cycles (10 weeks). The initial review of this trial suggested substantial toxicity, particularly mucositis and myelosuppression; however, local and regional control rates also were high. Most recently, paclitaxel has replaced cisplatin in this regimen. Recommended phase II doses were hydroxyurea 0.5 g orally twice daily for 11 doses, 5-FU 600 mg/m2/d for 5 days, and paclitaxel 20 mg/m2/d for 5 days, with radiation therapy administered twice daily in 1. 5-Gy fractions. A formal phase II study of this regimen in previously untreated patients with stage IV disease has recently completed accrual and is awaiting analysis. Evaluation of a simplified paclitaxel administration schedule (1-hour infusion on day 1 of chemoradiotherapy between the two radiation fractions) is under way. In addition, the feasibility of substituting gemcitabine for hydroxyurea is undergoing evaluation. Future trials in this disease should focus on developing new combinations that are less toxic and have similar efficacy.", "source": "https://pubmed.ncbi.nlm.nih.gov/10210543/"}
{"doc_id": "0fd66b6397cebf2424a79a0642146c4d", "sentence": "The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up , and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 50, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "ipilimumab", "start": 65, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "sunitinib", "start": 81, "end": 90, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "nivolumab", "start": 233, "end": 242, "token_start": 32, "token_end": 33}, {"span_id": 4, "text": "ipilimumab", "start": 248, "end": 258, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. ### methods In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. ### findings Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32\u00b74 months [IQR 13\u00b74-36\u00b73]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35\u00b76-not estimable] vs 26\u00b76 months [22\u00b71-33\u00b74]; hazard ratio [HR] 0\u00b766 [95% CI 0\u00b754-0\u00b780], p<0\u00b70001), progression-free survival (median 8\u00b72 months [95% CI 6\u00b79-10\u00b70] vs 8\u00b73 months [7\u00b70-8\u00b78]; HR 0\u00b777 [95% CI 0\u00b765-0\u00b790], p=0\u00b70014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0\u00b70001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37\u00b79 months [32\u00b72-not estimable]; HR 0\u00b771 [95% CI 0\u00b759-0\u00b786], p=0\u00b70003), progression-free survival (median 9\u00b77 months [95% CI 8\u00b71-11\u00b71] vs 9\u00b77 months [8\u00b73-11\u00b71]; HR 0\u00b785 [95% CI 0\u00b773-0\u00b798], p=0\u00b7027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0\u00b7015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. ### interpretation The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up , and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories . ### funding Bristol-Myers Squibb and ONO Pharmaceutical.", "source": "https://pubmed.ncbi.nlm.nih.gov/31427204/"}
{"doc_id": "478ed5b3c75c19eb591ce2aa273d8129", "sentence": "Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents , including anthracyclines ( daunorubicin and doxorubicin ) , epipodophyllotoxins ( etoposide ) , and anthracenediones ( mitoxantrone ) .", "spans": [{"span_id": 0, "text": "daunorubicin", "start": 148, "end": 160, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "doxorubicin", "start": 165, "end": 176, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "etoposide", "start": 203, "end": 212, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "mitoxantrone", "start": 240, "end": 252, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Hypoxia in solid tumors is associated with the development of chemoresistance. Although many studies have focused on the effect of hypoxia on drug-induced apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance has not been previously investigated. Here, we determined the effects of hypoxia on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents , including anthracyclines ( daunorubicin and doxorubicin ) , epipodophyllotoxins ( etoposide ) , and anthracenediones ( mitoxantrone ) . Results revealed a high degree of heterogeneity in nuclear and cytoplasmic alterations in response to acute drug exposure; however, the majority of exposed cells displayed morphologic and biochemical changes consistent with drug-induced senescence. Hypoxia decreased only the proportion of cells in the senescent population, whereas the small proportion of cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. Similar results were obtained with human HCT116 colon carcinoma cells, indicating that the protective effect of hypoxia on drug-induced senescence is not unique to MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key regulator of cellular adaptations to hypoxia, prevented hypoxia-induced resistance. HIF-1alpha small interfering RNA also selectively abolished the hypoxia-induced changes in the senescent population, indicating that the increased survival was due to protection against drug-induced senescence. These results support a requirement for HIF-1 in the adaptations leading to drug resistance and reveal that decreased drug-induced senescence is also an important contributor to the development of hypoxia-induced resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/18645006/"}
{"doc_id": "8189632e01c53b8d9f394d39b352a314", "sentence": "Hence , the aim of this study was to conduct an economic evaluation of anastrozole versus tamoxifen in early stage breast cancer .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 71, "end": 82, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "tamoxifen", "start": 90, "end": 99, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Economic Evaluation of Anastrozole Versus Tamoxifen for Early Stage Breast Cancer in Singapore. In Singapore, breast cancer is the leading female malignancy and its incidence has increased threefold over the past decades. For treatment of postmenopausal, hormone receptor positive early stage breast cancer, tamoxifen or aromatase inhibitors such as anastrozole are prescribed either as first-line therapy or sequentially. Currently, anastrozole is patented with a higher drug cost compared with tamoxifen. Hence , the aim of this study was to conduct an economic evaluation of anastrozole versus tamoxifen in early stage breast cancer . ### methods A Markov model with a lifetime horizon was developed by using results from the Arimidex, tamoxifen, Alone or in Combination trial. Direct medical costs were estimated by billing data obtained via financial electronic databases. Utility scores were elicited from 20 experienced oncology nurses using the visual analogue scale. Cost per quality-adjusted life-years was calculated by using the societal perspective. A discount rate of 3% for both charges (expressed in 2010 Singapore dollars) and benefits was used. ### results At an additional cost of S $17,597, anastrozole treatment resulted in a gain of 0.085 life-year survival and 0.154 quality-adjusted life-year. The incremental cost-effectiveness ratio of anastrozole was S $207,402 per life-year gained and S $114,061 per quality-adjusted life-year gained compared with tamoxifen. ### conclusion This is the first economic evaluation that used 10-year results from the Arimidex, tamoxifen, Alone or in Combination trial and utility elicited from the local population. If the World Health Organization's recommendation of 1 to 3 gross domestic product range is an acceptable threshold, anastrozole is deemed cost-effective compared with tamoxifen in the treatment of early stage breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/29702826/"}
{"doc_id": "122abf6ba48902522485dec0fbfcdd2d", "sentence": "A randomized trial of mobilization of peripheral blood stem cells with cyclophosphamide , etoposide , and granulocyte colony-stimulating factor with or without cisplatin in patients with malignant lymphoma receiving high-dose chemotherapy .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 71, "end": 87, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "etoposide", "start": 90, "end": 99, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "cisplatin", "start": 160, "end": 169, "token_start": 22, "token_end": 23}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A randomized trial of mobilization of peripheral blood stem cells with cyclophosphamide , etoposide , and granulocyte colony-stimulating factor with or without cisplatin in patients with malignant lymphoma receiving high-dose chemotherapy . The purpose of this study was to evaluate the addition of cisplatin to cyclophosphamide, etoposide, and granulocyte colony-stimulating factor (G-CSF) for the mobilization of peripheral blood stem cells (PBSC). Eighty-one patients with malignant lymphoma were randomized to receive either cyclophosphamide 4 g/m2 and etoposide 600 mg/m2 (CE), and G-CSF 6 microg/kg/day (n = 41), or the same drugs with cisplatin 105 mg/m2 (CEP; n = 40) followed by collection of PBSC. Seventy-eight of 81 patients (96%) had apheresis performed and 70 (86%) received high-dose chemotherapy (HDC) with PBSC support. The median number of CD34+ cells collected after CE was 19.77 compared with 9.39 x 10(6)/kg after CEP (p = 0.09). More patients receiving CEP had grade 3-4 gastrointestinal (p = 0.03) and neurologic toxicities (p = 0.05), had significant delays in recovery of neutrophils (p = 0.0001) and platelets (p = 0.009), and received more red blood cell (p = 0.03) and platelet (p = 0.08) transfusions than patients receiving CE. There were no significant differences in treatment-related deaths, relapse, survival, or event-free survival between patients receiving CE or CEP when all 81 patients or the 70 patients receiving HDC were evaluated. It was concluded that the addition of cisplatin to CE did not improve CD34+ cell yields, was associated with more morbidity and resource utilization, and was not associated with improvement in outcomes.", "source": "https://pubmed.ncbi.nlm.nih.gov/9708644/"}
{"doc_id": "d93a605049539ee873eb80044935d4ba", "sentence": "Treatment of pancreatic cancer with a combination of docetaxel , gemcitabine and granulocyte colony-stimulating factor : a phase II study of the Greek Cooperative Group for Pancreatic Cancer .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 53, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "gemcitabine", "start": 65, "end": 76, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Treatment of pancreatic cancer with a combination of docetaxel , gemcitabine and granulocyte colony-stimulating factor : a phase II study of the Greek Cooperative Group for Pancreatic Cancer . To evaluate the tolerance and efficacy of front-line docetaxel plus gemcitabine treatment in patients with inoperable pancreatic cancer. ### Patients And Methods Fifty-four patients with locally advanced or metastatic pancreatic cancer were enrolled. gemcitabine (1000 mg/m2) was administered on days 1 and 8 and docetaxel (100 mg/m2) on day 8, every three weeks; rh-G-CSF (150 ig/m2 s.c.) was given prophylactically on days 9-15. ### results Seven (13%) patients achieved partial response and 18 (33%) stable disease (intent-to-treat). The median duration of response was 24 weeks, time to tumour progression 32 weeks, and overall survival 26 weeks. Performance status was improved in 33% of patients, pain in 43%, asthenia in 16%, weight gain in 28% and appetite in 27%. Grade 3-4 neutropenia occurred in 17 (31%) patients and grade 3-4 thrombocytopenia in four (4%). Six (11%) patients developed febrile neutropenia and one of them died from sepsis. ### conclusions This combination is a relatively well-tolerated out-patient regimen for patients with inoperable pancreatic cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/11249034/"}
{"doc_id": "668cf1cd34592609ac6c5a94033486b9", "sentence": "Such situations are known as exposing to pneumococcal meningitis and to resistance of the strain involved to penicillin G. Both patients were cured by vancomycin in continuous infusion associated with rifampicin or fosfomycin .", "spans": [{"span_id": 0, "text": "vancomycin", "start": 151, "end": 161, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "rifampicin", "start": 201, "end": 211, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "fosfomycin", "start": 215, "end": 225, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Vancomycin in meningitis caused by penicillin G resistant Streptococcus pneumoniae]. We report two cases of penicillin G-resistant pneumococcal meningitis in adults, with clinical and bacteriological failure of amoxicillin and negative or incomplete response to third generation cephalosporins. Meningitis occurred in a man treated for myeloma and in an elderly woman under prolonged intermittent amoxicillin therapy for chronic otitis. Such situations are known as exposing to pneumococcal meningitis and to resistance of the strain involved to penicillin G. Both patients were cured by vancomycin in continuous infusion associated with rifampicin or fosfomycin . Contrary to third generation cephalosporins, which have higher minimal inhibitory concentrations, vancomycin and rifampicin are still fully active against penicillin G-resistant pneumococcal strains. Thus, vancomycin administered in continuous infusion and associated with rifampicin and fosfomycin deserves to be tried as first-line treatment of pneumococcal meningitis in patients at risk of resistance to penicillin G.", "source": "https://pubmed.ncbi.nlm.nih.gov/8309909/"}
{"doc_id": "d9618273421b43d587ebe3aff81f5bf6", "sentence": "We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors ( e.g. , etoposide and doxorubicin ) .", "spans": [{"span_id": 0, "text": "etoposide", "start": 152, "end": 161, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "doxorubicin", "start": 166, "end": 177, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors ( e.g. , etoposide and doxorubicin ) . Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/9199342/"}
{"doc_id": "33cfcb3cd74eb5b8b3d9504e685db473", "sentence": "In 2011 , the combination of rituximab with bendamustine ( 31 % ) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide ( 22 % ) regime .", "spans": [{"span_id": 0, "text": "rituximab", "start": 29, "end": 38, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "bendamustine", "start": 44, "end": 56, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Altered treatment of chronic lymphocytic leukemia in Germany during the last decade. Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66\u00a0%, 2009: 71\u00a0%, 2011: 77\u00a0%) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32\u00a0%, 2009: 14\u00a0%, fludarabine 2006: 23\u00a0%, 2009: 37\u00a0%). In 2011 , the combination of rituximab with bendamustine ( 31 % ) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide ( 22 % ) regime . Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15\u00a0%, 2011: 73\u00a0%). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.", "source": "https://pubmed.ncbi.nlm.nih.gov/27021305/"}
{"doc_id": "8ef1062bde923a162f10e0bedec07669", "sentence": "The combination of ofatumumab and bendamustine in elderly patients with diffuse large B-cell lymphoma demonstrated modest efficacy compared with standard of care .", "spans": [{"span_id": 0, "text": "ofatumumab", "start": 19, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bendamustine", "start": 34, "end": 46, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Phase II Study of Bendamustine and Ofatumumab in Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy.  The combination of ofatumumab and bendamustine in elderly patients with diffuse large B-cell lymphoma demonstrated modest efficacy compared with standard of care .The poor response may have been due to patient age and the high rate of treatment discontinuation. ### background This phase II trial evaluated the efficacy of bendamustine and ofatumumab in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were not candidates for rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). ### methods Patients received IV 90 mg/m ### results Twelve of 21 enrolled patients completed treatment; median age was 83 years. The most common reasons for treatment discontinuation were disease progression (three patients), intercurrent illness (two patients), and death (one patient due to drug-related sepsis and bowel necrosis and one patient due to unknown cause). Thrombocytopenia (14%), neutropenia (10%), diarrhea (10%), vomiting (10%), and dehydration (10%) were the most common grade \u22653 treatment-related adverse events. The overall response rate was 90.5% and the CRR was 33.3%. Median progression-free survival (PFS) and overall survival (OS) were 8.6 and 12.0 months, respectively. ### conclusion The combination of ofatumumab and bendamustine is feasible in elderly patients with DLBCL.", "source": "https://pubmed.ncbi.nlm.nih.gov/31073022/"}
{"doc_id": "795339d0baa8752d627554fdf49cadaf", "sentence": "Imatinib and nilotinib directly inhibit the kinase activity of KIT , while RAD001 ( everolimus ) inhibits mTOR .", "spans": [{"span_id": 0, "text": "Imatinib", "start": 0, "end": 8, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "nilotinib", "start": 13, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "everolimus", "start": 84, "end": 94, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET. Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT , while RAD001 ( everolimus ) inhibits mTOR . We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. ### methods Rag2-/-; \u03b3common -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. ### results After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0. ### conclusions As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/21192792/"}
{"doc_id": "9a8e6801e6379528eff10d0f0abe84bc", "sentence": "In this study the antiproliferative effects of Paclitaxel ( PAC ) , Epirubicin ( EPI ) and Tamoxifen ( TAM ) on growth kinetics of Ehrlich Ascites Tumor ( EAT ) cells were examined in culture .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 47, "end": 57, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Epirubicin", "start": 68, "end": 78, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "Tamoxifen", "start": 91, "end": 100, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Evaluation of the effect of paclitaxel, epirubicin and tamoxifen by cell kinetics parameters in estrogen-receptor-positive ehrlich ascites tumor (eat) cells growing in vitro.  In this study the antiproliferative effects of Paclitaxel ( PAC ) , Epirubicin ( EPI ) and Tamoxifen ( TAM ) on growth kinetics of Ehrlich Ascites Tumor ( EAT ) cells were examined in culture . An estrogen-receptor-positive ER (+) hyperdiploid EAT cell line growing in vitro was also analysed in the present study. IC50 doses of PAC, EPI and TAM (12 microg/ml, 12 microg/ml and 2 microg/ml, respectively) were used. Cells were treated with the above doses for 0, 4, 8, 16, 24 and 32 hrs. At the end of these periods, living cell numbers were determined by collecting EAT cells in every group for growth study rate and for MTT assay. Therefore, the mitotic index was determined in the same experimental groups. The proliferation of EAT cells, inhibited by PAC, EPI and TAM concentrations was compared to control with increasing treatment time (4-32 hrs). Treatment of PAC, EPI and TAM alone for 24 hrs decreased the proliferation rate of EAT cells by 50% with respect to control. The inhibition of proliferation rate was higher in double drug treatment than that in single drug treatment with increased treatment time. In the treatment of three drugs applied for 32 hrs, this effect reached a maximum and proliferation rate decreased by 12% as compared to the (100%) control. In our studies, when the mitotic index parameter data were evaluated to determine which phase of the cell cycle was affected by PAC to cause the repression of cell reproduction, it was found that PAC exerted of its cytotoxic effect by causing cell accumulation at mitosis. The accumulation of the cells resulted in an increase in mitotic index values, which was an expected consequence of PAC treatment. It was observed that depending on the drug treatments, inhibition of proliferation rate and mitotic index in EAT cells were increased with respect to control, being with statistically significant occurrence (p < 0.01 - p < 0.001). As a result, concomitant treatment combined with hormonal therapy has given improved results compared with single treatment and PAC + EPI + TAM treatments had a maximum synergistic effect for 32 hrs (p < 0.001).", "source": "https://pubmed.ncbi.nlm.nih.gov/17385543/"}
{"doc_id": "9102d006b4fd44a3746292aafa45c3af", "sentence": "The most common chemotherapy and route of administration for systemic treatment is paclitaxel plus carboplatin given intravenously .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 83, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "carboplatin", "start": 99, "end": 110, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Systemic therapy for non-serous ovarian carcinoma. Ovarian cancer is one of the top ten most common cancers in women around the world, with high-grade serous epithelial cancer being the most frequent type. However, around a quarter of cases consist of non-serous epithelial ovarian cancer (EOC), which is a heterogeneous group of malignancies that includes endometroid, mucinous, clear cell carcinoma (CCC), and carcinosarcoma. Another relevant group of nonepithelial tumors are those arising from germ cells or sex-cord stromal cells, which account for about 10% of all ovarian cancers. Although there are similarities in the presentation, evaluation, and management of these tumors, they have unique characteristics in terms of epidemiology, tumor biology, tumor marker expression, and response to treatment, warranting a different approach to each one of them. Collectively, the treatment of most of EOC include surgical cytoreduction followed by adjuvant systemic platinum-based chemotherapy. The most common chemotherapy and route of administration for systemic treatment is paclitaxel plus carboplatin given intravenously . However, the treatment of EOC has been rapidly evolving and emerging targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors, immune checkpoint inhibitors, and antiangiogenic agents are also available. On the other hand, non-EOC responds well to combination chemotherapy used to treat testicular cancer (bleomycin, etoposide, cisplatin) and has a good prognosis. Frontline chemotherapeutic regimen selection differs according to histological subtype, molecular alterations, and patient characteristics. Here, we review specific characteristics of non-serous and non-EOC emphasizing the peculiarities of systemic therapy for each subtype.", "source": "https://pubmed.ncbi.nlm.nih.gov/32787339/"}
{"doc_id": "fac0370d3f121156119782b95e4b40ee", "sentence": "Finally , the ability of givinostat , belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4 + T cell infection model .", "spans": [{"span_id": 0, "text": "belinostat", "start": 38, "end": 48, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "panobinostat", "start": 53, "end": 65, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. ### design In vitro study ### results The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat>givinostat \u2248belinostat>vorinostat>valproic acid. panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. ### methods The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally , the ability of givinostat , belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4 + T cell infection model . ### conclusion At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.", "source": "https://pubmed.ncbi.nlm.nih.gov/23370291/"}
{"doc_id": "86044cf678d60a50e49f28a5d757323e", "sentence": "Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan ( FOLFIRI ) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS , the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin ( FOLFOX ) or FOLFIRI .", "spans": [{"span_id": 0, "text": "Aflibercept", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "folinic acid", "start": 46, "end": 58, "token_start": 7, "token_end": 9}, {"span_id": 2, "text": "panitumumab", "start": 233, "end": 244, "token_start": 32, "token_end": 33}, {"span_id": 3, "text": "folinic acid", "start": 265, "end": 277, "token_start": 36, "token_end": 38}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Molecularly targeted drugs for metastatic colorectal cancer. The survival rate of patients with metastatic colorectal cancer (mCRC) has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan ( FOLFIRI ) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS , the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin ( FOLFOX ) or FOLFIRI . Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/24204124/"}
{"doc_id": "d81343860cdb91f3f2271e6e992965f8", "sentence": "The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 104, "end": 115, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "ifosfamide", "start": 132, "end": 142, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Systemic Therapy in Metastatic or Unresectable Well-Differentiated/Dedifferentiated Liposarcoma. Liposarcoma is one of the most common subtypes of soft-tissue sarcoma and consists of three main subtypes, of which well-differentiated liposarcoma and dedifferentiated liposarcoma account for 40-45%. The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting . Recently, eribulin and trabectedin have been approved by the US Food and Drug Administration for recurrent liposarcomas and progress in molecular characterization of these tumors has opened up new and potential novel treatment targets. This review will focus on the evidence base for current treatment strategies and will also discuss potential future options.", "source": "https://pubmed.ncbi.nlm.nih.gov/29250486/"}
{"doc_id": "f4fd1204cff04f98797ea524bf93568c", "sentence": "All patients received intravenous heparin after PTCA and aspirin was begun on the day prior to PTCA .", "spans": [{"span_id": 0, "text": "heparin", "start": 34, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "aspirin", "start": 57, "end": 64, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Effect of angiotensin converting enzyme inhibition on the incidence of restenosis after percutaneous transluminal coronary angioplasty. To determine whether angiotensin converting enzyme (ACE) inhibition may reduce the incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we retrospectively identified 322 consecutive patients who underwent a successful procedure from June 1988 to December 1989. No patients developed chest pain, ST segment elevation, positive cardiac enzymes, or other evidence of abrupt vessel closure following the PTCA. All patients received intravenous heparin after PTCA and aspirin was begun on the day prior to PTCA . Patients were separated into two groups: those at hospital discharge incidentally treated for hypertension or heart failure with ACE inhibitors (n = 36), and those treated with a drug regimen which did not include ACE inhibitors (n = 286). The two groups were similar with respect to age (61 +/- 13.5 vs. 60 +/- 12.5, p = NS) and other demographic characteristics. Restenosis, defined as the presentation to a physician with symptoms of angina within 6 months of the PTCA and the finding on repeat catheterization of a significant restenosis at the site of the PTCA, occurred in 30% of the patients who were discharged on a drug regimen which did not include ACE inhibitors vs. 3% (p less than .05) in those treated with an ACE inhibitor. Thus, it appears that the use of ACE inhibitors may significantly reduce the incidence of restenosis after successful PTCA.", "source": "https://pubmed.ncbi.nlm.nih.gov/1653645/"}
{"doc_id": "8486206d9c09508997f2a5a84ff5a6a4", "sentence": "In this article , we summarize available literature evidence on different chemotherapy agents used beyond the first-line , in locally advanced or MBC patients , including rechallenge with anthracyclines and taxanes , antimetabolite and antimicrotubule agents , such as vinorelbine , capecitabine , eribulin , ixabepilone , and the newest developed agents , such as vinflunine , irinotecan , and etirinotecan .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 269, "end": 280, "token_start": 39, "token_end": 40}, {"span_id": 1, "text": "capecitabine", "start": 283, "end": 295, "token_start": 41, "token_end": 42}, {"span_id": 2, "text": "ixabepilone", "start": 309, "end": 320, "token_start": 45, "token_end": 46}, {"span_id": 3, "text": "irinotecan", "start": 378, "end": 388, "token_start": 57, "token_end": 58}], "rels": [], "paragraph": "Chemotherapy Options beyond the First Line in HER-Negative Metastatic Breast Cancer. Despite the recent advances in the biological understanding of breast cancer (BC), chemotherapy still represents a key component in the armamentarium for this disease. Different agents are available as mono-chemotherapy options in patients with locally advanced or metastatic BC (MBC) who progress after a first- and second-line treatment with anthracyclines and taxanes. However, no clear indication exists on what the best option is in some populations, such as heavily pretreated, elderly patients, triple-negative BC (TNBC), and those who do not respond to the first-line therapy. In this article , we summarize available literature evidence on different chemotherapy agents used beyond the first-line , in locally advanced or MBC patients , including rechallenge with anthracyclines and taxanes , antimetabolite and antimicrotubule agents , such as vinorelbine , capecitabine , eribulin , ixabepilone , and the newest developed agents , such as vinflunine , irinotecan , and etirinotecan .", "source": "https://pubmed.ncbi.nlm.nih.gov/33312203/"}
{"doc_id": "569f2de3df24afb409bf9d3ae3878d96", "sentence": "After an initial 6 - 8 weeks of metformin , they received either letrozole ( 2.5 mg ) or clomiphene ( 100 mg ) from day 3 - 7 of their menstrual cycle .", "spans": [{"span_id": 0, "text": "metformin", "start": 32, "end": 41, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "letrozole", "start": 65, "end": 74, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "clomiphene", "start": 89, "end": 99, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Adding metformin to clomiphene citrate in clomiphene-resistant polycystic ovary syndrome (PCOS) patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. ### methods Infertile women with PCOS were randomly divided into metformin-letrozole (29 patients) and metformin-clomiphene groups (30 patients). After an initial 6 - 8 weeks of metformin , they received either letrozole ( 2.5 mg ) or clomiphene ( 100 mg ) from day 3 - 7 of their menstrual cycle . Estradiol (E2) levels, number of follicles, pregnancy rates and endometrial thickness were measured on the day of HCG administration. ### results Mean total E2 and E2 per mature follicle were significantly higher in clomiphene group without a difference in mean number of mature follicles >18 mm and ovulation rate. Endometrial thickness was significantly higher in letrozole group. The pregnancy rate in letrozole group (10 patients, 34.50%) as compared with clomiphene group (5 patients, 16.67%) did not show significant difference, whereas full-term pregnancies were higher in letrozole group [10 patients (34.50%) versus 3 patients (10%)]. ### conclusion In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.", "source": "https://pubmed.ncbi.nlm.nih.gov/16478764/"}
{"doc_id": "1aa150f13e8dd0036b14b0794d17455c", "sentence": "No study has evaluated the significance of CD30 expression in DLBCL patients treated with rituximab , etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( R-EPOCH ) .", "spans": [{"span_id": 0, "text": "rituximab", "start": 90, "end": 99, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "etoposide", "start": 102, "end": 111, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "prednisone", "start": 114, "end": 124, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "vincristine", "start": 127, "end": 138, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "cyclophosphamide", "start": 141, "end": 157, "token_start": 22, "token_end": 23}, {"span_id": 5, "text": "doxorubicin", "start": 164, "end": 175, "token_start": 25, "token_end": 26}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "CD30 expression and prognostic significance in R-EPOCH-treated patients with diffuse large B-cell lymphoma. A few recent studies investigated the prognostic impact of CD30 expression in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. No study has evaluated the significance of CD30 expression in DLBCL patients treated with rituximab , etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( R-EPOCH ) . In a group of 97 patients with DLBCL and high-risk features who received R-EPOCH induction therapy, we studied CD30 expression by immunohistochemistry using different cutoff values (>0% and \u226520% of lymphoma cells, respectively) and correlated with prognosis. CD30 expression was detected in 24 (25%) cases using a cutoff greater than 0% and in 12 (12%) cases using a cutoff of 20% or greater. The clinicopathological features were similar between CD30+ and CD30-negative groups. A major difference was that MYC rearrangement was infrequent in the CD30+ group: 2 (9%) of 23 in CD30+ versus 25 (35%) of 72 in CD30-negative group (P=.02). CD30 expression was not associated with germinal center B-cell-like (GCB) or non-GCB type. Overall survival (OS) was not significantly different between patients with CD30+ and patients with CD30-negative DLBCL, either for all patients or for the subset of patients without MYC rearrangement, regardless of cutoff (P>.05). CD30 expression was not associated with OS in either GCB or non-GCB subtype (P>.05, > 0% cutoff). In conclusion, CD30 expression was detected in up to 25% of cases of DLBCL and was more frequent in tumors without MYC rearrangement. CD30 expression was not associated with OS in R-EPOCH-treated de novo DLBCL patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/27816715/"}
{"doc_id": "b5116da421faea4246da9634e6a9dfbc", "sentence": "Although MAPK/ERK1/2 kinase inhibitors ( MEKi ) are useful antitumor agents in a clinical setting , including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib , there are limitations to their clinical utility , primarily adaptation of the BRAF pathway and ocular toxicities .", "spans": [{"span_id": 0, "text": "cobimetinib", "start": 181, "end": 192, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "trametinib", "start": 197, "end": 207, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Dual inhibition of MEK1/2 and MEK5 suppresses the EMT/migration axis in triple-negative breast cancer through FRA-1 regulation. Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors ( MEKi ) are useful antitumor agents in a clinical setting , including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib , there are limitations to their clinical utility , primarily adaptation of the BRAF pathway and ocular toxicities . The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells.\u00a0Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/33876843/"}
{"doc_id": "65c5329cada8f1320b2c0dfabcf7e776", "sentence": "Suggested evidence linking the association of the drug to the event includes knowing that Panitumumab and Irinotecan can contribute to all other possible causes of cardiac arrest , temporal relationship and pharmacological time plausibility , and recognized association with the product or the class .", "spans": [{"span_id": 0, "text": "Panitumumab", "start": 90, "end": 101, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "Irinotecan", "start": 106, "end": 116, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A patient with metastatic colon cancer to the liver presenting with cardiac arrest status post receiving combination irinotecan-panitumumab: a case report. panitumumab is a recombinant human Immunoglobulin G antibody. irinotecan is an S-phase cell cycle specific plant alkaloid. Life threatening adverse events occur with panitumumab-chemotherapy combination. A Fifty three years old male with metastatic colon cancer to the liver started panitumumab-irinotecan palliative combination chemotherapy. On cycle two day twenty six the patient presented in the emergency room with cardiac arrest. Suggested evidence linking the association of the drug to the event includes knowing that Panitumumab and Irinotecan can contribute to all other possible causes of cardiac arrest , temporal relationship and pharmacological time plausibility , and recognized association with the product or the class . It is possible that there is a true association linking cardiac arrest to irinotecan-panitumumab combination. The aim of reporting this adverse event is to emphasize the recommendations of the National Comprehensive Cancer Network of discontinuing the use of panitumumab-chemotherapy combination in metastatic colon cancer patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/21222364/"}
{"doc_id": "4780fc8f0fca92ed3f1c9809bf6f6a95", "sentence": "This study was designed to evaluate the effect of aprotinin on activated versus nonactivated whole blood clotting time using two different on-site methods and to quantify these anticoagulant properties when compared to heparin in a controlled , in vitro environment .", "spans": [{"span_id": 0, "text": "aprotinin", "start": 50, "end": 59, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "heparin", "start": 219, "end": 226, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Aprotinin prolongs activated and nonactivated whole blood clotting time and potentiates the effect of heparin in vitro.  This study was designed to evaluate the effect of aprotinin on activated versus nonactivated whole blood clotting time using two different on-site methods and to quantify these anticoagulant properties when compared to heparin in a controlled , in vitro environment . Blood specimens were obtained prior to heparin administration from 56 patients undergoing cardiac surgery. Specimens obtained from the first consecutive 20 patients were mixed with either normal saline (NS) or aprotinin (400 kallikrein inhibiting units (KIU)/mL), inserted into Hemochron tubes containing either NS or heparin (0.3 or 0.6 U/mL) and then used to measure celite-activated (celite ACT) and nonactivated whole blood clotting time (WBCT1) using four Hemochron instruments. Accordingly, specimens obtained from the second consecutive 20 patients were mixed with either NS or aprotinin, inserted into Automated Clot Timer cartridges containing either NS or heparin (0.06, 0.13, or 0.25 U/mL) and then used to measure kaolin-activated (kaolin ACT) or nonactivated whole blood clotting times (WBCT2) using four Automated Clot Timer instruments. Specimens obtained from the last 16 patients were mixed with either incrementally larger doses of aprotinin (0, 100, 200, 300, or 400 KIU/mL) or heparin (0, 0.12, 0.24, 0.36, 0.48, or 0.72 U/mL) and were then used for measurement of whole blood clotting time (WBCT2) using six Automated Clot Timer instruments. aprotinin significantly prolonged activated or nonactivated whole blood clotting time and potentiated the prolongation of whole blood clotting time by heparin. The linear relationship between whole blood clotting time and either heparin concentration (WBCT2 = H x 357 + 280, mean adjusted r2 = 0.88) or aprotinin concentration (WBCT2 = A x 0.97 + 300, mean adjusted r2 = 0.94) was variable among patients. On average, 200 KIU/mL of aprotinin prolonged WBCT2 to the same extent as 0.69 +/- 0.28 U/mL of heparin using linear regression models within each patient. aprotinin significantly prolongs activated or nonactivated whole blood clotting time measurements in a dose-dependent manner. Since prolongation of whole blood clotting time by heparin is potentiated by aprotinin in vitro, aprotinin's anticoagulant properties may in part account for the prolonged celite activated clotting time values observed in the presence of aprotinin.", "source": "https://pubmed.ncbi.nlm.nih.gov/8638779/"}
{"doc_id": "8c3b17fb6111c8666586a609f323991e", "sentence": "Cyclophosphamide , mitoxantrone , fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients .", "spans": [{"span_id": 0, "text": "Cyclophosphamide", "start": 0, "end": 16, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "mitoxantrone", "start": 19, "end": 31, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "fluorouracil", "start": 34, "end": 46, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Cyclophosphamide , mitoxantrone , fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients . 362 evaluable node-positive patients with stage II breast cancer were randomized, receiving either 6 cycles of conventional CMF or 6 cycles of the combination of cyclophosphamide (500 mg/m2), mitoxantrone (Novantrone 10 mg/m2), and fluorouracil (500 mg/m2; CNF). After a median follow-up of 51 months, 64 (36%) patients relapsed in the CMF group and 60 (33%) in the CNF group (p=0.8276). By Cox multivariate analysis, tumor size, menopausal status and number of involved nodes were retained as independently significant variables. Toxicities were remarkably similar in both groups. It appears that after a median follow-up of 51 months there is no significant difference in relapse-free survival between node-positive patients with breast cancer who received either 6 cycles of the conventional CMF or the CNF combination as adjuvant treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/8604240/"}
{"doc_id": "c42e30d67d6e1065eaf786efb226f38a", "sentence": "After the operation , an alternating vincristine , doxorubicin , and cyclophosphamide/ifosfamide and etoposide ( IE ) regimen was given for eight cycles , and the patient survived for 66 mo without progression .", "spans": [{"span_id": 0, "text": "vincristine", "start": 37, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "doxorubicin", "start": 51, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "etoposide", "start": 101, "end": 110, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Primitive neuroectodermal tumors of the abdominal wall and vulva in children: Report of two cases and review of the literature. Primitive neuroectodermal tumors are rare, highly malignant small round cell tumors belonging to the Ewing sarcoma family. The purpose of this article is to present clinical manifestation, histology, treatment, and prognosis of two primitive neuroectodermal tumors (PNETs) in extremely rare anatomic locations, the abdominal wall and vulva. ### Case Summary Case 1 was a 66-month-old girl with lesions on the abdominal wall; tumor size was about 3.4 cm \u00d7 6.1 cm \u00d7 2 cm. The patient underwent radical resection of the tumor. After the operation , an alternating vincristine , doxorubicin , and cyclophosphamide/ifosfamide and etoposide ( IE ) regimen was given for eight cycles , and the patient survived for 66 mo without progression . Case 2 was a 40-month-old girl, with a vulvar lesion; tumor size was about 3.3 cm \u00d7 5 cm \u00d7 2.5 cm. The tumor was partially resected by surgery. The family left treatment after two cycles of vincristine, pirarubicin, and cyclophosphamide/IE chemotherapy, and the patient died at home six months after surgery. ### conclusion PNET is a rare, fast-growing, highly malignant tumor that requires histologic and molecular analyses for exact diagnosis, and multimodal treatment is required to achieve a good prognosis.", "source": "https://pubmed.ncbi.nlm.nih.gov/31750352/"}
{"doc_id": "2abe808f1283fbec87893dc71eb3d9d0", "sentence": "A total of 34 patients with androgen-independent prostate cancer received doxorubicin , 30 mg/m(2 ) , every 2 weeks and ketoconazole daily , 400 mg orally every 8 hours .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 74, "end": 85, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "ketoconazole", "start": 120, "end": 132, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Biweekly doxorubicin/ketoconazole as second-line treatment in docetaxel-resistant, hormone-refractory prostate cancer. docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. Nevertheless, the prognosis subsequent to progression after first-line therapy is poor and no second-line treatment has been established. ### methods A total of 34 patients with androgen-independent prostate cancer received doxorubicin , 30 mg/m(2 ) , every 2 weeks and ketoconazole daily , 400 mg orally every 8 hours . All patients had been treated with docetaxel and had disease progression within 6 months after completion of first-line treatment. ### results Of the 32 evaluable patients, 13 (43.7%, 95% confidence interval [CI] 26.3% to 62.3%) had a prostate-specific antigen (PSA) response, and 4 (28%, 95% CI 8.4% to 58.1%) of 14 patients with measurable disease had a response to therapy. The median time to progression (TTP) was 3.9 months (95% CI 2.0 to 5.9), and the median overall survival (OS) was 13 months (95% CI 8.7 to 17.3). Toxicity was mild, with only 4 cases of nonhematologic grade 3 or 4 toxicity. The most frequent toxicity was nail changes (33 of 34 patients), which was mainly grade 1 (30 cases). ### conclusions The combination of biweekly doxorubicin and ketoconazole is an effective, well-tolerated, second-line therapy for hormone-refractory prostate cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/18400264/"}
{"doc_id": "9ab4556c1196ea2c960f5d09e418cdc3", "sentence": "All 35 patients were treated with the ANLL91 protocol consisting of etoposide , high-dose cytarabine , and anthracyclines .", "spans": [{"span_id": 0, "text": "etoposide", "start": 68, "end": 77, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "cytarabine", "start": 90, "end": 100, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group. This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide , high-dose cytarabine , and anthracyclines . Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/11739161/"}
{"doc_id": "bcc762ec6c76266e0e6aefaf388b355a", "sentence": "Three first-line drugs are recommended , pegylated interferon alfa-2a , entecavir and tenofovir .", "spans": [{"span_id": 0, "text": "pegylated interferon alfa-2a", "start": 41, "end": 69, "token_start": 6, "token_end": 9}, {"span_id": 1, "text": "entecavir", "start": 72, "end": 81, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "tenofovir", "start": 86, "end": 95, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "[Interferon-based versus direct antiviral therapy in patients with chronic hepatitis B]. Treatment of chronic hepatitis B is still challenging. Lots of parameters are needed to be considered before and during the therapy. There are several possible endpoints and their durability is very much variable. Patients with HBeAg-positive and HBeAg-negative hepatitis B need treatment. Two different strategies are available. Interferon-based therapy is a limited treatment, which might result in a sustained immune response in about one third of the patients, leading to an induced remission, sometimes years after the end of the treatment. According to the other strategy a continuous, indefinite oral nucleoside/nucleotide analogue (NA) treatment is administered to maintain a remission. However, relapse is rather frequent after the cessation of this therapy. During the long-term NA treatment drug resistance can lead to the loss of antiviral effect. Three first-line drugs are recommended , pegylated interferon alfa-2a , entecavir and tenofovir . If there is no contraindication to interferon, it is worth trying to achieve immune control and an induced remission. In patients, who do not respond to interferon, a sequential NA therapy is indicated.", "source": "https://pubmed.ncbi.nlm.nih.gov/21565754/"}
{"doc_id": "535a0b7e66c0a1aefa21cf4a5d88c31f", "sentence": "Whereas fluoxetine showed the highest level of specificity , followed by citalopram and fluvoxamine , the effect of paroxetine was nonspecific .", "spans": [{"span_id": 0, "text": "fluoxetine", "start": 8, "end": 18, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "citalopram", "start": 73, "end": 83, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "fluvoxamine", "start": 88, "end": 99, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "paroxetine", "start": 116, "end": 126, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Comparison of the effects of the selective serotonin-reuptake inhibitors fluoxetine, paroxetine, citalopram and fluvoxamine in alcohol-preferring cAA rats. Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity , followed by citalopram and fluvoxamine , the effect of paroxetine was nonspecific . The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.", "source": "https://pubmed.ncbi.nlm.nih.gov/10231167/"}
{"doc_id": "7d7538f51ee43a6cd516678f3e0cc07f", "sentence": "A countercurrent seepage bioreactor immobilized with Phanerochaete chrysosporium was continuously operated under non-sterile conditions to treat a synthetic wastewater spiked with naproxen and carbamazepine ( 1000\u03bcg/L each ) for 165days .", "spans": [{"span_id": 0, "text": "naproxen", "start": 180, "end": 188, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "carbamazepine", "start": 193, "end": 206, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Enhanced removal of naproxen and carbamazepine from wastewater using a novel countercurrent seepage bioreactor immobilized with Phanerochaete chrysosporium under non-sterile conditions.  A countercurrent seepage bioreactor immobilized with Phanerochaete chrysosporium was continuously operated under non-sterile conditions to treat a synthetic wastewater spiked with naproxen and carbamazepine ( 1000\u03bcg/L each ) for 165days . There were no serious bacterial contaminations occurred during the operational period. naproxen was always removed to the undetectable level regardless of the experimental conditions, while the average removal efficiency for carbamazepine, a well-known recalcitrant pharmaceutically active compound, reached around 80%. The excellent removal performance was mainly attributed to the application of countercurrent seepage mode and the cardhouse fabric of the carriers, which provided the high efficiency in the transfer of oxygen and nutrients inside the bioreactor. From the fungal immobilization combined with the temperature adjustment, the fungal activity including the enzyme production was protected as well as the bacterial contamination inside the reactor was suppressed effectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/26356119/"}
{"doc_id": "a8b7e8418f86bcec5b2f8c04f4141ca3", "sentence": "A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway .", "spans": [{"span_id": 0, "text": "tivozanib", "start": 21, "end": 30, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "durvalumab", "start": 51, "end": 61, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo. ### methods We conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated. ### results Twenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1\u2009mg per os once daily, 21 days on-7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement. ### conclusions Although this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway . ### Trial Registration ClinicalTrials.gov NCT01835223, registered on 15 April 2013.", "source": "https://pubmed.ncbi.nlm.nih.gov/32037403/"}
{"doc_id": "633a9c1a5d3f0a2ff30edccdc7a7b47d", "sentence": "Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3 , randomized , controlled , BOLERO-2 trial .", "spans": [{"span_id": 0, "text": "everolimus", "start": 84, "end": 94, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "exemestane", "start": 100, "end": 110, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "exemestane", "start": 131, "end": 141, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3 , randomized , controlled , BOLERO-2 trial . The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). ### methods Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. ### results Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). ### conclusions In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE.", "source": "https://pubmed.ncbi.nlm.nih.gov/23504821/"}
{"doc_id": "865421d64e83a88ada0161460aaf3811", "sentence": "Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 17, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "paclitaxel", "start": 32, "end": 42, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase 2 study of irinotecan and paclitaxel in patients with recurrent or refractory small cell lung cancer . Patients with extensive stage small cell lung cancer (SCLC) who develop disease progression with standard cisplatin-based therapy are reported to have a poor overall prognosis. irinotecan and paclitaxel are active as single agents and exhibit preclinical synergy in SCLC cell lines. A phase 2 study was conducted to evaluate this combination in patients with recurrent or refractory SCLC. ### methods Patients with SCLC who progressed with 1 prior chemotherapy regimen and had measurable disease present; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; and adequate bone marrow, hepatic, and renal function were included in the study. paclitaxel (at a dose of 75 mg/m(2)) and irinotecan (at a dose of 50 mg/m(2)) were administered intravenously on Days 1 and 8 of each 3-week treatment cycle. Therapy was continued until disease progression or unacceptable toxicity. The target response rate of interest was > or =30%. ### results A total of 55 patients were enrolled, 51 of whom received at least 1 dose of therapy. The majority of the patients had an ECOG PS of 0 or 1 (96%). A median of 3 cycles of treatment was administered, and 15 patients received > or =6 cycles. Seventeen patients experienced toxicity of grade 3 or higher (neutropenia in 8 patients and fatigue in 5 patients). The overall response rate was 21%. The median survival was 25.4 weeks, and the 1-year survival rate was 22%. ### conclusions The regimen of irinotecan and paclitaxel was found to be tolerated well in patients with recurrent or refractory SCLC. Although modest anticancer activity was noted, the efficacy failed to meet the primary endpoint of interest.", "source": "https://pubmed.ncbi.nlm.nih.gov/20082454/"}
{"doc_id": "8e26b126191a14bcd647bd171f672f4d", "sentence": "Administration of artesunate and artemether at a dose of 400mg/kg to O. viverrini-infected hamsters resulted in worm burden reductions of 77.6 % and 65.5 % , respectively .", "spans": [{"span_id": 0, "text": "artesunate", "start": 18, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "artemether", "start": 33, "end": 43, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Effect of artesunate and artemether against Clonorchis sinensis and Opisthorchis viverrini in rodent models. Food-borne trematodiasis is an emerging public health problem and there is a need to develop novel treatment options. We examined the in vivo efficacy of single oral doses of artesunate and artemether administered to rodents experimentally infected with either Clonorchis sinensis or Opisthorchis viverrini. Rats infected with adult C. sinensis were administered artesunate or artemether at doses of 75, 150 or 300 mg/kg. Hamsters infected with adult O. viverrini were administered artesunate or artemether at doses of 200, 400 or 600 mg/kg. Treatment efficacy was assessed according to reductions in worm burden compared with infected but untreated control animals. Worm burden reductions of 98.6-100% were found in C. sinensis-infected rats after a single dose of artesunate and artemether at 150 mg/kg. Administration of artesunate and artemether at a dose of 400mg/kg to O. viverrini-infected hamsters resulted in worm burden reductions of 77.6 % and 65.5 % , respectively . However, both drugs showed toxic effects when administered to O. viverrini-infected hamsters at a dose > or =400mg/kg. Our study demonstrates that artesunate and artemether possess excellent clonorchicidal activities in vivo. These findings provide a foundation for subsequent clinical trials. More laboratory investigations are warranted to investigate further the opisthorchicidal properties of the artemisinins.", "source": "https://pubmed.ncbi.nlm.nih.gov/16973335/"}
{"doc_id": "f2744a73ce29996ed3582ac62f9368c6", "sentence": "Whereas no effect on proliferation , cell culture density , or cell cycle was detected , the transfectants were more resistant than the parental cell line to apoptosis induced by chemotherapeutic agents including etoposide , daunorubicin , doxorubicin , cytosine arabinoside , methotrexate and vincristine and also to apoptosis induced by Fas/CD95 cross-linking .", "spans": [{"span_id": 0, "text": "etoposide", "start": 213, "end": 222, "token_start": 33, "token_end": 34}, {"span_id": 1, "text": "daunorubicin", "start": 225, "end": 237, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "doxorubicin", "start": 240, "end": 251, "token_start": 37, "token_end": 38}, {"span_id": 3, "text": "methotrexate", "start": 277, "end": 289, "token_start": 42, "token_end": 43}, {"span_id": 4, "text": "vincristine", "start": 294, "end": 305, "token_start": 44, "token_end": 45}], "rels": [], "paragraph": "Antiapoptotic effect of ectopic TAL1/SCL expression in a human leukemic T-cell line. Aberrant expression of TAL1 occurs frequently in human T-cell acute lymphoblastic leukemia. The effect of TAL1 expression in the T-cell lymphoid precursor, however, remains unclear. In the current study, we have developed TAL1 stable transfectants in a human immature T-cell lymphoid cell line. Whereas no effect on proliferation , cell culture density , or cell cycle was detected , the transfectants were more resistant than the parental cell line to apoptosis induced by chemotherapeutic agents including etoposide , daunorubicin , doxorubicin , cytosine arabinoside , methotrexate and vincristine and also to apoptosis induced by Fas/CD95 cross-linking . This effect was independent of the cytostatic effects of the drugs. The basic domain-deleted transfectants did not demonstrate altered sensitivity, suggesting that DNA binding was necessary for resistance to apoptosis. The ability to alter the response to a wide range of cell death-inducing stimuli suggests that TAL1 acts at a late stage of the apoptotic cascade. These data therefore provide direct evidence of an antiapoptotic effect of ectopic TAL1 expression in response to cytotoxic agents, thus providing insight into its oncogenic function in T-cell acute lymphoblastic leukemia and a novel experimental model to further investigate the underlying mechanisms. These data also have potential practical significance for cytotoxic therapy of this disorder.", "source": "https://pubmed.ncbi.nlm.nih.gov/9635597/"}
{"doc_id": "99715e32028be1dcc1747371a19df937", "sentence": "This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide , vincristine doxorubicin , dexamethasone ( modified R-hyperCVAD ) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years .", "spans": [{"span_id": 0, "text": "rituximab", "start": 47, "end": 56, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "cyclophosphamide", "start": 89, "end": 105, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "vincristine", "start": 108, "end": 119, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "doxorubicin", "start": 120, "end": 131, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "dexamethasone", "start": 134, "end": 147, "token_start": 18, "token_end": 19}, {"span_id": 5, "text": "rituximab", "start": 235, "end": 244, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. There is no standard first line treatment for mantle cell lymphoma. ### Patients And Methods This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide , vincristine doxorubicin , dexamethasone ( modified R-hyperCVAD ) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years . Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. ### results Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. ### conclusion In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/16766582/"}
{"doc_id": "a671a1895cecb359321715c750639925", "sentence": "The first line of treatment is selective serotonin reuptake inhibitors ( dapoxetine , which is the only drug with an official label for this indication , paroxetine , sertraline , fluoxetine , citalopram , escitalopram ) .", "spans": [{"span_id": 0, "text": "dapoxetine", "start": 73, "end": 83, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "paroxetine", "start": 154, "end": 164, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "sertraline", "start": 167, "end": 177, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "fluoxetine", "start": 180, "end": 190, "token_start": 30, "token_end": 31}, {"span_id": 4, "text": "citalopram", "start": 193, "end": 203, "token_start": 32, "token_end": 33}, {"span_id": 5, "text": "escitalopram", "start": 206, "end": 218, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "[THE FIRST CROATIAN GUIDELINES FOR DIAGNOSIS, TREATMENT AND FOLLOW-UP OF PERSONS WITH PREMATURE EJACULATION]. Premature ejaculation (PE) is a sexual disorder with high prevalence, defined by three characteristics: short intravaginal ejaculation latency time, poor control over delaying ejaculation and personal and/or partner distress. The diagnosis is reached by a thorough and comprehensive history taking, which should include presence/absence of other \u00adco-morbid conditions (e.g. erectile dysfunction, anxiety), and assessing the type of PE (primary, secondary, variable, subjective). It is important to counsel the patient (and, if possible, the partner) about this condition and treatment options. The first line of treatment is selective serotonin reuptake inhibitors ( dapoxetine , which is the only drug with an official label for this indication , paroxetine , sertraline , fluoxetine , citalopram , escitalopram ) . The first line of treatment also includes psychological/sexological treatment methods, such as behavioural methods (stop-start and squeeze techniques), and new functional sexological treatment. The choice of the method depends on the type of PE and on the patient preference. The second line of treatment are clomipramine and local anaesthetics, and the third line is tramadol.", "source": "https://pubmed.ncbi.nlm.nih.gov/30148566/"}
{"doc_id": "15cd880937122f95fe839bf853a93050", "sentence": "This trial will close to accrual in September 1995 , and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel , the degree of cross-resistance between the two compounds , and the relationship between steady-state paclitaxel levels and response to therapy .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 148, "end": 159, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "paclitaxel", "start": 164, "end": 174, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "paclitaxel", "start": 278, "end": 288, "token_start": 42, "token_end": 43}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Doxorubicin/paclitaxel combination chemotherapy for metastatic breast cancer: the Eastern Cooperative Oncology Group experience. The addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the therapeutic armamentarium for breast cancer has resulted in novel opportunities and challenges for the clinician. In a series of trials that began in 1992, the Eastern Cooperative Oncology Group (ECOG) investigated the role of paclitaxel in combination with doxorubicin for the treatment of patients with advanced breast cancer. The design of the first trial, a limited-institution pilot study, involved alternating doxorubicin and paclitaxel as single agents. The alternating schedule was well tolerated and associated with objective responses in seven of 12 patients entered into the trial. In the second trial, a limited-institution phase I trial, bolus doxorubicin was combined with paclitaxel administered over a 24-hour infusion, with administration of the two drugs separated by 4 hours. While no dose-limiting toxicity was seen at doses of 50 and 150 mg/m2 of doxorubicin and paclitaxel, respectively, dose-limiting mucositis occurred at respective doses of 60 and 175 mg/m2. Mucositis was more common when administration of paclitaxel preceded that of doxorubicin than when doxorubicin preceded paclitaxel. Based on these results, the ECOG initiated a phase III trial comparing single-agent paclitaxel, single-agent doxorubicin, and the combination of paclitaxel and doxorubicin. This study, now an Intergroup trial of ECOG, the Southwest Oncology Group, and the North Central Cancer Treatment Group, is designed to accrue 730 patients. This trial will close to accrual in September 1995 , and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel , the degree of cross-resistance between the two compounds , and the relationship between steady-state paclitaxel levels and response to therapy . In addition, ECOG is currently conducting a trial designed to confirm the striking activity of cisplatin and paclitaxel seen in the British Columbia trials. Future trials by the group will examine means of combining paclitaxel with other active agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/7481854/"}
{"doc_id": "b192b6a0aef4cfe50e4130cdcc468ea0", "sentence": "Neither systolic nor diastolic BP during daytime differed between losartan and quinapril treatments , but those during nighttime were lower with losartan treatment than with quinapril treatment .", "spans": [{"span_id": 0, "text": "losartan", "start": 66, "end": 74, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "quinapril", "start": 79, "end": 88, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "losartan", "start": 145, "end": 153, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "quinapril", "start": 174, "end": 183, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor. Treatment of nocturnal hypertension has been reported to be beneficial for primary and secondary prevention of stroke. We compared the effects of angiotensin II antagonist (losartan) and angiotensin converting enzyme inhibitor (quinapril) on nocturnal blood pressure (BP) and sympathetic nervous activity in patients with hypertension and stroke. ### methods According to a prospective, randomized, cross-over design, 30 hypertensive patients with a previous history of stroke (25 hemorrhage, 5 infarction) were assigned randomly to receive losartan (50 mg) or quinapril (10 mg) once daily for 4 weeks. The patients were switched to the alternative regimen for an additional 4-week period. In the last week of each treatment, 24-h ambulatory BP monitoring was performed every 30 min, and 24-h urine was collected for the measurement of catecholamine. ### results Neither systolic nor diastolic BP during daytime differed between losartan and quinapril treatments , but those during nighttime were lower with losartan treatment than with quinapril treatment . The nocturnal decreases in systolic and diastolic BP were both greater with losartan treatment than with quinapril treatment (systolic BP: 6.1% +/- 5.9% v 2.5% +/- 6.9%, diastolic BP: 6.4% +/- 6.5% v 3.3% +/- 7.8%, both P <.05). The nocturnal decrease in urinary norepinephrine excretion was greater with losartan treatment than with quinapril treatment (52.8% +/- 9.7% v 42.8% +/- 17.2%, P <.05). ### conclusions losartan enhances the nocturnal decrease in ambulatory BP compared with that of quinapril in patients with a previous history of stroke presumably by way of the suppression of nocturnal sympathetic nervous activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/12441222/"}
{"doc_id": "1a04ee3c95f14be4b4b3fab51f305686", "sentence": "Ferrochloroquine was 35 times more active than chloroquine ( 35-fold greater against chloroquine-resistant isolates ) , quinine , mefloquine , amodiaquine , cycloguanil and pyrimethamine .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 47, "end": 58, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "quinine", "start": 120, "end": 127, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "mefloquine", "start": 130, "end": 140, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "amodiaquine", "start": 143, "end": 154, "token_start": 20, "token_end": 21}, {"span_id": 4, "text": "pyrimethamine", "start": 173, "end": 186, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "In vitro activities of ferrochloroquine against 55 Senegalese isolates of Plasmodium falciparum in comparison with those of standard antimalarial drugs. The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, artesunate, atovaquone, cycloguanil and pyrimethamine were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo, Ndiop), using an isotopic micro-drug susceptibility test. The IC50 values for ferrochloroquine ranged from 0.55 to 28.2 nM and the geometric mean IC50 for the 55 isolates was 7.9 nM (95% CI, 6.5-9.7 nM). Ferrochloroquine was 35 times more active than chloroquine ( 35-fold greater against chloroquine-resistant isolates ) , quinine , mefloquine , amodiaquine , cycloguanil and pyrimethamine . Weak positive correlations were observed between the responses to ferrochloroquine and that to chloroquine, quinine, and amodiaquine, but not compulsorily predictive of cross-resistance. There was no significant correlation between the response to ferrochloroquine and that to mefloquine, halofantrine, artesunate, atovaquone, cycloguanil and pyrimethamine. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.", "source": "https://pubmed.ncbi.nlm.nih.gov/11903989/"}
{"doc_id": "a6bbfa01a0f2e4447d4dee91f8973540", "sentence": "26 patients received adjuvant chemotherapy ( carboplatin plus etoposide ) .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 45, "end": 56, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "etoposide", "start": 62, "end": 71, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Outcomes of adult medulloblastoma treated with a multimodality approach: A tertiary cancer center experience. Adult medulloblastoma (AMB) is a rare central nervous system tumor. We aimed to analyze the treatment outcomes of AMB treated at our institute with surgery followed by craniospinal irradiation (CSI) and adjuvant chemotherapy. ### methods We retrospectively evaluated the treatment charts of 31 patients of AMB treated from 2003-2011. The patient demography, treatment details and survival data were collected in a predesigned proforma. Kaplan Meier method was used to analyze disease free survival (DFS) and the impact of prognostic factors was determined by univariate analysis (log rank test). ### results Male: Female ratio was 21:10. Cerebrospinal fluid dissemination was noted in 16% cases. CSI (36 Gray at 1.8 Gray/fraction to entire neuraxis and 20 Gray at 2 Gray/fraction boost to posterior fossa) was used in all cases. 26 patients received adjuvant chemotherapy ( carboplatin plus etoposide ) . Median follows up was 26.85 months (9.47-119.73 months). The estimated 3 and 5 years DFS was found to be 84.9% and 50.7% respectively. On univariate analysis, tumor located laterally had a trend towards better DFS (HR 3.04; 95%CI 0.722 to 12.812; P = 0.07) compared to midline tumors. Other factors like adjuvant chemotherapy, age, gender, surgical extent had no statistically significant impact on survival. ### conclusion The results of our study (largest series from India) show that the regimen of surgery, adjuvant CSI and chemotherapy is feasible and confers descent survival. AMB patients should be treated with a multimodality approach in a tertiary care centre.", "source": "https://pubmed.ncbi.nlm.nih.gov/26981508/"}
{"doc_id": "a8cf0a76ea1128997862a247fb4b2943", "sentence": "A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified .", "spans": [{"span_id": 0, "text": "venetoclax", "start": 36, "end": 46, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "rituximab", "start": 116, "end": 125, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. venetoclax is indicated at a dosage of 400\u00a0mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified . The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400\u00a0mg daily QD was estimated to result in a substantial median PFS of 1.8\u00a0years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9\u00a0years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.", "source": "https://pubmed.ncbi.nlm.nih.gov/27982454/"}
{"doc_id": "b52fd7bcfc63c0a50d7d339cba68d21e", "sentence": "Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer .", "spans": [{"span_id": 0, "text": "Carboplatin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "taxanes", "start": 17, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "epirubicin", "start": 45, "end": 55, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "cyclophosphamide", "start": 61, "end": 77, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer . Platinum plays an important role in the treatment of triple-negative breast cancer (TNBC) in neoadjuvant and metastatic settings. However, its role in an adjuvant setting remains unclear. ### methods In this non-inferior randomized phase 2 trial, we randomly assigned 308 chemotherapy-naive patients with histologically confirmed TNBC after primary surgery to receive either six cycles of TP (docetaxel: 75\u00a0mg/m ### results At a median follow-up of 66.9\u00a0months, the 5-year DFS rate was 85.8% in the EC-T arm, and 84.4% in the TP arm (p non-inferiority\u2009=\u20090.034, p log-rank\u2009=\u20090.712). The 5-year overall survival (OS) rate was 94.4% in the EC-T arm and 93.5% in the TP arm (p\u2009=\u20090.770). Patients in the TP arm showed better compliance and experienced significantly lower frequencies of G3/4 neutrocytopenia and G3/4 alopecia, but higher rates of G1-4 thrombocytopenia than those in the EC-T arm. Patients with PD-L1 expressing tumors showed significantly improved DFS and OS. ### conclusions This study indicates that carboplatin plus taxanes could be a feasible adjuvant chemotherapy for patients with early TNBC who are cannot tolerate intensive chemotherapy with anthracycline.", "source": "https://pubmed.ncbi.nlm.nih.gov/32394350/"}
{"doc_id": "af17cef122c896fa9e25abf3226ef005", "sentence": "Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections : the efficacy , safety and effect on fecal flora .", "spans": [{"span_id": 0, "text": "ceftriaxone", "start": 21, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "cefuroxime", "start": 77, "end": 87, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "gentamicin", "start": 93, "end": 103, "token_start": 12, "token_end": 13}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections : the efficacy , safety and effect on fecal flora . To assess the efficacy of once daily monotherapy relative to standard combination antibiotic therapy for the initial management of patients suspected of serious bacterial infections, we conducted a randomized trial comparing ceftriaxone (Rocephin) with a combination of cefuroxime plus gentamicin. Of 105 patients, 53 were treated with ceftriaxone alone and 52 with the combination; 13 patients were considered not evaluable. 42 of 53 patients given ceftriaxone and 33 of 52 given cefuroxime plus gentamicin responded to treatment (p = 0.07). Three patients given ceftriaxone and 6 who received gentamicin plus cefuroxime died (p = 0.28). Definite bacterial infections were identified in 67 patients; of the evaluable patients with a definite infection 27 of 29 who received ceftriaxone and 21 of 31 who were treated with the combination were cured (p = 0.01). No difference was found in the number of side effects. However, therapy had to be discontinued due to treatment failure, an adverse effect or death in 1 of 33 patients given ceftriaxone and in 11 of 34 given the combination (p = 0.002). ceftriaxone was found to have an impact on the count of E. coli in intestinal microflora. Changes in normal bacterial composition did not lead to the overgrowth with resistant Enterobacteriaceae or Pseudomonas, however, colonization by yeast was observed. Using ceftriaxone reduced the cost of antimicrobial therapy per patient by 107 pounds (US$ 183). Moreover, the total time save per patient due to decreased nursing and drug administration time per day was 40 min.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/3149929/"}
{"doc_id": "53378bb1670658cc548bb5bc1d6ea7a4", "sentence": "A phase 1b , dose escalation study was performed to assess maximum tolerated dose , safety/toxicity , clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab .", "spans": [{"span_id": 0, "text": "entinostat", "start": 175, "end": 185, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "lapatinib", "start": 200, "end": 209, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "trastuzumab", "start": 226, "end": 237, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment. Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. ### methods A phase 1b , dose escalation study was performed to assess maximum tolerated dose , safety/toxicity , clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab . ### results The combination was safe. The MTD was lapatinib, 1000\u2009mg daily; entinostat, 12\u2009mg every other week; trastuzumab, 8\u2009mg/kg followed by 6\u2009mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. ### discussion This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.", "source": "https://pubmed.ncbi.nlm.nih.gov/31097774/"}
{"doc_id": "32ecc7a7d4e7ce44ea873d52018b5256", "sentence": "Objective and palliative effect of chemotherapy is marked for weekly doxorubicin , prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 69, "end": 80, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "prednisone", "start": 83, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "mitoxantrone", "start": 99, "end": 111, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "etoposide", "start": 116, "end": 125, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "[Study of the hormone-refractory prostate cancer clinical practice in an anti-cancer center]. We have examined 82 patients with hormonoresistant prostate cancer in a retrospective study. Bone and lymph node metastases were observed in 94% and 30% of patients respectively. However, the visceral metastases were frequent: liver (17%), lung (7%), bone marrow (4%), meningitis (4%). PSA is constantly high but 28% of the patients have elevated NSE, which is correlated with lymph node or visceral metastases. ACE is elevated in 27% of cases. Objective and palliative effect of chemotherapy is marked for weekly doxorubicin , prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation . This study suggests the presence of different subpopulations of patients with specific evolutive patterns, thus further specific therapy should be evaluated.", "source": "https://pubmed.ncbi.nlm.nih.gov/11792613/"}
{"doc_id": "3c2b7d83038604e036058333e14ca020", "sentence": "The recommendations derived from the comprehensive assessment of the literature and guidelines are to continue NSAIDs and low dose aspirin , and phosphodiesterase inhibitors ( dipyridamole , cilostazol , Aggrenox ) during interventional techniques .", "spans": [{"span_id": 0, "text": "aspirin", "start": 131, "end": 138, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "dipyridamole", "start": 176, "end": 188, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "cilostazol", "start": 191, "end": 201, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Assessment of bleeding risk of interventional techniques: a best evidence synthesis of practice patterns and perioperative management of anticoagulant and antithrombotic therapy. Interventional pain management is a specialty that utilizes invasive procedures to diagnose and treat chronic pain. Patients undergoing these treatments may be receiving exogenous anticoagulants and antithrombotics. Even though the risk of major bleeding is very small, the consequences can be catastrophic. However, the role of antithrombotic therapy for primary and secondary prevention of cardiovascular disease to decrease the incidence of acute cerebral and cardiovascular events is also crucial. Overall, there is a paucity of literature on the subject of bleeding risk in interventional pain management along with practice patterns and perioperative management of anticoagulant and anti-thrombotic therapy. ### Study Design Best evidence synthesis. ### objective To critically appraise and synthesize the literature with assessment of the bleeding risk of interventional techniques including practice patterns and perioperative management of anticoagulant and antithrombotic therapy. ### methods The available literature on the bleeding risk of interventional techniques and practice patterns and perioperative management of anticoagulant and antithrombotic therapy was reviewed. Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 through December 2012 and manual searches of the bibliographies of known primary and review articles. ### results There is good evidence for the risk of thromboembolic phenomenon in patients who discontinue antithrombotic therapy, spontaneous epidural hematomas occur with or without traumatic injury in patients with or without anticoagulant therapy associated with stressors such as chiropractic manipulation, diving, and anatomic abnormalities such as ankylosing spondylitis, and the lack of necessity of discontinuation of nonsteroidal anti-inflammatory drugs (NSAIDs), including low dose aspirin prior to performing interventional techniques. There is fair evidence that excessive bleeding, including epidural hematoma formation may occur with interventional techniques when antithrombotic therapy is continued, the risk of thromboembolic phenomenon is higher than the risk of epidural hematomas with discontinuation of antiplatelet therapy prior to interventional techniques, to continue phosphodiesterase inhibitors (dipyridamole [Persantine], cilostazol [Pletal], and Aggrenox [aspirin and dipyridamole]), and that anatomic conditions such as spondylosis, ankylosing spondylitis and spinal stenosis, and procedures involving the cervical spine; multiple attempts; and large bore needles increase the risk of epidural hematoma; and rapid assessment and surgical or nonsurgical intervention to manage patients with epidural hematoma can avoid permanent neurological complications. There is limited evidence to discontinue antiplatelet therapy with platelet aggregation inhibitors to avoid bleeding and epidural hematomas and/or to continue antiplatelet therapy clopidogrel (Plavix), ticlopidine (Ticlid), or prasugrel (Effient) during interventional techniques to avoid cerebrovascular and cardiovascular thromboembolic fatalities. There is limited evidence in reference to newer antithrombotic agents dabigatran (Pradaxa) and rivaroxaban (Xarelto) to discontinue to avoid bleeding and epidural hematomas during interventional techniques and to continue to avoid cerebrovascular and cardiovascular thromboembolic events. ### recommendations The recommendations derived from the comprehensive assessment of the literature and guidelines are to continue NSAIDs and low dose aspirin , and phosphodiesterase inhibitors ( dipyridamole , cilostazol , Aggrenox ) during interventional techniques . However, the recommendations for discontinuation of antiplatelet therapy with platelet aggregation inhibitors (clopidogrel, ticlopidine, prasugrel) is variable with clinical judgment to continue or discontinue based on the patient's condition, the planned procedure, risk factors, and desires, and the cardiologist's opinion. Low molecular weight heparin (LMWH) or unfractionated heparin may be discontinued 12 hours prior to performing interventional techniques. warfarin should be discontinued or international normalized ratio (INR) be normalized to 1.4 or less for high risk procedures and 2 or less for low risk procedures based on risk factors. It is also recommended to discontinue Pradaxa for 24 hours for paravertebral interventional techniques in 2 to 4 days for epidural interventions in patients with normal renal function and for longer periods of time in patients with renal impairment, and to discontinue rivaroxaban for 24 hours prior to performing interventional techniques. ### limitations The paucity of the literature. ### conclusion Based on the available literature including guidelines, the recommendations in patients with antithrombotic therapy for therapy prior to interventional techniques are provided.", "source": "https://pubmed.ncbi.nlm.nih.gov/23615893/"}
{"doc_id": "d358239751ac6f0d9f4ac77dc9304e1e", "sentence": "Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 97, "end": 106, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "silibinin", "start": 111, "end": 120, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. ### methods Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. ### results gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin . ### conclusions Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.", "source": "https://pubmed.ncbi.nlm.nih.gov/25834802/"}
{"doc_id": "21678481cdac2e4a2d6bb2321f3269d1", "sentence": "The effects of the Acanthopanax obovatus polysaccharide ( AOPS ) as well as its combination with cyclophosphamide ( CY ) or prednisolone on immune responses were investigated in mice .", "spans": [{"span_id": 0, "text": "Acanthopanax obovatus polysaccharide", "start": 19, "end": 55, "token_start": 4, "token_end": 7}, {"span_id": 1, "text": "cyclophosphamide", "start": 97, "end": 113, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "prednisolone", "start": 124, "end": 136, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Immunomodulatory activity of polysaccharide from Acanthopanax obovatus roots.  The effects of the Acanthopanax obovatus polysaccharide ( AOPS ) as well as its combination with cyclophosphamide ( CY ) or prednisolone on immune responses were investigated in mice . AOPS (250 mg/kg i.p. x 5) increased the spleen weight and the number of spleen cells, and augmented the phagocytosis of peritoneal macrophages both in normal mice and in immunosuppressed mice. In a haemagglutinin assay AOPS increased the production of specific antibodies and antagonized the suppressive effect of CY. AOPS not only enhanced the degree of in vitro spleen cell-mediated red blood cells (SRBC) hemolysis (quantitative hemolysis of SRBC) but also restored the suppressive effect of CY completely. From these results, AOPS was shown to have an enhancing and a modulating activity on immune responses.", "source": "https://pubmed.ncbi.nlm.nih.gov/1775572/"}
{"doc_id": "e07cec6f9983820e95f4733a21635993", "sentence": "We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma .", "spans": [{"span_id": 0, "text": "lenalidomide", "start": 58, "end": 70, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dexamethasone", "start": 76, "end": 89, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma . Here we report the long-term follow-up results of the trial. ### methods We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (\u22646 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363. ### findings Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0\u00b724 [95% CI 0\u00b714-0\u00b741]; p<0\u00b70001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0\u00b743 [95% CI 0\u00b721-0\u00b792], p=0\u00b7024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1\u00b734 [95% CI 0\u00b754-3\u00b730]; p=0\u00b750). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0\u00b7070). ### interpretation This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. ### funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).", "source": "https://pubmed.ncbi.nlm.nih.gov/27402145/"}
{"doc_id": "1c63535ff27c71fba0866e0d8056bd30", "sentence": "Of the patients , 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia ( BEACOPP -- bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisolone ) and 26 with a regimen known to have a much milder effect on gonadal function ( ABVD -- doxorubicin , bleomycin , vincristine , and dacarbazine ) .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 136, "end": 145, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "etoposide", "start": 148, "end": 157, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "doxorubicin", "start": 160, "end": 171, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "cyclophosphamide", "start": 174, "end": 190, "token_start": 28, "token_end": 29}, {"span_id": 4, "text": "vincristine", "start": 193, "end": 204, "token_start": 30, "token_end": 31}, {"span_id": 5, "text": "procarbazine", "start": 207, "end": 219, "token_start": 32, "token_end": 33}, {"span_id": 6, "text": "prednisolone", "start": 226, "end": 238, "token_start": 35, "token_end": 36}, {"span_id": 7, "text": "doxorubicin", "start": 328, "end": 339, "token_start": 55, "token_end": 56}, {"span_id": 8, "text": "bleomycin", "start": 342, "end": 351, "token_start": 57, "token_end": 58}, {"span_id": 9, "text": "vincristine", "start": 354, "end": 365, "token_start": 59, "token_end": 60}, {"span_id": 10, "text": "dacarbazine", "start": 372, "end": 383, "token_start": 62, "token_end": 63}], "rels": [{"class": "POS", "spans": [8, 9, 10, 7], "is_context_needed": false}, {"class": "NEG", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": false}], "paragraph": "The impact of systemic chemotherapy on testicular FDG activity in young men with Hodgkin's lymphoma. Based on prior reports suggesting a positive correlation between fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT and total sperm count and concentration, we sought to identify changes in testicular FDG uptake over the course of chemotherapy in young men with Hodgkin's lymphoma. ### methods Fifty-two patients with a mean age of 24.2 years (range 15.5-44.4) at diagnosis monitored with FDG PET/CT to assess treatment response for Hodgkin's lymphoma were selected for this retrospective analysis under an Institutional Review Board waiver. Of the patients , 26 were treated with a chemotherapy regimen known to cause prolonged and sometimes permanent azoospermia ( BEACOPP -- bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisolone ) and 26 with a regimen known to have a much milder effect on gonadal function ( ABVD -- doxorubicin , bleomycin , vincristine , and dacarbazine ) . Each patient underwent one FDG PET/CT before treatment and at least one FDG PET/CT after start of chemotherapy. In all examinations, FDG activity was measured in the testes with different quantification metrics: maximum standardized uptake value (SUVmax), SUVmean, functional volume (FV) and total testicular glycolysis (TTG), and blood pool activity determined (SUVmean). ### results Testicular FDG uptake (SUVmax) was significantly associated with blood pool activity (p < 0.001). Furthermore, testicular FDG uptake metrics incorporating volume (e.g., FV and TTG) were associated with age. There was no significant change in SUVmax, SUVmean, FV, and TTG from the PET/CT at baseline to the PET/CTs over the course of chemotherapy either for patients treated with BEACOPP or for patients treated with ABVD. ### conclusion For patients undergoing chemotherapy for Hodgkin's lymphoma, there is a significant association between testicular FDG uptake and blood pool activity, but no significant changes in FDG uptake over the course of chemotherapy. Therefore, FDG uptake may not be a feasible surrogate marker for fertility monitoring in patients with Hodgkin's lymphoma undergoing chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/23389428/"}
{"doc_id": "37fbb54580564543d8ebd2a93b285c7c", "sentence": "Tissue from preclinical models and patients ' biopsies were collected pre-treatment and on Cycle ( C ) 1 , Day ( D ) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 149, "end": 160, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "salirasib", "start": 165, "end": 174, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). ### Patients And Methods In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-na\u00efve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients ' biopsies were collected pre-treatment and on Cycle ( C ) 1 , Day ( D ) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels . Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. ### results salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. ### conclusion The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.", "source": "https://pubmed.ncbi.nlm.nih.gov/22547163/"}
{"doc_id": "18e879f7de2bdc1c9e943375a4e184a0", "sentence": "An isocratic liquid chromatographic method with UV detection at 210 nm is described for simultaneous determination of amoxicillin sodium and sulbactam sodium in a new combination formulation .", "spans": [{"span_id": 0, "text": "amoxicillin", "start": 118, "end": 129, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "sulbactam", "start": 141, "end": 150, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "A liquid chromatographic method for simultaneous determination of amoxicillin sodium and sulbactam sodium in a combination formulation.  An isocratic liquid chromatographic method with UV detection at 210 nm is described for simultaneous determination of amoxicillin sodium and sulbactam sodium in a new combination formulation . Chromatographic separation of the two drugs was achieved on a Hypersil C(18) column using a mobile phase consisting of a binary mixture of methanol and 0.01mol/l sodium acetate (5:95, v/v). The commonly used paired-ion aqueous mobile phase for the determination of penicillins was avoided in this study. The developed LC method offers symmetric peak shape, good resolution and reasonable retention time for both drugs. Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 155.3-1553.0microg/ml for amoxicillin sodium and 45.0-450.0microg/ml for sulbactam sodium. The proposed LC method can be used for the quality control of formulated products containing these two drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/15522531/"}
{"doc_id": "f8b084512a37315824007183d5246093", "sentence": "The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine .", "spans": [{"span_id": 0, "text": "halofantrine", "start": 84, "end": 96, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "mefloquine", "start": 106, "end": 116, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "In vitro effects of racemates, separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes. 1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed Km and Vmax, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine Ki of metoprolol alpha-hydroxylation and O-demethylation were 3.4 and 5.8 microM respectively, whereas those of halofantrine were 0.15 and 0.32 microM respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine . The potency order for metoprolol metabolism inhibition was halofantrine >> mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.", "source": "https://pubmed.ncbi.nlm.nih.gov/10426558/"}
{"doc_id": "f07923010602dbb6e955ec6a8773218e", "sentence": "In total , 417 patients were included : 312 ( 74\u00b78 % ) received vancomycin and 105 ( 25\u00b72 % ) received daptomycin .", "spans": [{"span_id": 0, "text": "vancomycin", "start": 64, "end": 74, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "daptomycin", "start": 103, "end": 113, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "A retrospective analysis of adverse events among patients receiving daptomycin versus vancomycin during outpatient parenteral antimicrobial therapy. Outpatient parenteral antimicrobial therapy (OPAT) is a safe and effective alternative to prolonged inpatient stays for patients requiring long-term intravenous antimicrobials, but antimicrobial-associated adverse events remain a significant challenge. Thus, we sought to measure the association between choice of antimicrobial agent (vancomycin vs daptomycin) and incidence of adverse drug events (ADEs). ### methods Patients receiving OPAT treatment with vancomycin or daptomycin for skin and soft-tissue infections, bone and joint infections, endocarditis, and bacteremia or endovascular infections during the period from July 1, 2013, through September 30, 2016, were included. Demographic and clinical data were abstracted from the medical record. Logistic regression was used to compare ADEs requiring a change in or early discontinuation of therapy, hospital readmission, and emergency room visits between groups. Time from OPAT enrollment to ADE was compared using the log-rank test. ### results In total , 417 patients were included : 312 ( 74\u00b78 % ) received vancomycin and 105 ( 25\u00b72 % ) received daptomycin . After adjusting for age, Charlson comorbidity index, location of OPAT treatment, receipt of combination therapy with either \u03b2-lactam or fluoroquinolone, renal function, and availability of safety labs, patients receiving vancomycin had significantly higher incidence of ADEs (adjusted odds ratio [aOR], 3\u00b771; 95% CI, 1\u00b764-8\u00b740). ADEs occurred later in the treatment course for patients treated with daptomycin (P<\u00b701). Rates of readmission and emergency room visits were similar. ### conclusions In the OPAT setting, vancomycin use was associated with higher incidence of ADEs than daptomycin use. This finding is an important policy consideration for programs aiming to optimize outcomes and minimize cost. Careful selection of gram-positive agents for prolonged treatment is necessary to limit toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/29893658/"}
{"doc_id": "d1fdcb21dc3ac637ff1841ff0a3e35ef", "sentence": "The effect of dasatinib , an inhibitor of Src and Abl kinases , on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts .", "spans": [{"span_id": 0, "text": "dasatinib", "start": 14, "end": 23, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "paclitaxel", "start": 67, "end": 77, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. ### methods A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib , an inhibitor of Src and Abl kinases , on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts . The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. ### results Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. ### conclusion Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression.", "source": "https://pubmed.ncbi.nlm.nih.gov/21813412/"}
{"doc_id": "ccb7554fd73847eaa41e1e62f835d6c3", "sentence": "The maximum tolerated dose ( MTD ) was 20 mg/m2/day I.V. bolus for 5 days of fludarabine plus 60 mg/m2/day I.V. of paclitaxel given as a continuous infusion over 72 hours .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 77, "end": 88, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "paclitaxel", "start": 115, "end": 125, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I study of fludarabine and paclitaxel for the treatment of low-grade non-Hodgkin's lymphoma. We conducted a phase I clinical trial of a new combination of fludarabine and paclitaxel in which 19 patients with histologically confirmed recurrent low-grade non-Hodgkin's lymphoma (NHL) were treated at five dose levels. fludarabine was administered intravenously by bolus for 5 days and paclitaxel was given by intravenous (I.V.) continuous infusion for 96 or 72 hours starting day 1. Courses were repeated every 4 weeks. Patients whose disease responded received a maximum of six courses. All 19 patients received at least one course and could be evaluated for toxic effects, and 18 patients could be evaluated for response. The maximum tolerated dose ( MTD ) was 20 mg/m2/day I.V. bolus for 5 days of fludarabine plus 60 mg/m2/day I.V. of paclitaxel given as a continuous infusion over 72 hours . The limiting toxic effect was neutropenic fever, which was observed in five of the seven patients treated at the highest dose level. Grade 3 non-hematologic toxic effects of stomatitis (14%), neuropathy (14%), and hypotension (14%) were also observed at the highest dose level. No grade 4 non-hematologic toxic effects or treatment-related deaths occurred. One patient had herpes zoster infection of the skin 1 year after the completion of therapy. The overall response rate was 50%, with the two patients whose disease completely responded remaining disease free at 22 and 17 months. Patients with no prior exposure to either paclitaxel or fludarabine had 62% response rate. We conclude that the combination of fludarabine and paclitaxel appears to have promising activity for the treatment of recurrent low-grade NHL.", "source": "https://pubmed.ncbi.nlm.nih.gov/9250790/"}
{"doc_id": "042e0b2d00ed9a033094dd9f6010fe84", "sentence": "Further studies are needed to identify predictors of response and toxicity to this approach , as well as the optimal scheduling of ipilimumab with maintenance nivolumab .", "spans": [{"span_id": 0, "text": "ipilimumab", "start": 131, "end": 141, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "nivolumab", "start": 159, "end": 168, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Salvage ipilimumab associated with a significant response in sarcomatoid renal cell carcinoma. Metastatic sarcomatoid renal cell carcinoma (sRCC) is an aggressive variant of RCC with generally poor prognosis. Treatment with vascular endothelial growth factor inhibitors or chemotherapy generates only short-lived responses. Recent research has suggested a role for combination checkpoint inhibition as first line treatment for metastatic sRCC. This therapy consists of induction with cytotoxic T-lymphocyte-associated protein 4 inhibitor, ipilimumab, administered with programmed cell death protein 1 (PD-1) inhibitor, nivolumab. After completion of four cycles of combination therapy, single-agent maintenance nivolumab is recommended until progression. Patients who progress on maintenance nivolumab are switched to alternate therapy. Herein, we present a case of a patient with RCC who progressed on maintenance nivolumab who, on retreatment with ipilimumab, demonstrated a significant response In addition, we summarize important findings to support the role of salvage ipilimumab in patients with sRCC. ### Case Presentation A 46-year-old man presented with flank pain and hematuria, the work up of which noted a left kidney mass for which he underwent nephrectomy and was diagnosed with localized sRCC with 60% sarcomatoid differentiation. Within 3 months of nephrectomy, he presented with recurrent flank pain and was diagnosed with recurrence of disease. He was treated with ipilimumab 1\u2009mg/kg and nivolumab 3\u2009mg/kg for four doses and demonstrated a partial response. He was then transitioned to single agent nivolumab maintenance. After 3\u2009months on maintenance therapy, he was noted to have progression of disease. Given prior response to immune check point combination, it was decided to rechallenge the patient with 1\u2009mg/kg ipilimumab. After two doses of ipilimumab and nivolumab combination therapy, the patient was noted to have a partial response. He maintained a response for an additional 9 months and treatment was eventually discontinued due to grade 3 toxicity and progression. ### conclusions This case report demonstrates the utility of retreatment with ipilimumab as a salvage option for patients progressing on maintenance PD-1 inhibitors in metastatic RCC. Further studies are needed to identify predictors of response and toxicity to this approach , as well as the optimal scheduling of ipilimumab with maintenance nivolumab .", "source": "https://pubmed.ncbi.nlm.nih.gov/32114501/"}
{"doc_id": "1cb0a51408e696ebb1a532c4f5f6f8dd", "sentence": "Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer : a phase II study .", "spans": [{"span_id": 0, "text": "palonosetron", "start": 12, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "aprepitant", "start": 30, "end": 40, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer : a phase II study . Antiemetic recommendations during concurrent chemoradiotherapy (cisplatin-based concurrent chemoradiotherapy (CCRT)) have not been established yet. The aim of this study was to investigate whether the combination of palonosetron plus aprepitant, without routine use of dexamethasone, could alleviate chemoradiotherapy-induced nausea and vomiting (CRINV). ### methods This was a non-randomized, prospective, single-center, open phase II study. Patients with cervical cancer, who were treated with daily low-dose cisplatin (8\u00a0mg/m(2)/day) and concurrent radiation (2\u00a0Gy/day, 25 fractions, five times a week), were enrolled in this study. All patients received intravenous palonosetron (0.75\u00a0mg on day 1 of each week) and oral aprepitant (125\u00a0mg on day 1 and 80\u00a0mg on days 2 and 3 of each week). The primary endpoint was the percentage of patients with a complete response, defined as no emetic episodes and no use of antiemetic rescue medication during the treatment. ### results Twenty-seven patients (median age, 50\u00a0years; range, 33-72\u00a0years) were enrolled in this study between June 2013 and April 2014. A total of 13 (48\u00a0%) patients showed a complete response to the antiemetic regimen, while 8 patients (30\u00a0%) had emetic episodes and 6 patients (22\u00a0%) used rescue medication without emetic episodes. No severe adverse effects caused by palonosetron plus aprepitant were observed. ### conclusion The combination of palonosetron plus aprepitant was permissive for the prevention of CRINV. This regimen should be considered for patients in whom dexamethasone is contraindicated or not well tolerated.", "source": "https://pubmed.ncbi.nlm.nih.gov/27286875/"}
{"doc_id": "809bac232f0bd17c3ad9fcd2ed5be67a", "sentence": "Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant ( 500 mg ) and either palbociclib ( 125 mg/day ; 3 weeks on/1 week off ; n = 347 ) or placebo ( n = 174 ) . Prespecified exploratory analyses compared the efficacy ( data cutoff : October 23 , 2015 ) , safety , and pharmacokinetics ( data cutoff : December 5 , 2014 ) in Japanese women versus the overall population .", "spans": [{"span_id": 0, "text": "fulvestrant", "start": 72, "end": 83, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "palbociclib", "start": 106, "end": 117, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. In the double-blind, phase 3 PALOMA-3 study, palbociclib-fulvestrant significantly prolonged progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3. ### methods Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant ( 500 mg ) and either palbociclib ( 125 mg/day ; 3 weeks on/1 week off ; n = 347 ) or placebo ( n = 174 ) . Prespecified exploratory analyses compared the efficacy ( data cutoff : October 23 , 2015 ) , safety , and pharmacokinetics ( data cutoff : December 5 , 2014 ) in Japanese women versus the overall population . ### results A total of 35 Japanese women were randomized to palbociclib-fulvestrant (n\u2009=\u200927) or placebo-fulvestrant (n\u2009=\u20098). Median progression-free survival was 13.6\u00a0months (95% CI, 7.5-not estimable) in the Japanese palbociclib-fulvestrant group and 11.2\u00a0months (95% CI, 5.6-not estimable) in the placebo-fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4\u00a0ng/mL, 86.3\u00a0ng/mL, and 74.8\u00a0ng/mL, respectively). ### Conclusion S The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2\u2012 MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135).", "source": "https://pubmed.ncbi.nlm.nih.gov/30392115/"}
{"doc_id": "58a8767d39033b741e150619c271a967", "sentence": "was lowest in the propofol + dexmedetomidine group ( all , P < 0.05 ) , and the AUC of pulse oximetry was significantly higher in the propofol + dexmedetomidine and propofol + ketamine groups compared to the other 2 groups ( both , P < 0.05 ) .", "spans": [{"span_id": 0, "text": "propofol", "start": 18, "end": 26, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "dexmedetomidine", "start": 29, "end": 44, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "propofol", "start": 134, "end": 142, "token_start": 27, "token_end": 28}, {"span_id": 3, "text": "dexmedetomidine", "start": 145, "end": 160, "token_start": 29, "token_end": 30}, {"span_id": 4, "text": "propofol", "start": 165, "end": 173, "token_start": 31, "token_end": 32}, {"span_id": 5, "text": "ketamine", "start": 176, "end": 184, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [4, 5], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Efficacy and Tolerability of Sufentanil, Dexmedetomidine, or Ketamine Added to Propofol-based Sedation for Gastrointestinal Endoscopy in Elderly Patients: A Prospective, Randomized, Controlled Trial. To investigate the optimal agent combined with propofol for sedation in elderly patients undergoing gastrointestinal endoscopy. ### methods A total of 120 elderly patients scheduled for gastrointestinal endoscopy under propofol-based sedation were randomly allocated to receive propofol\u00a0+\u00a0saline (control group), propofol\u00a0+\u00a0sufentanil 0.1\u00a0\u03bcg/kg, propofol\u00a0+\u00a0dexmedetomidine 0.4\u00a0\u03bcg/kg, or propofol\u00a0+\u00a0ketamine 0.4\u00a0mg/kg. Mean arterial pressure, heart rate, pulse oximetry, pressure of end-tidal carbon dioxide, respiratory rate, and Ramsay sedation scale score were recorded. Induction time, procedure time, recovery time, propofol dose, and adverse events were also recorded. ### findings During the sedation procedure, the AUC\u00a0of HR was lowest in the propofol + dexmedetomidine group ( all , P < 0.05 ) , and the AUC of pulse oximetry was significantly higher in the propofol + dexmedetomidine and propofol + ketamine groups compared to the other 2 groups ( both , P < 0.05 ) . The propofol\u00a0+\u00a0dexmedetomidine group had the highest prevalences of hypotension and bradycardia, and the control group experienced the largest number of hypoxia episodes (all, P\u00a0<\u00a00.05). The control group consumed the highest dose of propofol, while the propofol\u00a0+\u00a0ketamine group needed the lowest dose (all, P\u00a0<\u00a00.05). ### implications The combination of propofol\u00a0+ ketamine 0.4\u00a0mg/kg maintained hemodynamic and respiratory stability, as evidenced by less hypotension, bradycardia, and hypoxia events, in elderly patients undergoing gastrointestinal endoscopy. China clinical trial registration (chictr.org.cn) ID: ChiCTR-INR-17013710.", "source": "https://pubmed.ncbi.nlm.nih.gov/31345559/"}
{"doc_id": "0bd777658d84790649190009cef1cce2", "sentence": "Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action .", "spans": [{"span_id": 0, "text": "Ethosuximide", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "topiramate", "start": 105, "end": 115, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "zonisamide", "start": 120, "end": 130, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (ethosuximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available. These AEDs do not appear to have a common mechanism of action in that both inhibitory gamma-aminobutyric acid (GABA; e.g., clobazam, clonazepam, and valproate) and excitatory glutamate (e.g., lamotrigine and topiramate) mechanisms are involved. Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action . In contrast, levetiracetam is unique in that it may act via a specific binding site in the brain. In terms of their pharmacokinetic characteristics, all eight AEDs are rapidly absorbed after oral ingestion with peak blood concentration being achieved within 1-4 hours. Bioavailability is 100% with the exception clonazepam (90%) and topiramate (81-95%). Plasma protein binding is variable with valproate (90%), clobazam (85%) and clonazepam (86%) showing substantial binding, lamotrigine (55%) and zonisamide (50%) intermediate binding, and levetiracetam (0%), ethosuximide (0%) and topiramate (10%) being minimally bound. However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin. All AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and therefore susceptible to pharmacokinetic interactions. lamotrigine metabolism is via hepatic glucuronidation, a process that is also susceptible to induction and inhibition by concurrent drugs. levetiracetam is minimally metabolized (by hydrolysis in blood), is excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Using a semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics, a direct comparison between AEDs is possible. Thus valproic acid, regarded as the drug of first choice in the treatment of IGEs, rates lowest with respect to favorable pharmacokinetic characteristics, mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and its high propensity to interact both with other AEDs and non-AEDs. levetiracetam rates highest with topiramate in second place.", "source": "https://pubmed.ncbi.nlm.nih.gov/16302888/"}
{"doc_id": "3ce316a06e76c599b5da16e5786d3991", "sentence": "Patients aged 15 to 60 years , presenting with newly diagnosed acute myeloid leukemia ( AML ) were randomized to receive either high-dose cytarabine , 3 g/m2 12 hourly on days 1 , 3 , 5 , and 7 for 8 doses , daunorubicin 50 mg/m2 days 1 to 3 , etoposide 75 mg/m2 days 1 to 7 , ( HIDAC-3 - 7 ) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above ( 7 - 3 - 7 ) .", "spans": [{"span_id": 0, "text": "cytarabine", "start": 138, "end": 148, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "daunorubicin", "start": 208, "end": 220, "token_start": 43, "token_end": 44}, {"span_id": 2, "text": "etoposide", "start": 244, "end": 253, "token_start": 51, "token_end": 52}, {"span_id": 3, "text": "cytarabine", "start": 310, "end": 320, "token_start": 67, "token_end": 68}, {"span_id": 4, "text": "daunorubicin", "start": 379, "end": 391, "token_start": 77, "token_end": 78}, {"span_id": 5, "text": "etoposide", "start": 396, "end": 405, "token_start": 79, "token_end": 80}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [3, 4, 5], "is_context_needed": true}], "paragraph": "A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. High-dose cytarabine (ara-c) may overcome cytarabine resistance in leukemic blasts. It has been used as a successful salvage and in postremission therapy but not as initial induction treatment. Patients aged 15 to 60 years , presenting with newly diagnosed acute myeloid leukemia ( AML ) were randomized to receive either high-dose cytarabine , 3 g/m2 12 hourly on days 1 , 3 , 5 , and 7 for 8 doses , daunorubicin 50 mg/m2 days 1 to 3 , etoposide 75 mg/m2 days 1 to 7 , ( HIDAC-3 - 7 ) or standard dose cytarabine 100 mg/m2 continuous intravenous infusion for 7 days with daunorubicin and etoposide at the same dose and schedule as above ( 7 - 3 - 7 ) . Patients could receive a second or third induction course if complete remission (CR) was not achieved. All patients received the same postinduction consolidation therapy (5-2-5) for 2 courses. Eligible patients had no prior chemotherapy or myelodysplastic disease. Patients have been followed for a median of 4.5 years. Of 301 patients treated, complete response (CR) was achieved in 71% with HIDAC-3-7 and 74% with 7-3-7. For patients in CR, the estimated median remission duration was 45 months with HIDAC-3-7 and 12 months with 7-3-7 (P = .0005 univariate analysis, P = .0004 multivariate analysis). The estimated percentage of patients relapse free 5 years after achieving a CR was 49% on HIDAC-3-7 and 24% on 7-3-7. Patients in CR tended to survive longer with HIDAC-3-7 but there were no overall survival differences between the two arms. HIDAC-3-7 was associated with significantly more toxicity in induction with more leukopenia, thrombocytopenia, nausea, and vomiting and eye toxicity (all P < .001) but a similar incidence of severe central nervous system and cerebellar toxicity compared to 7-3-7. The consolidation treatment was the same in both arms but caused significantly more leukopenia and thrombocytopenia in patients previously treated with HIDAC-3-7 induction (P < .0001). We conclude that a dose-effect exists for cytarabine in AML and that HIDAC-3-7 prolongs remission duration and disease-free survival and is tolerable when used as initial induction therapy in patients with de novo AML.", "source": "https://pubmed.ncbi.nlm.nih.gov/8634416/"}
{"doc_id": "fe01e044f02622902299f2dc04336c22", "sentence": "Therefore , if a combination regimen is necessary to control CMV in a patient , foscarnet and ganciclovir should be used first .", "spans": [{"span_id": 0, "text": "foscarnet", "start": 80, "end": 89, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "ganciclovir", "start": 94, "end": 105, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination antiviral therapy for cytomegalovirus disease in patients with AIDS. Currently, combination therapy with ganciclovir and foscarnet should be reserved for patients with disease progression while receiving monotherapy or for those who are unresponsive to either agent alone. Although cidofovir and ganciclovir were shown to have synergistic activity against human CMV in vitro, there have been no in vivo studies to confirm this activity. Therefore , if a combination regimen is necessary to control CMV in a patient , foscarnet and ganciclovir should be used first . There are several advantages of the combination therapy regimen. For instance, lower doses of the individual agents can be used with superior efficacy to monotherapy and similar toxicities. Also, for neurologic CMV involvement, the combination therapy may be superior to monotherapy because of the variable CSF penetration of either drug alone. In addition, combined therapy may be beneficial in treating and/or preventing drug-resistant strains of CMV. Even though combination therapy has evidence of superior efficacy compared with monotherapy in the treatment of CMV, several issues must be considered. First, combination therapy has longer administration times because of the infusion of multiple drugs, which may be an inconvenience. Also, even though the toxic effects are similar with both combined therapy and monotherapy, the adverse effects associated with combination therapy may be less well tolerated and may negatively affect the patient's quality of life. Finally, combination therapy is more expensive than monotherapy with ganciclovir or foscarnet alone. Patients should be evaluated with these issues in mind before combination therapy is initiated.", "source": "https://pubmed.ncbi.nlm.nih.gov/9296250/"}
{"doc_id": "af03c3fd5445015f03271eeae6b1445d", "sentence": "A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib .", "spans": [{"span_id": 0, "text": "Afatinib", "start": 23, "end": 31, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "Nimotuzumab", "start": 52, "end": 63, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "Gefitinib", "start": 131, "end": 140, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "Erlotinib", "start": 144, "end": 153, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib . In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non-small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. ### Experimental Design In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. ### results In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7-16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3-5.7 months] and 11.7 months (95% CI, 9.4-14.0 months), respectively. ### conclusions Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139-45. \u00a92015 AACR.", "source": "https://pubmed.ncbi.nlm.nih.gov/26667485/"}
{"doc_id": "190ab2480d9e1091cc333569085fc69f", "sentence": "RESULTS In first-line treatment , compared with sunitinib , improvement of one-year CPFS for the nivolumab plus ipilimumab group after living for 0.5 and 0.75 years were 14 % ( from 53.0 % to 67.0 % ) and 16 % ( from 57.0 % to 73.0 % ) higher than the one-year PFS of 6.5 % ( from 42.9 % to 49.4 % ) , with similar results for one-year COS following first-line treatment .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 48, "end": 57, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "nivolumab", "start": 97, "end": 106, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "ipilimumab", "start": 112, "end": 122, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Conditional Survival in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab. BACKGROUND nivolumab is approved for the treatment of advanced renal cell carcinoma (RCC). However, traditional overall survival (OS) or progression-free survival (PFS) do not reflect patient prognosis after initial management. Therefore, this study aimed to evaluate conditional overall survival (COS) and conditional progression-free survival (CPFS) in patients with advanced RCC treated with nivolumab. MATERIAL AND METHODS There were 847 patients with advanced RCC treated with first-line nivolumab plus ipilimumab (n=425) and sunitinib (n=422), and 821 patients were treated with second-line nivolumab (n=410) and everolimus (n=411). Primary endpoints were COS and CPFS. Individual patient data of PFS and OS were digitally reconstructed from two large randomized controlled trials (CheckMate 025 and CheckMate 214). RESULTS In first-line treatment , compared with sunitinib , improvement of one-year CPFS for the nivolumab plus ipilimumab group after living for 0.5 and 0.75 years were 14 % ( from 53.0 % to 67.0 % ) and 16 % ( from 57.0 % to 73.0 % ) higher than the one-year PFS of 6.5 % ( from 42.9 % to 49.4 % ) , with similar results for one-year COS following first-line treatment . For second-line treatment, compared with everolimus, the improvement of one-year CPFS for the nivolumab group after living for 0.5 and 0.75 years were 19% (from 25.0% to 44.0%) and 19% (from 27.0% to 46.0%) and significantly higher than the one-year PFS of 4.5% (from 18.5% to 23.0%). CONCLUSIONS Survival benefit for patients with advanced RCC from nivolumab (plus ipilimumab) compared with sunitinib was more evident from conditional survival (CS) analysis of first-line treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/31469816/"}
{"doc_id": "a9871c42260965ad80e7f1e460de10fe", "sentence": "Two model drugs , omeprazole and verapamil , were used to test the integrated model .", "spans": [{"span_id": 0, "text": "omeprazole", "start": 18, "end": 28, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "verapamil", "start": 33, "end": 42, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "A versatile, compartmentalised gut-on-a-chip system for pharmacological and toxicological analyses. A novel, integrated, in vitro gastrointestinal (GI) system is presented to study oral bioavailability parameters of small molecules. Three compartments were combined into one hyphenated, flow-through set-up. In the first compartment, a compound was exposed dynamically to enzymatic digestion in three consecutive microreactors, mimicking the processes of the mouth, stomach, and intestine. The resulting solution (chyme) continued to the second compartment, a flow-through barrier model of the intestinal epithelium allowing absorption of the compound and metabolites thereof. The composition of the effluents from the barrier model were analysed either offline by electrospray-ionisation-mass spectrometry (ESI-MS), or online in the final compartment using chip-based ESI-MS. Two model drugs , omeprazole and verapamil , were used to test the integrated model . omeprazole was shown to be broken down upon treatment with gastric acid, but reached the cell barrier unharmed when introduced to the system in a manner emulating an enteric-coated formulation. In contrast, verapamil was unaffected by digestion. Finally, a reduced uptake of verapamil was observed when verapamil was introduced to the system dissolved in apple juice, a simple food matrix. It is envisaged that this integrated, compartmentalised GI system has potential for enabling future research in the fields of pharmacology, toxicology, and nutrition.", "source": "https://pubmed.ncbi.nlm.nih.gov/33649376/"}
{"doc_id": "7b07311a9256b5756499cbd58b924bca", "sentence": "This study analysed 126 patients with relapsed , advanced stage follicular lymphoma who received BEAM ( BCNU [ carmustine ] , cytarabine , etoposide , melphalan)-alemtuzumab allogeneic HSCT ( BEAM-allo ) ( n = 44 ) or BEAM-autologous HSCT ( BEAM-auto ) ( n = 82 ) .", "spans": [{"span_id": 0, "text": "carmustine", "start": 111, "end": 121, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "cytarabine", "start": 126, "end": 136, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "etoposide", "start": 139, "end": 148, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "melphalan)-alemtuzumab", "start": 151, "end": 173, "token_start": 25, "token_end": 26}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma. The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed , advanced stage follicular lymphoma who received BEAM ( BCNU [ carmustine ] , cytarabine , etoposide , melphalan)-alemtuzumab allogeneic HSCT ( BEAM-allo ) ( n = 44 ) or BEAM-autologous HSCT ( BEAM-auto ) ( n = 82 ) . The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0.001) but received a higher median number of therapies pretransplant (P = 0.015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0.001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0.01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0.99) or disease-free survival (DFS) (P = 0.90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.", "source": "https://pubmed.ncbi.nlm.nih.gov/18318762/"}
{"doc_id": "db97dfb3cf6a40983ab012c41fb37b15", "sentence": "Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel .", "spans": [{"span_id": 0, "text": "Apixaban", "start": 0, "end": 8, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "rivaroxaban", "start": 13, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "aspirin", "start": 180, "end": 187, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "clopidogrel", "start": 192, "end": 203, "token_start": 30, "token_end": 31}], "rels": [{"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease. Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel . Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.", "source": "https://pubmed.ncbi.nlm.nih.gov/26952877/"}
{"doc_id": "2b166d1bac8f4c6d0718ee9b3736bf26", "sentence": "Systemic and local effects of lidocaine or mepivacaine when used for intravenous regional anaesthesia of the distal limb in standing sedated horses .", "spans": [{"span_id": 0, "text": "lidocaine", "start": 30, "end": 39, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "mepivacaine", "start": 43, "end": 54, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Systemic and local effects of lidocaine or mepivacaine when used for intravenous regional anaesthesia of the distal limb in standing sedated horses . Local anaesthetics are being combined clinically with amikacin in intravenous regional limb perfusion (IVRLP), with limited knowledge on the analgesia provided and its onset and duration of action after tourniquet application and release. ### objective To evaluate the systemic clinical effect, limb withdrawal to nociceptive stimulation, and plasma and synovial fluid concentrations after IVRLP with lidocaine or mepivacaine in standing sedated horses. ### Study Design Prospective, controlled, randomised, cross-over study. ### methods Six healthy adult horses were sedated and received IVRLP with lidocaine, mepivacaine or saline (negative control), or perineural anaesthesia of the medial and lateral palmar and palmar metacarpal nerves (positive control) in one forelimb with a 3-week washout period between trials. Electrical and mechanical stimuli were used to test nociceptive threshold of the limb before and after IVRLP/perineural anaesthesia. For lidocaine and mepivacaine trials, blood was collected from the jugular vein and synovial fluid from the radiocarpal joint before, during and out to 24\u00a0hours after IVRLP. Drug concentrations were measured using high-performance liquid chromatography. ### results Nociceptive thresholds for lidocaine, mepivacaine and perineural anaesthesia trials were significantly increased compared with saline and baseline values at 10, 20 and 30\u00a0minutes, with no differences between anaesthetic trials. During this time, horses had lower heart rates than IVRLP with saline. After tourniquet release at 30\u00a0minutes, nociceptive thresholds for lidocaine and mepivacaine trials gradually returned to baselines, whereas perineural anaesthesia trial remained unchanged out to an hour. Plasma lidocaine and mepivacaine concentrations were \u226450\u00a0ng/mL while the tourniquet was in place, significantly increasing 10\u00a0minutes after tourniquet release. Maximal lidocaine and mepivacaine concentrations in synovial fluid were reached 25\u00a0minutes after IVRLP injection. ### Main Limitations amikacin was not included in the perfusate. ### conclusion Similar to perineural anaesthesia, IVRLP with lidocaine or mepivacaine provides anti-nociception to the distal limb in standing sedated horses while a tourniquet is applied with concentrations remaining below toxic levels in plasma and synovial fluid.", "source": "https://pubmed.ncbi.nlm.nih.gov/31972065/"}
{"doc_id": "a65f5670ed4d904725cedd2fd71cae69", "sentence": "These 18 TMP-resistant E. coli were also resistant to ampicillin ( 44 % ) , azithromycin ( 11 % ) , chloramphenicol ( 39 % ) , ciprofloxacin ( 11 % ) , doxycycline ( 89 % ) , erythromycin ( 100 % ) , furazolidone ( 72 % ) , levofloxacin ( 17 % ) , trimethoprim-sulfamethoxazole ( 89 % ) and trovafloxacin ( 17 % ) .", "spans": [{"span_id": 0, "text": "ampicillin", "start": 54, "end": 64, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "azithromycin", "start": 76, "end": 88, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "chloramphenicol", "start": 100, "end": 115, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "ciprofloxacin", "start": 127, "end": 140, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "doxycycline", "start": 152, "end": 163, "token_start": 33, "token_end": 34}, {"span_id": 5, "text": "erythromycin", "start": 175, "end": 187, "token_start": 39, "token_end": 40}, {"span_id": 6, "text": "furazolidone", "start": 200, "end": 212, "token_start": 45, "token_end": 46}, {"span_id": 7, "text": "levofloxacin", "start": 224, "end": 236, "token_start": 51, "token_end": 52}], "rels": [], "paragraph": "Emergence of trimethoprim-resistant Escherichia coli in healthy persons in the absence of prophylactic or therapeutic antibiotics during travel to Guadalajara, Mexico. Thirty-nine healthy US students without diarrheal disease and who had not received prophylactic or therapeutic antibiotics were monitored for emergence of trimethoprim-resistant gram-negative fecal flora for a 3-week period after arrival in Guadalajara, Mexico. During this time period, most students showed no change in total fecal gram-negative bacteria (p > 0.05) but showed an increasing level of trimethoprim (TMP) resistance (p < 0.01) among fecal coliforms. Escherichia coli was the TMP-resistant organism isolated in 18 of 39 (46%) healthy students. These 18 TMP-resistant E. coli were also resistant to ampicillin ( 44 % ) , azithromycin ( 11 % ) , chloramphenicol ( 39 % ) , ciprofloxacin ( 11 % ) , doxycycline ( 89 % ) , erythromycin ( 100 % ) , furazolidone ( 72 % ) , levofloxacin ( 17 % ) , trimethoprim-sulfamethoxazole ( 89 % ) and trovafloxacin ( 17 % ) . In the absence of prophylactic and therapeutic antibiotics, increased acquisition of TMP-resistant gram-negative fecal flora in this developing country is probably due to poor sanitary conditions and the recurrent and heavy exposure to antimicrobial-resistant indigenous flora as a result of contaminated food and drink.", "source": "https://pubmed.ncbi.nlm.nih.gov/11760159/"}
{"doc_id": "433151d677929e57b93ffac5089d0b96", "sentence": "Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide .", "spans": [{"span_id": 0, "text": "VPA", "start": 14, "end": 17, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "fludarabine", "start": 62, "end": 73, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "flavopiridol", "start": 76, "end": 88, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "bortezomib", "start": 91, "end": 101, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "thalidomide", "start": 104, "end": 115, "token_start": 13, "token_end": 14}, {"span_id": 5, "text": "lenalidomide", "start": 120, "end": 132, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [0, 3], "is_context_needed": false}], "paragraph": "Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide . VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/19710697/"}
{"doc_id": "4d85c68f8f355389e68b163f110214ab", "sentence": "Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer .", "spans": [{"span_id": 0, "text": "pertuzumab", "start": 122, "end": 132, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "trastuzumab", "start": 135, "end": 146, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "docetaxel", "start": 153, "end": 162, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer . The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Monitoring the host microenvironments in cancer plays a significant role in predicting prognoses and curative effects. It is important to clarify the role of immune related gene expression in tumor-infiltrating lymphocytes in the tumor microenvironment. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. ### methods The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor, progesterone receptor, Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, programmed death ligand (PD-L) 1, CD163, phosphatase and tensin homolog and lymphocyte activation gene 3 were evaluated in biopsy specimens, by immunostaining. ### results CD8 ### conclusions This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/29615076/"}
{"doc_id": "a6693732092e0544b1d827509c89c425", "sentence": "The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery .", "spans": [{"span_id": 0, "text": "doxycycline", "start": 57, "end": 68, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "rifampicin", "start": 71, "end": 81, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "levofloxacin", "start": 84, "end": 96, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "amikacin", "start": 101, "end": 109, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "[Diagnosis and treatment of seven patients with brucellosis in non-pastoral areas]. To explore how to diagnose and treat brucellosis accurately and timely in patients with fever of unkown origin in non-pastoral areas. The epidemiological history, clinical symptoms, complete blood counts, procalcitonin and treatment efficacy of 7 patients with brucellosis were analyzed retrospectively. Some characteristic manifestations should be differentiated from tuberculosis. The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery . The overall response rate was 6/7. No relapse occurred during half year follow-up.", "source": "https://pubmed.ncbi.nlm.nih.gov/31365982/"}
{"doc_id": "16b2c7d23f8c877898632000b4557b53", "sentence": "Validated LC-MS/MS method for the simultaneous determination of enalapril maleate , nitrendipine , hydrochlorothiazide , and their major metabolites in human plasma .", "spans": [{"span_id": 0, "text": "enalapril", "start": 64, "end": 73, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "nitrendipine", "start": 84, "end": 96, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "hydrochlorothiazide", "start": 99, "end": 118, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Validated LC-MS/MS method for the simultaneous determination of enalapril maleate , nitrendipine , hydrochlorothiazide , and their major metabolites in human plasma . Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C", "source": "https://pubmed.ncbi.nlm.nih.gov/32706446/"}
{"doc_id": "35b9071f8063de81491292ca8f730a8c", "sentence": "Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months .", "spans": [{"span_id": 0, "text": "exemestane", "start": 117, "end": 127, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "toremifene", "start": 130, "end": 140, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "fulvestrant", "start": 147, "end": 158, "token_start": 26, "token_end": 27}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[An Elderly Patient with Metastatic Breast Cancer Who Developed Severe Adverse Events such as Stomatitis and Interstitial Pneumonia after Everolimus plus Exemestane Treatment]. An 80-year-old woman was diagnosed with right breast cancer with clinical Stage IIIA 6 years previously. She underwent mastectomy and axillary lymph node dissection. The pathological diagnosis was invasive micropapillary carcinoma with lymph node involvement. Immunohistochemically, the tumor was positive for estrogen receptor and progesterone receptor, and negative for HER2. Postoperatively, the patient was treated with adjuvant chemotherapy consisting of cyclophosphamide, epirubicin, 5-fluorouracil, and paclitaxel, followed by endocrine therapy with letrozole. Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months . However, she developed carcinomatous pleurisy and was treated with eribulin. This last treatment was ineffective. Subsequently, she received combination therapy with everolimus and exemestane. Although the pleural effusion reduced markedly after 5 weeks, stomatitis, diarrhea, melena, and interstitial pneumonia occurred as adverse events. The symptoms improved after drug discontinuation and steroid therapy. The combination therapy with everolimus and exemestane is a prospective therapy for hormone-resistant recurrent breast cancer, but the management of adverse events is very important.", "source": "https://pubmed.ncbi.nlm.nih.gov/27306814/"}
{"doc_id": "8b2f7e675c635b8226a3a0e2b639ba5b", "sentence": "Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess .", "spans": [{"span_id": 0, "text": "doxazosin", "start": 22, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "atenolol", "start": 37, "end": 45, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess . Herein we report on a young girl with recurrent, functioning paraganglioma of the organ of Zuckerkandl and severe and sustained arterial hypertension (systolic pressure >200, diastolic pressure >120 mmHg); with evidence of cardiac damage induced by chronic cathecolamine excess. She promptly and steadily improved after the institution of doxazosin (6 mg/day) plus atenolol (50 mg bid) treatment. This case demonstrates that a correct therapeutic strategy in the long-term management of patients with inoperable catecholamine-producing neuroendocrine tumors (pheochromocytomas and paragangliomas) can maintain arterial pressure in the normal range and reverse the cardiac damage induced by chronic cathecolamine excess.", "source": "https://pubmed.ncbi.nlm.nih.gov/15636433/"}
{"doc_id": "c03f66304e0843a28ace324a46a466ac", "sentence": "To evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA .", "spans": [{"span_id": 0, "text": "low-molecular-weight heparin", "start": 23, "end": 51, "token_start": 5, "token_end": 7}, {"span_id": 1, "text": "aspirin", "start": 90, "end": 97, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "unfractionated heparin", "start": 238, "end": 260, "token_start": 37, "token_end": 39}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin.  To evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA . ### design Prospective, controlled, multicenter pilot study. ### setting Two academically based reproductive health centers. ### Patient S Patients with three or more pregnancy losses and positive APA. ### Intervention S Patients were treated with LMWH and LDA (n = 25) or UFH and LDA (n = 25). ### Main Outcome Measure S Fetal outcome and maternal complications from treatments were compared between the two treatment groups. ### Result S Of the 25 patients in the LMWH group, 21 (84%) delivered a viable infant and 4 (16%) miscarried. Of the 25 patients in the UFH group, 20 (80%) delivered a viable infant and 5 (20%) miscarried. These differences were not statistically significant. No major bleeding episodes occurred during pregnancy or at the time of delivery. No cases of deep venous thrombosis, thrombocytopenia, pre-eclampsia, gestational diabetes, or bone fractures were noted in either of the two groups. ### Conclusion S In this pilot study, the use of LDA in combination with LMWH during pregnancy for the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome seems to be as safe as UFH plus LDA. Large, randomized trials will be required to determine differences in outcome with LMWH and LDA compared with treatment with UFH combined with LDA in this group of patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/15749498/"}
{"doc_id": "e8d4b3349c6eea6a256541a6d78a9023", "sentence": "Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine .", "spans": [{"span_id": 0, "text": "neostigmine", "start": 61, "end": 72, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dexmedetomidine", "start": 197, "end": 212, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "dexmedetomidine", "start": 234, "end": 249, "token_start": 40, "token_end": 41}, {"span_id": 3, "text": "neostigmine", "start": 252, "end": 263, "token_start": 42, "token_end": 43}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Addition of dexmedetomidine and neostigmine to 1.5 % lidocaine and triamcinolone for epidural block to reduce the duration of analgesia in patients suffering from chronic low back pain. Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 \u03bcg [0.5 \u03bcg/kg]), and grou [ND (neostigmine 0.5 mg, and 35 \u03bcg dexmedetomidine, all of which were added to the triamcinolone and lidocaine solution in each group. Medications were injected into the epidural space using an interlaminar approach. Subsequently, scores of pain and duration of analgesia were recorded in questionnaires and analysed using SPSS version 23. One month after the injections, pain scores recorded in the N group were 7.6\u00b11.4, followed by 5.88\u00b11.2 in group D and 5.42 \u00b11.1 in group ND. Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine . Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine's impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention.", "source": "https://pubmed.ncbi.nlm.nih.gov/31666828/"}
{"doc_id": "8bfbe9c7d915500340b3aea9a8db333e", "sentence": "[ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 64, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "docetaxel", "start": 80, "end": 89, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] . The established standard treatment for advanced ovarian cancer is carboplatin and paclitaxel. However, more than 70% of patients have recurrent disease. The standard therapy for recurrent ovarian cancer has not been confirmed. It was reported that docetaxel had a 30-40% of response rate in patients with recurrent ovarian cancer, and that gemcitabine had a 13-22% response rate. The combination chemotherapy of gemcitabine and docetaxel is also applied to non-small cell lung cancer. We use a regimen of 800 mg/m2 of gemcitabine on day 1 and day 8 in combination with 70 mg/m2 of docetaxel on day 8 with a 3-week interval. We treated 2 patients with recurrent ovarian cancer who responded completely to combination chemotherapy with gemcitabine and docetaxel.", "source": "https://pubmed.ncbi.nlm.nih.gov/12557720/"}
{"doc_id": "dab3736d683a7224d59c55170994934b", "sentence": "Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone .", "spans": [{"span_id": 0, "text": "trilostane", "start": 73, "end": 83, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dexamethasone", "start": 88, "end": 101, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone . Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.", "source": "https://pubmed.ncbi.nlm.nih.gov/4064349/"}
{"doc_id": "ae1b9bc6b0bae9ca6b9cc05a23b32ab5", "sentence": "After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 90, "end": 101, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "leucovorin", "start": 138, "end": 148, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). ### Patients And Methods Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol . Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. ### results Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. ### conclusion The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/16009952/"}
{"doc_id": "eae2d307ad1816139a7a952f27d111a2", "sentence": "Furthermore methysergide ( 10 mg/kg i.p . ) , but not muscimol ( 2 mg/kg i.p . ) elicited jumping behavior when combined with clonidine ( 0.5 mg/kg i.p . ) , TRH ( 20 mg/kg i.p . ) , haloperidol ( 4 mg/kg i.p . ) or atropine ( 5 mg/kg i.p . ) .", "spans": [{"span_id": 0, "text": "methysergide", "start": 12, "end": 24, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "clonidine", "start": 126, "end": 135, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "haloperidol", "start": 183, "end": 194, "token_start": 40, "token_end": 41}, {"span_id": 3, "text": "atropine", "start": 216, "end": 224, "token_start": 48, "token_end": 49}], "rels": [], "paragraph": "Neuronal mechanisms involved in drug-induced jumping behavior in mice. Previously we have found that lithium chloride (250 mg/kg i.p.) plus haloperidol (4 mg/kg i.p.), or apomorphine (0.25 mg/kg i.p.) plus thyrotropin releasing hormone (TRH, 20 mg/kg i.p.), elicited a jumping behavior which involves dopaminergic and cholinergic inhibition, and noradrenergic activation. Pretreatment with antiserotonergic agents such as methysergide (5 and 10 mg/kg i.p.) and cyproheptadine (5 mg/kg i.p.) enhanced the jumping behavior induced by these drugs. 5-Methoxy-N,N-dimethyltryptamine (5-MDMT, 5 mg/kg i.p.), a serotonergic receptor agonist, inhibited the jumping behavior. Muscimol, a GABA receptor agonist, at 2 mg/kg, potentiated jumping. GABA receptor antagonists such as bicuculline (4 mg/kg i.p.) and picrotoxin (0.2 and 1 mg/kg i.p.) depressed jumping. An antihistamine agent, diphenhydramine (5 mg/kg i.p.), also potentiated the jumping behavior. Furthermore methysergide ( 10 mg/kg i.p . ) , but not muscimol ( 2 mg/kg i.p . ) elicited jumping behavior when combined with clonidine ( 0.5 mg/kg i.p . ) , TRH ( 20 mg/kg i.p . ) , haloperidol ( 4 mg/kg i.p . ) or atropine ( 5 mg/kg i.p . ) . These results suggest that in addition to dopaminergic, cholinergic and noradrenergic mechanisms, serotonergic inhibition may be directly contributing to the initiation of jumping behavior, whereas GABAergic activation appears to be a modulating factor in this behavior.", "source": "https://pubmed.ncbi.nlm.nih.gov/2992995/"}
{"doc_id": "f69bd6ea16caddaaa4ec412cadbda9fc", "sentence": "Then , doxorubicin with or without flavopiridol was injected .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 7, "end": 18, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "flavopiridol", "start": 35, "end": 47, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model. A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. ### methods An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then , doxorubicin with or without flavopiridol was injected . The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism. ### results Tumor growth was significantly suppressed in the doxorubicin\u00a0+\u00a0flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression. ### conclusions These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.", "source": "https://pubmed.ncbi.nlm.nih.gov/25989942/"}
{"doc_id": "c5102e62153a779d0d7e6bb781df4865", "sentence": "Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 .", "spans": [{"span_id": 0, "text": "bicalutamide", "start": 78, "end": 90, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "tremelimumab", "start": 120, "end": 132, "token_start": 24, "token_end": 25}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 . The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.", "source": "https://pubmed.ncbi.nlm.nih.gov/22210552/"}
{"doc_id": "85404bd608e6bd5211c9821f0c43e636", "sentence": "In the search better tumoral response in the treatment of epithelial ovarian cancer new drugs have surged that promise good results , including docetaxel , topotecan and gemcitabine ,", "spans": [{"span_id": 0, "text": "docetaxel", "start": 144, "end": 153, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "topotecan", "start": 156, "end": 165, "token_start": 25, "token_end": 26}, {"span_id": 2, "text": "gemcitabine", "start": 170, "end": 181, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "[Chemotherapy in germinal and epithelial ovarian cancer]. Generically, ovarian cancer represents a group of tumors with diverse biological and clinical behavior. Thus, germinal cells ovarian tumors, in the vast majority of patients are successfully treated utilizing traditional based on cisplatin chemotherapy. Epithelial ovarian cancer, that accounts for 90% of these cases, although sensitive to chemotherapy has not shown satisfactory results. In the search better tumoral response in the treatment of epithelial ovarian cancer new drugs have surged that promise good results , including docetaxel , topotecan and gemcitabine , both as single agents, or in combination with other therapies utilizing monoclonal antibodies.", "source": "https://pubmed.ncbi.nlm.nih.gov/10824448/"}
{"doc_id": "0abbccd3e357a08b76ee3ada594b61ba", "sentence": "This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac .", "spans": [{"span_id": 0, "text": "ropivacaine", "start": 84, "end": 95, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "hydromorphone", "start": 98, "end": 111, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "ketorolac", "start": 126, "end": 135, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Peri-operative pain management in children with cerebral palsy: comparative efficacy of epidural vs systemic analgesia protocols. Selective Dorsal Rhizotomy (SDR) is the only surgical intervention with class I evidence supporting permanent reduction in spasticity for children with cerebral palsy (Paediatr Anaesth, 12, 2002, 296; Neurosurg Focus, 21, 2006, e2). Postoperatively, adequate analgesia can be difficult to achieve (J Neurosurg, 105, 2006, 8; Childs Nerv Syst, 17, 2001, 556; Pediatr Neurosurg, 43, 2007, 107; Anesth Analg, 79, 1994, 340; Reg Anesth Pain Med, 24, 1999, 438; Pediatr Anesth, 19, 2009, 1213). This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac . This regimen was compared to a protocol utilizing systemic fentanyl and diazepam. ### methods Following IRB approval, 31 patients receiving epidural analgesia were compared with 41 patients who received systemic analgesia. All surgeries were performed by one surgeon with standardized anesthetic and nursing care. Studied outcomes included: pain scores; episodes of severe pain; nausea, itching; oxygen desaturation; and ICU admission. Data were analyzed using Mann-Whitney U-test, CHI square, and Fisher exact test where indicated with P\u00a0<\u00a00.05 considered significant. ### results Studied groups had similar demographics, biometrics and disease burdens. Patients in the epidural group had statistically and clinically significant reductions in peak recorded pain scores for each 4-h period in the first 24 postoperative hours. Severe pain (score >5) was markedly reduced in the epidural group with 9% of epidural patients vs. 68% of systemic patients experiencing at least one episode. Fewer epidural patients experienced oxygen desaturation during the first two postoperative days (6.5% vs. 41%, 6.5% vs. 39%). ### conclusion Epidural analgesia resulted in substantial improvements in pain control and safety. The data supports the superiority of a multimodal analgesia approach centered on epidural analgesia. A similar protocol should be considered following simple laminectomies or procedures associated with lower-extremity muscle spasm.", "source": "https://pubmed.ncbi.nlm.nih.gov/23682965/"}
{"doc_id": "ba59c84a3cf9e17a9d6292e9b7171f24", "sentence": "S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur ( FT ) , 0.4 M 5-chloro-2 , 4-dihydroxypyrimidine ( gimeracil ) , and 1 M potassium oxonate ( oteracil ) , with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric , head and neck cancers .", "spans": [{"span_id": 0, "text": "tegafur", "start": 115, "end": 122, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "gimeracil", "start": 175, "end": 184, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "A phase II study of S-1 in patients with metastatic breast cancer--a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group.  S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur ( FT ) , 0.4 M 5-chloro-2 , 4-dihydroxypyrimidine ( gimeracil ) , and 1 M potassium oxonate ( oteracil ) , with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric , head and neck cancers . We investigated its clinical efficacy against metastatic breast cancer. ### methods A non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n=111) were enrolled, and 108 patients were regarded as eligible. S-1 was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times. ### results Among the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CR+PR) of 41.7% (95% confidence interval: CI, 32.3-51.5%). The incidences of toxicity (> or =grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group. ### conclusion S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/15550867/"}
{"doc_id": "6bbff03274770e14695de22449bed79b", "sentence": "Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 38, "end": 49, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "capecitabine", "start": 112, "end": 124, "token_start": 20, "token_end": 21}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer. To evaluate the pharmacokinetics (PK) of capecitabine and cisplatin, administered in combination with or without trastuzumab, in Japanese patients with HER2-positive advanced gastric cancer (AGC). ### methods Patients eligible for this PK study (study JP19959), which was carried out during treatment Cycle 1 of the ToGA study, received either capecitabine and cisplatin (XP arm) or trastuzumab plus capecitabine and cisplatin (HXP arm). All patients received capecitabine (1,000 mg/m(2) orally, twice daily for 14 days) and cisplatin (80 mg/m(2) intravenous infusion on Day 1). Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine . No further study medication was administered during study JP19959. Serial plasma samples for PK analysis were obtained at intervals before and after the administration of capecitabine and cisplatin on Day 1. ### results Twenty-two patients were enrolled in this PK study: eight in the HXP arm and 14 in the XP arm. All blood samples were available for PK analysis. Co-administration of trastuzumab resulted in no statistically or clinically significant changes in the PK profiles of capecitabine or its metabolites, or of cisplatin (total or unbound platinum). ### conclusions Variability in the AUC(last) and C (max) values for the capecitabine was consistent with the known PK profile of capecitabine and fell within established limits. Concurrent trastuzumab therapy is unlikely to alter the PK or safety profile of capecitabine or cisplatin in Japanese patients with HER2-positive AGC.", "source": "https://pubmed.ncbi.nlm.nih.gov/22116464/"}
{"doc_id": "616aeea94625bb1c07aa03e86b2018bc", "sentence": "Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 27, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "capecitabine", "start": 121, "end": 133, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update. Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. ### Areas Covered Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. ### Expert Opinion Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine . Novel agents are currently investigated.", "source": "https://pubmed.ncbi.nlm.nih.gov/25032884/"}
{"doc_id": "ff7836748885fded1e16ef3e312f2170", "sentence": "Anaemia was present in patients who had just been diagnosed with rheumatoid arthritis and had never taken disease modifying agents or biologicals ( non-specific therapy group ) , but not in those taking either leflunomide or adalimumab .", "spans": [{"span_id": 0, "text": "leflunomide", "start": 210, "end": 221, "token_start": 34, "token_end": 35}, {"span_id": 1, "text": "adalimumab", "start": 225, "end": 235, "token_start": 36, "token_end": 37}], "rels": [], "paragraph": "Treatment with either leflunomide or adalimumab reduces anaemia in patients with rheumatoid arthritis. Rheumatoid arthritis is a chronic disease of the joints, which causes joint pain and disability. Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis, affecting 30-70% of the patients; presenting a negative impact on patient\u00b4s quality of life. Some of the drugs used in rheumatoid arthritis treatment improve anaemia; but little is known on the beneficial effects of the anti-rheumatic leflunomide or the anti-TNF\u03b1 adalimumab, in this parameter. We investigated the incidence of anaemia in rheumatoid arthritis patients treated or not with leflunomide or adalimumab. We also assessed whether anaemia correlates with disease activity. Anaemia was present in patients who had just been diagnosed with rheumatoid arthritis and had never taken disease modifying agents or biologicals ( non-specific therapy group ) , but not in those taking either leflunomide or adalimumab . The erythrocyte sedimentation rate was increased in patients with non-specific therapy in comparison with those taking either leflunomide or adalimumab. Anaemia correlated with increased erythrocyte sedimentation rate. We suggest that leflunomide and adalimumab may be useful in treating anaemia in patients with rheumatoid arthritis.", "source": "https://pubmed.ncbi.nlm.nih.gov/29947664/"}
{"doc_id": "480bbd37984bbf7f13020279517910d8", "sentence": "Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics , as measured by visual counts , although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60 % as great as the percentage of cells infected with Karp in the presence of azithromycin .", "spans": [{"span_id": 0, "text": "doxycycline", "start": 182, "end": 193, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "azithromycin", "start": 358, "end": 370, "token_start": 63, "token_end": 64}], "rels": [], "paragraph": "In vitro effectiveness of azithromycin against doxycycline-resistant and -susceptible strains of Rickettsia tsutsugamushi, etiologic agent of scrub typhus. In an effort to find a potential alternative treatment for scrub typhus, we evaluated the effectiveness of the standard drug doxycycline and the new macrolide azithromycin against a doxycycline-susceptible strain (Karp) and a doxycycline-resistant strain (AFSC-4) of Rickettsia tsutsugamushi. The antibiotics were tested in an in vitro assay system in which infected mouse fibroblast cells (L929) were incubated for 3 days in various concentrations of the drugs. Rickettsial growth was evaluated by direct visual counts of rickettsiae in Giemsastained cells or by flow cytometry. Initial tests were conducted at the concentration of each antibiotic considered to be the upper breakpoint for susceptibility (16 micrograms/ml for doxycycline and 8 micrograms/ml for azithromycin). Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics , as measured by visual counts , although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60 % as great as the percentage of cells infected with Karp in the presence of azithromycin . Flow cytometry confirmed that rickettsial growth occurred in the absence of antibiotics, but it failed to detect it in the presence of high concentrations of either drug. Visual counts of rickettsial growth at lower concentrations of the antibiotics (0.25 to 0.0078 microgram/ml) showed that the Karp strain was 16 times more susceptible that the AFSC-4 strain to doxycycline. azithromycin was much more effective than doxycycline against AFSC-4, inhibiting rickettsial growth at 0.0156 microgram/ml to levels below that achieved by 0.25 microgram of doxycycline per ml. azithromycin was also more effective than doxycycline against the Karp strain, causing greater reductions in the number of rickettsiae per cell at lower concentrations. If in vivo testing confirms the in vitro effectiveness of azithromycin, it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women, who should not take doxycycline, and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found. When tested in an in vitro assay system, azithromycin was more effective than doxycycline against doxycycline-susceptible and -resistant strains of R. tsutsugamushi.", "source": "https://pubmed.ncbi.nlm.nih.gov/8585717/"}
{"doc_id": "1c074798259151bb612a3d01ec0f749a", "sentence": "The Society of Critical Care Medicine ( SCCM ) released updated guidelines for management of pain , agitation , and delirium in the ICU and recommended nonbenzodiazepines , such as dexmedetomidine and propofol , as first line sedation agents .", "spans": [{"span_id": 0, "text": "dexmedetomidine", "start": 181, "end": 196, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "propofol", "start": 201, "end": 209, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Interpatient variability in dexmedetomidine response: a survey of the literature. Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine ( SCCM ) released updated guidelines for management of pain , agitation , and delirium in the ICU and recommended nonbenzodiazepines , such as dexmedetomidine and propofol , as first line sedation agents . Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/24558330/"}
{"doc_id": "a08ea9aa644400399c6f95f2ea19c86a", "sentence": "An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 26, "end": 38, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "gentamicin", "start": 59, "end": 69, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "In vitro assessment of dual drug combinations to inhibit growth of Neisseria gonorrhoeae. The development of resistance to first-line antimicrobial therapies has led to recommendations for combination therapies for the treatment of gonorrhea infection. Recent studies have shown the success of combination therapies in treating patients, but few have reported on the in vitro activities of these drug combinations. An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections .", "source": "https://pubmed.ncbi.nlm.nih.gov/25624328/"}
{"doc_id": "e0bf2084b1a8a8bf198f94062b7fbefa", "sentence": "Among antimicrobials , ciprofloxacin ( 22 ( 22.7 % ) ) was the most common drug followed by metronidazole ( 21 ( 18.5 % ) ) .", "spans": [{"span_id": 0, "text": "ciprofloxacin", "start": 23, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "metronidazole", "start": 92, "end": 105, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Prescription pattern in the department of surgery in a tribal district hospital of andhra pradesh, India. Usually, surgical management cannot be completed without the use of antimicrobial and analgesic drugs. Irrational prescription may lead to severe postoperative complications. ### aim The objective of this study was to evaluate the prescription trend in the surgery department of a tribal district hospital so as to determine the extent of rational use of medicines. ### Materials And Methods It was a retrospective study in which 50 cases were selected randomly. Case records were analyzed for prescription trend. Data was analyzed using Microsoft Office Excel 2007 and values were presented descriptively. ### results Most of the cases were between the age group of 21 and 40 years, 18 cases (36%). Commonest cause of hospitalization was renal calculi (10 (20%)) followed by acute abdomen and abscess (6, (12%)). Total of 255 numbers of drugs were used with an average of 5.1 drugs per patient. Most preferred route was intravenous route (174 drugs, 68.2%). Antimicrobial was the most common (97 (38.0%)) group of drugs followed by analgesic/antipyretics (50 (19.6%)). Among antimicrobials , ciprofloxacin ( 22 ( 22.7 % ) ) was the most common drug followed by metronidazole ( 21 ( 18.5 % ) ) . All the cases were managed by empirical treatment. Two different antimicrobials were prescribed to 20 (40%) of cases. Dosage of 83 (32.6%) drugs was inappropriate while frequency was inappropriate in 26 (10.2%) cases. ### conclusion Urgent steps like specific guidelines, training, and monitoring of drugs use are needed to correct some irrational approaches.", "source": "https://pubmed.ncbi.nlm.nih.gov/24116329/"}
{"doc_id": "c23445106fee40505d6ccd1d1c8ee609", "sentence": "Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) .", "spans": [{"span_id": 0, "text": "rituximab", "start": 45, "end": 54, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "fludarabine", "start": 57, "end": 68, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "mitoxantrone", "start": 73, "end": 85, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "rituximab", "start": 108, "end": 117, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. ### Design And Methods Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) . Pharmacokinetic analysis was assessed in 17 patients. ### results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). ### conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).", "source": "https://pubmed.ncbi.nlm.nih.gov/22511498/"}
{"doc_id": "1d8fbabbaa29b8243097f0ffe742dcc4", "sentence": "Palliative chemotherapy with carboplatin and etoposide produced a minimal response .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 29, "end": 40, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "etoposide", "start": 45, "end": 54, "token_start": 5, "token_end": 6}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Merkel cell carcinoma: A case of palliative upper limb amputation in a patient with refractory in-transit metastases. We report an unusual case of Merkel cell carcinoma in a 70-year-old woman with the rapid development of left upper limb in-transit and hepatic metastases. The patient had a preceding history of left-sided breast cancer. Palliative chemotherapy with carboplatin and etoposide produced a minimal response . The in-transit metastases rapidly progressed and were refractory to chemotherapy and a single fraction of palliative radiotherapy, leading to a marked impact on her quality of life, secondary to sepsis and bleeding. After lengthy discussion, she consented to an above-elbow amputation resulting in a marked improvement in her well-being. In this case, we believe that palliative amputation of the involved arm was justified and beneficial to the patient.", "source": "https://pubmed.ncbi.nlm.nih.gov/25754425/"}
{"doc_id": "7a765b6c37dfd52980521a00277bb151", "sentence": "In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination .", "spans": [{"span_id": 0, "text": "clindamycin", "start": 64, "end": 75, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "gentamicin", "start": 78, "end": 88, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "vancomycin", "start": 95, "end": 105, "token_start": 14, "token_end": 15}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination . A broth dilution assay was used to determine the in vitro susceptibilities of 10 ocular isolates of Bacillus cereus to clindamycin, gentamicin, and vancomycin both alone and in combination. The checkerboard technique was used to determine fractional inhibitory and bactericidal concentration indices for combinations of clindamycin-gentamicin and vancomycin-gentamicin.", "source": "https://pubmed.ncbi.nlm.nih.gov/1901697/"}
{"doc_id": "de0c335311bff300b085c7c5d7917de8", "sentence": "Most ( \u2265 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy .", "spans": [{"span_id": 0, "text": "etoposide", "start": 42, "end": 51, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "methylprednisolone", "start": 54, "end": 72, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "cytarabine", "start": 75, "end": 85, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "cisplatin", "start": 88, "end": 97, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "cisplatin", "start": 110, "end": 119, "token_start": 21, "token_end": 22}, {"span_id": 5, "text": "cytosine arabinoside", "start": 122, "end": 142, "token_start": 23, "token_end": 25}, {"span_id": 6, "text": "dexamethasone", "start": 145, "end": 158, "token_start": 26, "token_end": 27}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [4, 6], "is_context_needed": true}], "paragraph": "Treatment response and overall outcome of patients with relapsed and refractory peripheral T-cell lymphoma compared to diffuse large B-cell lymphoma. The purpose of the study was to assess treatment response and overall outcome in a cohort of patients with relapsed and refractory peripheral T-cell lymphoma and to compare the results with those for patients with diffuse large B-cell lymphoma treated in a similar manner. We retrospectively analyzed data of 40 consecutive adult patients with relapsed and refractory peripheral T-cell lymphoma referred to our institution for consideration of second-line chemotherapy aiming for autologous stem cell transplant between January 1999 and December 2006. A cohort of 126 patients with diffuse large B-cell lymphoma managed similarly served as a comparison group. Most ( \u2265 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy . From first relapse/progression, overall survival at 2 years was 54% (95% confidence interval [CI]: 38-76) for the peripheral T-cell lymphoma cohort and 49% (95% CI: 39-60) for the diffuse large B-cell lymphoma cohort (p = 0.098). Overall response rate to salvage chemotherapy was similar between both groups (63% vs. 52%). Post-autologous stem cell transplant, 1-year progression-free survival was 20% (95% CI: 9-48) for patients with peripheral T-cell lymphoma and 47% (95% CI: 36-61) for patients with diffuse large B-cell lymphoma. Two-year overall survival post-autologous stem cell transplant was 43% (95% CI: 26-71) and 54% (95% CI: 43-68), respectively. Patients with relapsed and refractory peripheral T-cell lymphoma and diffuse large B-cell lymphoma showed a similar response to salvage chemotherapy and overall survival. Likely due to imbalances in risk factors at relapse, progression-free survival post-autologous stem cell transplant was inferior in the peripheral T-cell lymphoma group. Strategies aiming to maintain response duration post-autologous stem cell transplant could improve the outcome of patients with peripheral T-cell lymphoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/22897731/"}
{"doc_id": "02c33d81ce0c8812a656cd04ddcfa86a", "sentence": "Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 88, "end": 97, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "cyclophosphamide", "start": 100, "end": 116, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "doxorubicin", "start": 119, "end": 130, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "etoposide", "start": 137, "end": 146, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. ### Patients And Methods One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease . After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. ### results The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. ### conclusion Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/10715296/"}
{"doc_id": "541e4b1e01753806de482ac53c89b090", "sentence": "184 ( 62\u00b70 % , 95 % CI 56\u00b72 - 67\u00b75 ) patients in the cetuximab group achieved an objective response compared with 171 ( 58\u00b70 % , 52\u00b71 - 63\u00b77 ) in the bevacizumab group ( odds ratio 1\u00b718 , 95 % CI 0\u00b785 - 1\u00b764 ; p=0\u00b718 ) .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 53, "end": 62, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "bevacizumab", "start": 150, "end": 161, "token_start": 34, "token_end": 35}], "rels": [], "paragraph": "FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. ### methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. ### findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 ( 62\u00b70 % , 95 % CI 56\u00b72 - 67\u00b75 ) patients in the cetuximab group achieved an objective response compared with 171 ( 58\u00b70 % , 52\u00b71 - 63\u00b77 ) in the bevacizumab group ( odds ratio 1\u00b718 , 95 % CI 0\u00b785 - 1\u00b764 ; p=0\u00b718 ) . Median progression-free survival was 10\u00b70 months (95% CI 8\u00b78-10\u00b78) in the cetuximab group and 10\u00b73 months (9\u00b78-11\u00b73) in the bevacizumab group (hazard ratio [HR] 1\u00b706, 95% CI 0\u00b788-1\u00b726; p=0\u00b755); however, median overall survival was 28\u00b77 months (95% CI 24\u00b70-36\u00b76) in the cetuximab group compared with 25\u00b70 months (22\u00b77-27\u00b76) in the bevacizumab group (HR 0\u00b777, 95% CI 0\u00b762-0\u00b796; p=0\u00b7017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). ### interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. ### funding Merck KGaA.", "source": "https://pubmed.ncbi.nlm.nih.gov/25088940/"}
{"doc_id": "4c5a498fed553d821b8f2a8a00d1d861", "sentence": "These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 31, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "carboplatin", "start": 46, "end": 57, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. ### Aim Of The Study We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. ### results Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). ### conclusion These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC .", "source": "https://pubmed.ncbi.nlm.nih.gov/20229232/"}
{"doc_id": "d06ffe27a43f3698e5557482f82a036b", "sentence": "' Side-effects ' such as tiredness , decreased inclination to work , and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine , and peaked 2 h after clonidine but only 4 - 6 h after guanfacine .", "spans": [{"span_id": 0, "text": "clonidine", "start": 139, "end": 148, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "guanfacine", "start": 179, "end": 189, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "clonidine", "start": 213, "end": 222, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "guanfacine", "start": 246, "end": 256, "token_start": 46, "token_end": 47}], "rels": [], "paragraph": "Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. 1. Three double-blind studies in young normotensive male volunteers were carried out: a study in ten awake subjects, comparing guanfacine  2.0 and 4.0 mg with clonidie 0.15 and 0.30 mg and placebo; and two polygraphic sleep studies each with six subjects, comparing guanfacine 1.0 and 2.0 mg with placebo, and clonidine 0.15 and 0.30 mg with placebo, respectively. 2. In awake subjects, both drugs reduced systolic blood pressure without significantly altering diastolic blood pressure, pulse rate and objective performance parameters. ' Side-effects ' such as tiredness , decreased inclination to work , and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine , and peaked 2 h after clonidine but only 4 - 6 h after guanfacine . 3. clonidine 0.15 and 0.30 mg given in the evening was followed by a substantial and dose-dependent reduction in rapid eye movement (REM) sleep. guanfacine 1.0 mg did not alter REM sleep and 2.0 mg of guanfacine had less effect than both doses of clonidine in this respect. clonidine's effect on REM sleep began after about 2 h, whereas guanfacine's action on REM sleep began 5 h after the dose. 4. guanfacine and clonidine possess a qualitatively similar pattern of activity with regard to the parameters studied; but the central effects are less pronounced and occur later after guanfacine than after clonidine in equiactive doses.", "source": "https://pubmed.ncbi.nlm.nih.gov/6994771/"}
{"doc_id": "0af2862b59df99b0532361a20f92de95", "sentence": "The recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 33, "end": 43, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "docetaxel", "start": 85, "end": 94, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. ### methods Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11). Dose escalation and MTD determination were based on the occurrence of dose-limiting toxicities in cycle 1 only. ### results A total of 36 patients were enrolled, 26 of whom had NSCLC. All patients received at least one dose of study drug at one of five dose levels. The MTD of the combined regimen was determined to be 1.0/75 mg/m bortezomib/docetaxel. The combination was generally well tolerated. Toxicities were manageable, and no additive toxicities were observed. The most common adverse events were fatigue (67% of patients), nausea (50%), diarrhea (39%), and neutropenia (39%). Two patients with NSCLC achieved a partial response, and seven (19%) patients achieved stable disease (including six patients with NSCLC). ### conclusion The combination of bortezomib and docetaxel was feasible and well tolerated in patients with advanced NSCLC or other solid tumors. The recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days . Therapeutic doses of docetaxel and bortezomib are achievable for this combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/17409841/"}
{"doc_id": "ba671ded376e5c6516f0848405d9eaf8", "sentence": "Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI .", "spans": [{"span_id": 0, "text": "formoterol", "start": 96, "end": 106, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "formoterol", "start": 114, "end": 124, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "formoterol", "start": 276, "end": 286, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "budesonide", "start": 367, "end": 377, "token_start": 53, "token_end": 54}], "rels": [{"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Bronchodilation of formoterol administered with budesonide: device and formulation effects. Previous single-dose crossover studies have established therapeutic equivalence of formoterol when administered at the same nominal dose via a dry powder inhaler (DPI) or pressurized hydrofluoroalkane (HFA) metered-dose inhaler (pMDI). Demonstration of equivalent bronchodilation for formoterol administered as formoterol DPI or combined with budesonide in one pMDI (budesonide/formoterol pMDI) would indicate that the greater clinical efficacy of the budesonide/formoterol pMDI combination is due to the budesonide contribution and not to differences in formoterol formulation or delivery device. ### objective To determine whether the formoterol-related bronchodilatory effects of formoterol DPI and budesonide/formoterol pMDI are similar, despite formoterol formulation and delivery device differences. ### methods This was a multicenter, open-label, five-period crossover study conducted in 201 adult patients with stable asthma. The study included a screening visit, a 7- to 14-day run-in period, during which patients were treated with budesonide pMDI (80 microg per inhalation, two inhalations twice daily), and a randomized treatment period that included five single-day treatment periods, during which patients received single-dose crossover treatments, each of which was separated by a 3- to 14-day washout period. Patients were randomized to five of seven single-dose treatments (one, two, or four inhalations of budesonide/formoterol pMDI 80/4.5 microg; four inhalations of budesonide pMDI 80 microg plus one, two, or four inhalations of formoterol DPI 4.5 microg; or four inhalations of budesonide pMDI 80 microg alone). At clinic visits, the budesonide pMDI dose was coordinated with the budesonide dose delivered via the budesonide/formoterol pMDI such that all patients received a 320-microg dose of budesonide. The primary variable was average forced expiratory volume in 1 s (FEV1) from the area under the curve divided by time from 12-h serial spirometry. ### results Average 12-h FEV1 values were similar, regardless of delivery device, among treatments with the same nominal formoterol doses and dose-ordered within each device; mean FEV1 values were significantly higher for treatments containing formoterol versus budesonide alone. The formoterol dose potency ratio for budesonide/formoterol pMDI:formoterol DPI (0.97; 95% confidence interval, 0.73-1.27) demonstrated clinical equivalence in bronchodilation at the same formoterol dose. ### conclusion Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI .", "source": "https://pubmed.ncbi.nlm.nih.gov/17625985/"}
{"doc_id": "9662c83eea1af48ce3ddb410a6ff064f", "sentence": "In this review , we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC , with focus on cetuximab and panitumumab .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 101, "end": 110, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "panitumumab", "start": 115, "end": 126, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. The standard treatment of metastatic colorectal cancer (mCRC) is combination of 5- fluorouracil/folinic acid with irinotecan or oxaliplatin-based chemotherapy. Epidermal growth factor receptor (EGFR) is overexpressed in 70%-80% of colorectal cancers (CRC). EGFR overexpression is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis. Monoclonal antibodies targeting EGFR have shown antitumor activity and improved the efficacy of chemotherapy. cetuximab is a chimeric immunoglobulin (Ig) G1 anti-EGFR monoclonal antibody (MoAb). Several clinical studies have shown cetuximab, either as a single agent or in combination with irinotecan, having promising efficacy in patients with metastatic CRC. cetuximab with 5-fluorouracil/LV (leucovorin) plus irinotecan or oxaliplatin-based chemotherapy has shown higher response rate and longer time to progression as first-line treatment of mCRC. Currently, there are no data showing that addition of cetuximab would prolong overall survival in randomized studies. panitumumab, a fully human IgG2 monoclonal antibody, has also shown antitumor activity against EGFR-expressing mCRC with less allergic reaction. Anti-EGFR MoAbs are well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR MoAb is an acneform skin rash, which is a surrogate marker of efficacy of treatment with MoAbs. In this review , we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC , with focus on cetuximab and panitumumab .", "source": "https://pubmed.ncbi.nlm.nih.gov/17438669/"}
{"doc_id": "4efd21316f0481148a77a63c76a5f6f0", "sentence": "A 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 67, "end": 78, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "bleomycin", "start": 81, "end": 90, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "vinblastine", "start": 93, "end": 104, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "dacarbazine", "start": 111, "end": 122, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Ototoxicity associated with vinblastine. To describe a patient with ototoxicity associated with vinblastine chemotherapy. ### Case Summary A 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles . He reported tinnitus after each treatment, with an onset of about six hours and a duration of seven to 10 days. This interfered with reading, watching television, and general concentration. Symptoms returned to baseline prior to the beginning of each subsequent cycle. Audiograms performed before and after several cycles showed mild sensorineural hearing loss in the high-decibel range, but no loss of speech recognition. ### discussion No reported cases of ototoxicity or tinnitus from ABVD were found. All concomitant medications were eliminated as possible causes either due to lack of temporal association with the symptoms or no reports of ototoxicity in the literature. vincristine, a more commonly used vinca alkaloid very similar to vinblastine, was noted to have caused several cases of sensorineural hearing loss. ### conclusions This case suggests that vinblastine may cause ototoxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/10332533/"}
{"doc_id": "721292621e495e6bbdfd29d25c905670", "sentence": "This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement .", "spans": [{"span_id": 0, "text": "venetoclax", "start": 84, "end": 94, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "rituximab", "start": 100, "end": 109, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The combination of venetoclax and rituximab for the treatment of patients with recurrent chronic lymphocytic leukemia. In patients with recurrent chronic lymphocytic leukemia (CLL), treatment with targeted agents such as Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax is rapidly replacing chemo-immunotherapy regimens. venetoclax has demonstrated efficacy as monotherapy in patients with previously treated CLL and has been evaluated in combination with the anti-CD20 monoclonal antibody rituximab. ### Areas Covered This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement . Data from PubMed indexed papers as well as from abstracts presented at major international conferences are included. ### Expert Opinion Deep responses with venetoclax-based regimens have been shown to allow time-limited treatment and prolonged remission off-therapy in patients with CLL. The clinical benefit of venetoclax and rituximab over chemo-immunotherapy has been demonstrated in recurrent CLL. Potential advantages of time-limited treatment approaches include avoidance of long-term toxicities, high drug costs, and the selection of resistant subclones.", "source": "https://pubmed.ncbi.nlm.nih.gov/32700593/"}
{"doc_id": "5b765f09ddf9ed7800e75e50233d9dda", "sentence": "Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide .", "spans": [{"span_id": 0, "text": "buserelin", "start": 62, "end": 71, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "flutamide", "start": 118, "end": 127, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide . Ten men with advanced breast cancer were evaluated for response to treatment with the luteinizing hormone-releasing hormone (LH-RH) analogue, buserelin, alone or in combination with the antiandrogen, flutamide. One of five patients receiving buserelin as a single agent had a partial remission lasting 12 months, and with the addition of flutamide, this lasted over 24 additional months. Three patients had stable disease with a median duration of 6 months (range, two to 14). One patient had progressive disease. Of five patients receiving the combination of buserelin and flutamide from the beginning of therapy, four patients had a partial remission with a median duration of over 15 months (range, over five to 16). One patient's disease remained stable for 12 months. Major side effects were hot flushes, loss of libido, and impotence. buserelin initiates a castration-like endocrine response and has potential in the treatment of men with disseminated breast cancer when used either alone or in combination with flutamide.", "source": "https://pubmed.ncbi.nlm.nih.gov/3134119/"}
{"doc_id": "9bc8203e277056b06b80ff1c46a3b6ba", "sentence": "A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis .", "spans": [{"span_id": 0, "text": "piroxicam", "start": 36, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "naproxen", "start": 50, "end": 58, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis . A multicentre, double-blind study of unprecedented size was conducted to compare the safety and efficacy of piroxicam and naproxen in the treatment of osteoarthritis. The study comprised 2,035 patients and a treatment period of 12 weeks. The dosage was 20 mg piroxicam and 750 mg naproxen daily with the option to reduce to 10 and 500 mg, respectively, at week 4 or 8. No major difference between the drugs was observed with regard to overall incidence of adverse events. The frequency of serious adverse events was about 1% for both drugs. A statistically significant decline of adverse events with age was found in both sexes. piroxicam was significantly superior to naproxen for pain at rest and pain on movement at 12 weeks and degree of restriction in daily activity at 4 weeks. A significantly increasing beneficial effect was observed with both drugs between 4 and 12 weeks of treatment. The comparable safety observed for the two drugs is in contrast to perceptions based on spontaneous reports to official monitoring systems.", "source": "https://pubmed.ncbi.nlm.nih.gov/3514082/"}
{"doc_id": "522231d038b48f5d5f178e20d202d187", "sentence": "Effects of estradiol , cyproterone acetate , tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits .", "spans": [{"span_id": 0, "text": "cyproterone acetate", "start": 23, "end": 42, "token_start": 4, "token_end": 6}, {"span_id": 1, "text": "raloxifene", "start": 58, "end": 68, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Effects of estradiol , cyproterone acetate , tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits . Different hormonal replacement regimens are used for treating climacteric complaints; however, not all of them have the same clinical profile. Cardiovascular disease (CVD) is a major health problem and tibolone, raloxifene, estradiol (alone or with cyproterone acetate) have been added to cholesterol-fed rabbits to study atherosclerosis. ### methods A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. Forty rabbits underwent bilateral ovariectomy and the other eight were sham operated (group S). The ovariectomized rabbits were allocated to five groups of eight animals each receiving tibolone (Group T, 6 mg/day), raloxifene (R, 35 mg/day), estradiol valerate (E, 3 mg/day), estradiol valerate plus cyproterone acetate (EC, 3+0.5 mg/day, respectively), and no treatment for the control group (C). The sham group received no treatment too. ### results After 4 months the percentage of the extent of atherosclerosis in the aorta was 30.4% in C group, 24.5% in S group, 10.2% in T group, 30.3% in R group, 17.9% in E group and 28.1% in EC group (P<0.05 T vs. C, R, EC). The aortic cholesterol content compared with aortic weight was 8.55 microg/mg in C group, 11.97 microg/mg in S group, 1.86 microg/mg in T group, 3.82 microg/mg in R group, 2.86 microg/mg in E group and 5.24 microg/mg in EC group (P<0.05 T vs. EC, C, S; R vs. C, S; E vs. C, S). Uterine weights in grams were: 1.89 (C group), 2.24 (S), 7.38 (T), 1.94 (R), 9.92 (E), and 5.94 (EC); P<0.05 (C, S, R, vs. T, E, EC; T vs. E; EC vs. T, E). ### conclusion Our study showed a decrease in the extent of aortic atherosclerosis in oophorectomized cholesterol-fed rabbits treated with tibolone or estradiol, and a decrease in aortic cholesterol content in rabbits treated with tibolone, raloxifene and estradiol. However, rabbits treated with tibolone showed an increased uterine weight, which is contrary to that observed in humans.", "source": "https://pubmed.ncbi.nlm.nih.gov/12753945/"}
{"doc_id": "6c2565fadd59a9088ef00ee067a33af8", "sentence": "Patients were randomly divided into three groups : group I : band ligation ; group II : propranolol ; group III : carvedilol .", "spans": [{"span_id": 0, "text": "propranolol", "start": 88, "end": 99, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "carvedilol", "start": 114, "end": 124, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Efficacy of carvedilol versus propranolol versus variceal band ligation for primary prevention of variceal bleeding. Band ligation and propranolol are the current therapies for primary prevention of variceal bleeding. carvedilol is a rising nonselective beta-blocker used for reducing portal pressure with favorable outcome. The aim of this study to assess the efficacy of carvedilol, propranolol, and band ligation for primary prevention of variceal bleeding based on the effect of each regimen on progression of Child score and portal hypertensive gastropathy after 1\u00a0year. ### methods The study included 264 cirrhotic patients with medium/large-sized varices who were candidates for primary prophylaxis of variceal bleeding. Patients were randomly divided into three groups : group I : band ligation ; group II : propranolol ; group III : carvedilol . ### results Group\u00a0I showed higher success rate of 75\u00a0%, followed by group\u00a0III with 70.2\u00a0% and group\u00a0II with 65.2\u00a0%. Risk of bleeding was comparable between the three groups, with group\u00a0II carrying the highest rate of complications (34.7\u00a0%) followed by group\u00a0III (14.2\u00a0%) and finally group\u00a0I (5.7\u00a0%). After 1\u00a0year of follow-up, Child score did not improve in any of the studied groups, while portal hypertensive gastropathy significantly increased in group\u00a0I but decreased in groups\u00a0II and III. ### conclusions Band ligation is the best treatment option for primary prevention of variceal bleeding with minimal complications. carvedilol is a good pharmaceutical alternative medicine to propranolol with lesser side-effects. Progress of liver disease as represented by Child score is not affected by any of the primary variceal prophylactic regimens, although medical treatment reduces portal hypertensive gastropathy. Choice of treatment depends on patient will, compliance with treatment, and endoscopist competence.", "source": "https://pubmed.ncbi.nlm.nih.gov/29185106/"}
{"doc_id": "64e45e423684bb5204c4c8609ec162af", "sentence": "Nevertheless , there are serious doubts as to the specificity of these actions of DA as a number of other substances like naloxone , nicotine , acetylcholine or glutamate-diethylester occasionally had very similar effects on membrane potential , firing rate and cortically evoked EPSP-IPSP sequences .", "spans": [{"span_id": 0, "text": "naloxone", "start": 122, "end": 130, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "nicotine", "start": 133, "end": 141, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "acetylcholine", "start": 144, "end": 157, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "glutamate-diethylester", "start": 161, "end": 183, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Iontophoretically applied dopamine depolarizes and hyperpolarizes the membrane of cat caudate neurons. Dopamine (DA) was applied iontophoretically on intracellularly recorded cat caudate neurons. Ejected approximately 100 micrometers away from the cell soma, it caused slow depolarizations of the membrane while the ongoing firing rate was reduced. This last effect was not due to sodium inactivation. Cortically evoked EPSP-IPSP sequences were inhibited during the depolarizations. The latency of cortically evoked action potentials was consistently increased during DA-ejections. These effects were blocked by fluphenazine, relatively selective blocker of the DA-sensitive adenylate cyclase. Nevertheless , there are serious doubts as to the specificity of these actions of DA as a number of other substances like naloxone , nicotine , acetylcholine or glutamate-diethylester occasionally had very similar effects on membrane potential , firing rate and cortically evoked EPSP-IPSP sequences . If DA was applied nearer to the soma, approximately 50 micrometers away, 70% of the recorded neurons continued to display the slow depolarizations above described, while 30% of the cells now reacted by a hyperpolarization accompanied also by a reduced firing rate. If DA was applied for prolonged periods on such cells, the initial hyperpolarization was followed by the slow depolarization. The observation that during the slow depolarization there is a decrease in firing rate and amplitude of the cortically evoked IPSP is explained by the assumption that the region of the axon hillock is hyperpolarized by DA, and that the slow depolarization is a phenomenon restricted to the distant recording site and possibly to the dendritic region. None of the 74 responsive neurons displayed an increased firing fate when DA was ejected either continuously, i.e. for more than 5 sec, or in short pulses of 50--500 msec.", "source": "https://pubmed.ncbi.nlm.nih.gov/7378798/"}
{"doc_id": "cee5496f94c2c2a1f3b6457c5f9fea7d", "sentence": "Here , we validated an indirect competitive enzyme-linked immunosorbent assay ( icELISA ) for quantification of ARTs and found that 50 % of inhibitory concentrations of dihydroartemisinin , artemether , and artesunate were 8.1 , 207.0 , and 4.7 ng/mL , respectively .", "spans": [{"span_id": 0, "text": "dihydroartemisinin", "start": 169, "end": 187, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "artemether", "start": 190, "end": 200, "token_start": 28, "token_end": 29}, {"span_id": 2, "text": "artesunate", "start": 207, "end": 217, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Validation of ELISA for quantitation of artemisinin-based antimalarial drugs. The circulation of counterfeit or substandard artemisinins (ARTs) in malaria-endemic areas poses a serious threat to the long-term use of these drugs. Here , we validated an indirect competitive enzyme-linked immunosorbent assay ( icELISA ) for quantification of ARTs and found that 50 % of inhibitory concentrations of dihydroartemisinin , artemether , and artesunate were 8.1 , 207.0 , and 4.7 ng/mL , respectively . We compared the icELISA with high-performance liquid chromatography (HPLC) for quantifying ART and its derivatives in 22 convenience samples of commercial antimalarial drugs. Paired t tests showed a borderline significant difference between the two methods (mean = 0.03, 95% confidence interval [CI] 0.00-0.07, P = 0.074) and the icELISA results were more variable than those of the HPLC analysis (P < 0.001), suggesting that further improvement is needed to enhance the performance of the icELISA. Our results showed that the icELISA has the potential to be improved for quality assurance of ARTs at the point of care in endemic settings.", "source": "https://pubmed.ncbi.nlm.nih.gov/24080636/"}
{"doc_id": "bf232023efbbd15ef0b3176d7706a57c", "sentence": "In an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir .", "spans": [{"span_id": 0, "text": "mitoxantrone", "start": 39, "end": 51, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "cidofovir", "start": 93, "end": 102, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone. mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. mitoxantrone demonstrated an EC(50) of 0.25 \u03bcM against cowpox and 0.8 \u03bcM against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5 mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir . In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5 mg/kg mitoxantrone and 100 mg/kg cidofovir than with 100 mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model.", "source": "https://pubmed.ncbi.nlm.nih.gov/22182595/"}
{"doc_id": "cf9e40c666bed03242c02340d9cd3df4", "sentence": "In our study , the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients .", "spans": [{"span_id": 0, "text": "atorvastatin", "start": 117, "end": 129, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "bezafibrate", "start": 134, "end": 145, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment. Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL. ### design One hundred and sixteen subjects participating in the ATOMIX study (atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. ### results Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05). ### conclusions In our study , the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients . Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.", "source": "https://pubmed.ncbi.nlm.nih.gov/12059987/"}
{"doc_id": "8527f70e6e09f5dd3955194e23024012", "sentence": "A prospective open-label study comparing the efficacy and safety of methotrexate ( MTX ) and chloroquine ( CQ ) in articular and cutaneous manifestations of systemic lupus erythematosus ( SLE ) .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 68, "end": 80, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "chloroquine", "start": 93, "end": 104, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus.  A prospective open-label study comparing the efficacy and safety of methotrexate ( MTX ) and chloroquine ( CQ ) in articular and cutaneous manifestations of systemic lupus erythematosus ( SLE ) . ### methods Consecutive SLE patients were randomly assigned to either 10 mg MTX weekly or 150 mg CQ daily during 24 weeks. Outcome measures were: numbers of swollen and tender joints, duration of morning stiffness, visual analog scale (VAS) for articular pain, physician global assessment index, patient global assessment index, SLE Disease Activity Index (SLEDAI), disappearance of skin rash and erythrocyte sedimentation rate (ESR). ### results Forty-one patients consented to participate, 15 were allocated in the MTX group and 26 in the CQ group. Two patients on MTX dropped out due to side-effects and two in the CQ group, one due to side-effects and one due to inefficacy. Baseline demographic, clinical and laboratory parameters of the two groups were nearly identical. In both groups the clinical and laboratory parameters improved significantly over 24 weeks, except the ESR in the MTX group. The results of the outcome measures at the end of the trial did not differ significantly between the two groups, except morning stiffness (P < 0.05 in favor of the MTX group) and ESR (P < 0.01 in favor of the CQ group). Rise of serum alanine aminotransferase was observed in two cases in the MTX group and in none in the CQ group. ### conclusion Low-dose MTX appears to be as effective as CQ in patients with articular and cutaneous manifestations of SLE, having an acceptable toxicity profile. Results of this prospective study need to be confirmed in a larger study.", "source": "https://pubmed.ncbi.nlm.nih.gov/22324948/"}
{"doc_id": "101863d8e60e61f4ea40f098ce840a75", "sentence": "In the current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells .", "spans": [{"span_id": 0, "text": "diltiazem", "start": 80, "end": 89, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "gemcitabine", "start": 122, "end": 133, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "5-FU", "start": 138, "end": 142, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Diltiazem potentiates the cytotoxicity of gemcitabine and 5-fluorouracil in PANC-1 human pancreatic cancer cells through inhibition of P-glycoprotein. Pancreatic cancer (PC) is one of the most aggressive tumors with dismal survival and a high death rate due to chemotherapeutic failure. P-glycoprotein (P-gp) plays a pivotal role in PC response to gemcitabine and 5-fluorouracil (5-FU). diltiazem, a calcium channel blocker, is a P-gp inhibitor. In the current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells . ### Main Methods The cytotoxic effect of diltiazem, gemcitabine, and 5-FU in single and combined forms against PANC-1 and AsPC-1 cells were assayed by MTT. Flow cytometric analysis was used for the determination of cell cycle, apoptosis, and stemness markers in PC cells. Besides, immunoblotting was used for assessment of Bax, caspase 3, cyclin D1, and P-gp expressions. ### Key Findings diltiazem co-treatment, either with gemcitabine or 5-FU, synergistically reduced cell viability, induced apoptosis, and caused cell cycle arrest. In addition, diltiazem co-treatment decreased the expressions of stem cell markers CD24 and CD44, increased the expressions of Bax and cleaved caspase 3, enhanced DNA fragmentation, and attenuated cyclin D1 and P-gp expressions as compared to cells treated with either gemcitabine or 5-FU alone. ### significance Our findings suggest that diltiazem may be potential neoadjuvant therapy to enhance the response of PC to gemcitabine or 5-FU treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/33011221/"}
{"doc_id": "e6511ffdb1212e6e1b04d1c32e5a0aea", "sentence": "An additional 2 patients ( 1 in each group ) met the protocol definition of virologic failure between weeks 48 and 96 ; no known resistance mutations were observed in the raltegravir recipient ; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations .", "spans": [{"span_id": 0, "text": "raltegravir", "start": 171, "end": 182, "token_start": 31, "token_end": 32}, {"span_id": 1, "text": "efavirenz", "start": 199, "end": 208, "token_start": 35, "token_end": 36}], "rels": [], "paragraph": "Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection. ### methods Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNA > or =5000 copies per milliliter and CD4 T cells > or =100 cells per microliter. ### results One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA <400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved <50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4 T cells (221 vs 232 cells/uL, respectively). An additional 2 patients ( 1 in each group ) met the protocol definition of virologic failure between weeks 48 and 96 ; no known resistance mutations were observed in the raltegravir recipient ; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations . Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in >10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir. ### conclusions In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.", "source": "https://pubmed.ncbi.nlm.nih.gov/19648823/"}
{"doc_id": "30dbeb9740d6e87d257a7122b0ad6aed", "sentence": "In all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 99, "end": 109, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "etoposide", "start": 169, "end": 178, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Experience with ifosfamide combinations (etoposide or DDP) in non-small cell lung cancer.  In all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 . Therapeutic regimens were repeated after 4 weeks. Supportive treatment with mesna (20% of the ifosfamide doses at 0, 4, and 8 h) was performed. cisplatin treatment was supported by mannitol-induced diuretic hydration. The overall response rate of ifosfamide/etoposide was calculated to be 27%, with 1 complete and 24 partial remissions. The median survival time for all patients was 8.5 months, for responders 14 months (P less than 0.05), for patients with no change 9.5 months, and for patients with tumor progression 4 months. With ifosfamide/cisplatin, there were 4 complete and 21 partial remissions (response rate 35%). The median survival time for all patients was 8.3 months, for responders 11.5 months, and for patients with tumor progression 4 months. Age, sex, and histological tumor type had no significant effect on survival. Patients with better performance stage and limited disease lived significantly longer. The main side-effects of the cisplatin combination were vomiting, bone marrow depression, and neuropathy. The etoposide combination was tolerated better. Urotoxicity was not significant, as a consequence of treatment with mesna. The results show that the combination ifosfamide/etoposide or ifosfamide/cisplatin are effective in the treatment of non-small cell lung cancer, being comparable to other combinations of etoposide/cisplatin and vindesine/cisplatin. Because of the better tolerability, the combination ifosfamide/etoposide is superior to cisplatin combinations.", "source": "https://pubmed.ncbi.nlm.nih.gov/3028662/"}
{"doc_id": "4e64148cc3d63e797e29955a1e5599cd", "sentence": "In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures .", "spans": [{"span_id": 0, "text": "amodiaquine", "start": 114, "end": 125, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "primaquine", "start": 156, "end": 166, "token_start": 24, "token_end": 25}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Mass administration of an antimalarial drug combining 4-aminoquinoline and 8-aminoquinoline in Tanganyika. For the eradication of malaria from hyperendemic regions of tropical Africa it is apparent that use may have to be made of antimalarial drugs, administered individually on a census basis, in addition to measures directed against the mosquito. The suppressive activity of existing compounds among individuals having different degrees of immunity is well established, and trials among large groups of people have been conducted with single drugs and with combination of drugs. In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures . It was found that treatment of 93% of the population at intervals of one or two weeks resulted in a reduction of the malaria indices to a very low level but such success was not obtained when the combination of drugs was administered every four weeks, although in the area concerned population coverage was less satisfactory owing to migration.", "source": "https://pubmed.ncbi.nlm.nih.gov/14021798/"}
{"doc_id": "995fb1567f527dad4c82bd259bd632cb", "sentence": "In transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 64, "end": 74, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "lenalidomide", "start": 77, "end": 89, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "dexamethasone", "start": 92, "end": 105, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Multiple myeloma accounts for approximately 10% of hematologic malignancies. ### diagnosis The diagnosis requires \u226510% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis \u226560%, serum involved/uninvolved free light chain (FLC) ratio \u2265100 (provided involved FLC is \u2265100\u2009mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). ### Risk Stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. ### Risk Adapted Initial Therapy In transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) . In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12\u2009cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). ### Maintenance Therapy After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. ### Management Of Refractory Disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.", "source": "https://pubmed.ncbi.nlm.nih.gov/32212178/"}
{"doc_id": "ffe6e1e3c4c2087fd48b402e210e30e0", "sentence": "Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines .", "spans": [{"span_id": 0, "text": "Genistein", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "docetaxel", "start": 55, "end": 64, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "bicalutamide", "start": 67, "end": 79, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines . To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP). ### Materials And Methods The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel. ### results GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP-R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP-mediated induction of G1 arrest interfering with docetaxel activity. ### conclusion These data suggest that GCP, an isoflavone-enriched compound with minimal side-effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP.", "source": "https://pubmed.ncbi.nlm.nih.gov/18565171/"}
{"doc_id": "7a9e2e3120bc08702b1f8f43efe006d3", "sentence": "Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis .", "spans": [{"span_id": 0, "text": "bosentan", "start": 25, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "sildenafil", "start": 38, "end": 48, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[Efficacy of combination therapy with bosentan and sildenafil for refractory pulmonary arterial hypertension associated with fibrotic lung in systemic sclerosis]. A 54-year-old woman with a 20-year history of Raynaud phenomenon was admitted to our hospital complaining of progressive dyspnea on exertion since 5 years previously. Interstitial lung disease was diagnosed, accompanied by pulmonary arterial hypertension (PAH) associated with systemic sclerosis. After oxygen therapy and treatment with sildenafil, her clinical condition and PAH gradually improved. However, she was readmitted due to deterioration of Raynaud phenomenon and progressive dyspnea in March 2009. Right heart catheterization findings demonstrated that her mean pulmonary arterial pressure (PAP) was elevated, at 48 mmHg. bosentan was therefore added to an increased dose of sildenafil. Consequently, her dyspnea, 6-min walking distance, serum brain natriuretic peptide level, and PAP improved. Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis .", "source": "https://pubmed.ncbi.nlm.nih.gov/21066870/"}
{"doc_id": "a37b060ccdcd200503f49e6cf490f6c8", "sentence": "All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept , and all resided in HC-endemic regions .", "spans": [{"span_id": 0, "text": "infliximab", "start": 83, "end": 93, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "etanercept", "start": 97, "end": 107, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products. ### methods The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept. ### results Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept , and all resided in HC-endemic regions . ### conclusion Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.", "source": "https://pubmed.ncbi.nlm.nih.gov/12384912/"}
{"doc_id": "4c12db4480499b3f103a64641ccf2593", "sentence": "Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months .", "spans": [{"span_id": 0, "text": "vincristine", "start": 107, "end": 118, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "etoposide", "start": 129, "end": 138, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "carboplatin", "start": 155, "end": 166, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma.  Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months . ### purpose To determine the efficacy of postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin in the prevention of metastasis for patients with high-risk retinoblastoma. ### methods Retrospective, nonrandomized, interventional case series of 52 eyes in 51 patients with high-risk retinoblastoma consisting of tumor invasion into the anterior segment, posterior uvea 3 mm or greater, postlaminar optic nerve, or any combination of posterior uvea and optic nerve involvement. ### results Of 51 consecutive patients with high-risk retinoblastoma, there were 30 males (59%) and 21 females (41%), with a median age of 28 months at diagnosis. All 52 eyes were classified as group E. The main histopathologic risk factors included anterior segment invasion (7 [13%]), isolated massive posterior uveal invasion of 3 mm or greater (6 [12%]), isolated postlaminar optic nerve invasion (15 [29%]), or any posterior uveal invasion with any optic nerve involvement (24 [46%]). There was additional invasion into the sclera (3 [6%]) and extrascleral structures, including the orbit (1 [2%]). A single histopathologic high-risk factor was present in 32 eyes (62%), whereas 20 eyes (38%) manifested 2 or more high-risk characteristics. Based on previously published series, untreated high-risk retinoblastoma carries at least a 24% risk for metastatic disease. In the present series, using vincristine, etoposide, and carboplatin in all cases, there was no metastasis during a mean follow-up of 66 months (median [range], 55 [12-202] months). ### conclusions Retinoblastoma with invasion into the postlaminar optic nerve and/or posterior uvea is at high risk for metastasis and death. In this study, postenucleation chemotherapy using vincristine, etoposide, and carboplatin was effective in preventing metastasis in every case (100%).", "source": "https://pubmed.ncbi.nlm.nih.gov/22084213/"}
{"doc_id": "5c011db3395f3d8e96b2b38ca08ad876", "sentence": "Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer : systematic review and economic evaluation .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 35, "end": 47, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "tegafur", "start": 52, "end": 59, "token_start": 6, "token_end": 7}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer : systematic review and economic evaluation . To evaluate the clinical and cost-effectiveness of capecitabine and tegafur with uracil (UFT/LV) as first-line treatments for patients with metastatic colorectal cancer, as compared with 5-fluorouracil/folinic acid (5-FU/FA) regimens. ### Data Sources Electronic databases, reference lists of relevant articles and sponsor submissions were also consulted. ### Review Methods Systematic searches, selection against criteria and quality assessment were performed to obtain data from relevant studies. Costs were estimated through resource-use data taken from the published trials and the unpublished sponsor submissions. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to compare the cost-effectiveness of capecitabine and UFT/LV with three intravenous 5-FU/LV regimens widely used in the UK: the Mayo, the modified de Gramont regimen and the inpatient de Gramont regimens. ### results The evidence suggests that treatment with capecitabine improves overall response rates and has an improved adverse effect profile in comparison with 5-FU/LV treatment with the Mayo regimen, with the exception of hand-foot syndrome. Time to disease progression or death after treatment with UFT/LV in one study appears to be shorter than after treatment with 5-FU/LV with the Mayo regimen, although it also had an improved adverse effect profile. Neither capecitabine nor UFT/LV appeared to improve health-related quality of life. Little information on patient preference was available for UFT/LV, but there was indicated a strong preference for this over 5-FU/LV. The total cost of capecitabine and UFT/LV treatments were estimated at 2111 pounds and 3375 pounds, respectively, compared with the total treatment cost for the Mayo regimen of 3579 pounds. Cost estimates were also presented for the modified de Gramont and inpatient de Gramont regimens. These were 3684 pounds and 6155 pounds, respectively. No survival advantage was shown in the RCTs of the oral drugs against the Mayo regimen. Cost savings of capecitabine and UFT/LV over the Mayo regimen were estimated to be 1461 pounds and 209 pounds, respectively. Drug acquisition costs were higher for the oral therapies than for the Mayo regimen, but were offset by lower administration costs. Adverse event treatment costs were similar across the three regimens. It was inferred that there was no survival difference between the oral drugs and the de Gramont regimens. Cost savings of capecitabine and UFT/LV over the modified de Gramont regimen were estimated to be 1353 pounds and 101 pounds, respectively, and over the inpatient de Gramont regimen were estimated to be 4123 pounds and 2870 pounds, respectively. ### conclusions The results show that there are cost savings associated with the use of oral therapies. No survival difference has been proven between the oral drugs and the Mayo regimen. In addition, no evidence of a survival difference between the Mayo regimen and the de Gramont regimens has been identified. However, improved progression-free survival and an improved adverse event profile have been shown for the de Gramont regimen over the Mayo regimen. Further research is recommended into the following areas: quality of life data should be included in trials of colorectal cancer treatments; the place of effective oral treatments in the treatment of colorectal cancer, the safety mechanisms needed to ensure compliance and the monitoring of adverse effects; the optimum duration of treatment; the measurement of patient preference; and a phase III comparative trial of capecitabine and UFT/LV versus modified de Gramont treatment to determine whether there was any survival advantage and to collate the necessary economic data.", "source": "https://pubmed.ncbi.nlm.nih.gov/14604497/"}
{"doc_id": "c4f2d09db81566c47c4b6b76bd9ed471", "sentence": "All strains were susceptible to phenoxymethylpenicillin , cephalosporins , erythromycin , azithromycin , clindamycin , vancomycin , doxycycline , and ciprofloxacin but were resistant to trimethoprim-sulfamethoxazole .", "spans": [{"span_id": 0, "text": "erythromycin", "start": 75, "end": 87, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "azithromycin", "start": 90, "end": 102, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "clindamycin", "start": 105, "end": 116, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "vancomycin", "start": 119, "end": 129, "token_start": 15, "token_end": 16}, {"span_id": 4, "text": "doxycycline", "start": 132, "end": 143, "token_start": 17, "token_end": 18}, {"span_id": 5, "text": "ciprofloxacin", "start": 150, "end": 163, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Antimicrobial susceptibility of Arcanobacterium haemolyticum. The susceptibilities of 138 clinical isolates of Arcanobacterium haemolyticum to 11 antimicrobial agents were tested. All strains were susceptible to phenoxymethylpenicillin , cephalosporins , erythromycin , azithromycin , clindamycin , vancomycin , doxycycline , and ciprofloxacin but were resistant to trimethoprim-sulfamethoxazole .", "source": "https://pubmed.ncbi.nlm.nih.gov/8141569/"}
{"doc_id": "95afbabbb2b4898b8b0ab8854f3e5333", "sentence": "The inhibition by the agonist oxotremorine is comparable to that of carbachol and 1 mM pilocarpine inhibited the binding by 21 % .", "spans": [{"span_id": 0, "text": "oxotremorine", "start": 30, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "carbachol", "start": 68, "end": 77, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "pilocarpine", "start": 87, "end": 98, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Muscarinic binding sites in a catecholaminergic human neuroblastoma cell line. Tyrosine hydroxylase (TH) a characteristic enzyme activity for the catecholaminergic clonal cell line LA-N-1 and choline acetyltransferase (ChAT) a characteristic enzyme activity for the cholinergic clonal cell line LA-N-2 were previously shown to be increased in these cells exposed to 10(-5) M retinoic acid (RA) as differentiating agent. An investigation of the receptor characteristics suggests a complementarity between the two cell lines. The binding of QNB, a muscarinic ligand, was undetectable with the LA-N-2 cells but was present in the LA-N-1 cells and possessed a kD of 1.8 nM and 2.2 nM and a Bmax of 0.56 and 0.68 for control and RA grown cells respectively. There was a gradual increase in QNB binding to LA-N-1 cells from 2 days in vitro (DIV) until 6 DIV in both control and RA grown cells. An IC50 of 2.5 x 10(-8) M and 0.9 x 10(-8) M for atropine inhibition was obtained for the control and RA grown cells respectively. The corresponding values for carbachol inhibition were 7 x 10(-2) M and 3 x 10(-2) M respectively. The inhibition by the agonist oxotremorine is comparable to that of carbachol and 1 mM pilocarpine inhibited the binding by 21 % . QNB binding showed a low affinity for pirenzepine and for AF-DX-116 but was inhibited with a rather high affinity by 4-DAMP (IC50:110 microM) thus suggesting the presence of an M3 receptor. Acetylcholine (100 microM) plus eserine (50 microM) and BW284c55 (1 microM), an acetylcholinesterase inhibitor, reduced the binding of QNB by approximately 25%.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/1320213/"}
{"doc_id": "a6f95bc857398a035571a727142fe48e", "sentence": "Cost-effectiveness of cetuximab , cetuximab plus irinotecan , and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 22, "end": 31, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "cetuximab", "start": 34, "end": 43, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "irinotecan", "start": 49, "end": 59, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "panitumumab", "start": 66, "end": 77, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Cost-effectiveness of cetuximab , cetuximab plus irinotecan , and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer . To estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service. ### methods An \"an area under the curve\" cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources. ### results Patients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan. panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of \u00a395,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at \u00a3187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at \u00a388,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money. ### conclusions All three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries.", "source": "https://pubmed.ncbi.nlm.nih.gov/23538180/"}
{"doc_id": "86aa3323dfc7081ec77bbad12601a64d", "sentence": "Limits of quantification were 0.12 , 1.09 , 1.46 , 1.47 , 5.70 , 1.32 , 1.33 \u00b5g/L for haloperidol , aripiprazole , olanzapine , quetiapine , clozapine , risperidone , and paliperidone , respectively .", "spans": [{"span_id": 0, "text": "haloperidol", "start": 86, "end": 97, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "aripiprazole", "start": 100, "end": 112, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "olanzapine", "start": 115, "end": 125, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "quetiapine", "start": 128, "end": 138, "token_start": 25, "token_end": 26}, {"span_id": 4, "text": "clozapine", "start": 141, "end": 150, "token_start": 27, "token_end": 28}, {"span_id": 5, "text": "risperidone", "start": 153, "end": 164, "token_start": 29, "token_end": 30}, {"span_id": 6, "text": "paliperidone", "start": 171, "end": 183, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Multiplexed therapeutic drug monitoring of antipsychotics in dried plasma spots by LC-MS/MS. In this work, a convenient method for the therapeutic monitoring of seven common antipsychotic drugs in \"dried plasma spot\" samples has been developed. It is based on the liquid chromatography tandem mass spectrometry technique, operating in multiple reaction monitoring mode, and a straightforward procedure for the simultaneous extraction of all antipsychotics in a single step, with high extraction yield. The method was fully validated with proper accuracy, precision, selectivity and sensitivity, for all the drugs. Limits of quantification were 0.12 , 1.09 , 1.46 , 1.47 , 5.70 , 1.32 , 1.33 \u00b5g/L for haloperidol , aripiprazole , olanzapine , quetiapine , clozapine , risperidone , and paliperidone , respectively . Accuracy, intra- and interday precision values were\u00a0<10% for all drugs at all concentration levels examined. The method was tested in the analysis of 30 plasma samples from real patients for each drug. The proposed analytical approach, by combining practical and logistical advantages of microsampling with liquid chromatography tandem mass spectrometry analytical performance, could offer an ideal strategy for accurate and timely therapeutic drug monitoring of antipsychotic drugs in most clinical settings, even in remote centers and/or in out-patient settings, bringing so many potential improvements in psychiatric patient care.", "source": "https://pubmed.ncbi.nlm.nih.gov/32077627/"}
{"doc_id": "00e37a3a571029baa205896e8b8af80a", "sentence": "Sensitization to doxorubicin and etoposide with BPTF knockdown ( KD ) was associated with increased DNA damage , topoisomerase II ( TOP2 ) crosslinking and autophagy ; however , there was only a modest increase in apoptosis and no increase in senescence .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 17, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "etoposide", "start": 33, "end": 42, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor. Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown ( KD ) was associated with increased DNA damage , topoisomerase II ( TOP2 ) crosslinking and autophagy ; however , there was only a modest increase in apoptosis and no increase in senescence . Sensitization to doxorubicin was confirmed", "source": "https://pubmed.ncbi.nlm.nih.gov/33811160/"}
{"doc_id": "5164a0a4ccd664fee504b3a219d45e02", "sentence": "This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) regimen given in 14-day intervals ( BEACOPP-14 ) with granulocyte colony-stimulating factor ( G-CSF ) support in advanced Hodgkin 's lymphoma .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 89, "end": 98, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "etoposide", "start": 101, "end": 110, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "doxorubicin", "start": 113, "end": 124, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "cyclophosphamide", "start": 127, "end": 143, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "vincristine", "start": 146, "end": 157, "token_start": 20, "token_end": 21}, {"span_id": 5, "text": "procarbazine", "start": 160, "end": 172, "token_start": 22, "token_end": 23}, {"span_id": 6, "text": "prednisone", "start": 179, "end": 189, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": true}], "paragraph": "14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group.  This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP ) regimen given in 14-day intervals ( BEACOPP-14 ) with granulocyte colony-stimulating factor ( G-CSF ) support in advanced Hodgkin 's lymphoma . ### Patients And Methods From July 1997 until March 2000, 94 patients with Hodgkin's lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy. ### results All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin's lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively. ### conclusion Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin's Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial.", "source": "https://pubmed.ncbi.nlm.nih.gov/12721249/"}
{"doc_id": "b5a492e63b8d042a91334a25354a0c87", "sentence": "Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment .", "spans": [{"span_id": 0, "text": "daclatasvir", "start": 23, "end": 34, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "asunaprevir", "start": 39, "end": 50, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment . Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment. ### methods The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12\u00a0weeks after the end of treatment and safety was evaluated according to renal function. ### results Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44\u00a0mL/min/1.73\u00a0m ### conclusion daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe.", "source": "https://pubmed.ncbi.nlm.nih.gov/27943523/"}
{"doc_id": "e0a5e104ff27dc22c4bac651946a3093", "sentence": "We report the results of replacement of steroids by azathioprine ( AZA ) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone ( MP ) .", "spans": [{"span_id": 0, "text": "azathioprine", "start": 52, "end": 64, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "CsA", "start": 148, "end": 151, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "methylprednisolone", "start": 156, "end": 174, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients. In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine ( AZA ) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone ( MP ) . MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/3276062/"}
{"doc_id": "74f50f05d8872caba44cad3755e29d2a", "sentence": "Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms , respectively ( HR , 0.62 ; 95 % CI , 0.44 to 0.89 ; P = .009 ) .", "spans": [{"span_id": 0, "text": "panitumumab", "start": 42, "end": 53, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "bevacizumab", "start": 58, "end": 69, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS. ### Patients And Methods Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety. ### results Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms , respectively ( HR , 0.62 ; 95 % CI , 0.44 to 0.89 ; P = .009 ) . In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms. ### conclusion PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti-epidermal growth factor receptor therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/24687833/"}
{"doc_id": "7851400849edea591bab081dcce35070", "sentence": "One group of patients was treated with oral mefloquine ( 750 mg ) and artemether ( 600 mg by injection , 200 mg initially and 100 mg every 12 h ) .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 44, "end": 54, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "artemether", "start": 70, "end": 80, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria. 30 pairs of patients with complicated Plasmodium falciparum malaria (with anaemia, hyperpyrexia, jaundice or more than 5% of erythrocytes parasitized) were studied. Patients with cerebral signs and symptoms were excluded. One group of patients was treated with oral mefloquine ( 750 mg ) and artemether ( 600 mg by injection , 200 mg initially and 100 mg every 12 h ) . The second group of patients was treated with quinine (10 mg/kg orally every 8 h for 7 d). All patients were admitted to hospital for 7 d and examined subsequently on days 14, 21 and 28. All those treated with mefloquine plus artemether survived and their parasite clearance time and fever clearance time were significantly shorter than those of patients receiving quinine. 2 patients treated with quinine died. There was no recrudescence in any patient of either group.", "source": "https://pubmed.ncbi.nlm.nih.gov/3075350/"}
{"doc_id": "79e1e6d499310e1367d0b0ff3798ad16", "sentence": "The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 12, "end": 22, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "oxaliplatin", "start": 27, "end": 38, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer . Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/11346931/"}
{"doc_id": "303584137532ab3adfbf9a922097c40e", "sentence": "In both cases , chemotherapy comprising rituximab + dose-adjusted EPOCH regimen ( etoposide , prednisone , vincristine , cyclophosphamide and doxorubicin ) was administered .", "spans": [{"span_id": 0, "text": "rituximab", "start": 40, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "etoposide", "start": 82, "end": 91, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "prednisone", "start": 94, "end": 104, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "vincristine", "start": 107, "end": 118, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "cyclophosphamide", "start": 121, "end": 137, "token_start": 18, "token_end": 19}, {"span_id": 5, "text": "doxorubicin", "start": 142, "end": 153, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "Successful Treatment of Gastrosplenic Fistula Arising from Diffuse Large B-Cell Lymphoma with Chemotherapy: Two Case Reports. Gastrosplenic fistula (GSF) is a rare condition arising from gastric or splenic lymphomas. Surgical resection is the most common treatment, as described in previous reports. We report two cases of GSF in diffuse large B-cell lymphoma (DLBCL) patients that were successfully treated with chemotherapy and irradiation without surgical resection. Case 1 was of a 63-year-old man who had primary gastric DLBCL with a large lesion outside the stomach wall, leading to a spontaneous fistula in the spleen. Case 2 was of a 59-year-old man who had primary splenic DLBCL, which proliferated and infiltrated directly into the stomach. In both cases , chemotherapy comprising rituximab + dose-adjusted EPOCH regimen ( etoposide , prednisone , vincristine , cyclophosphamide and doxorubicin ) was administered . Case 1 had significant bleeding from the lesion of the stomach during the treatment cycle; however, endoscopic hemostasis was achieved. Case 2 developed a fistula between the stomach and the spleen following therapeutic chemotherapy; however, no complications related to the fistula were observed thereafter. In both cases, irradiation was administered, and complete remission was achieved.", "source": "https://pubmed.ncbi.nlm.nih.gov/31182954/"}
{"doc_id": "895f8f092802706aa4d15f7d7c46540b", "sentence": "Bleeding prophylaxis included combinations of plasma-derived factor ( VWD ) or recombinant factor ( haemophilia A and haemophilia B ) , desmopressin and/or tranexamic acid .", "spans": [{"span_id": 0, "text": "desmopressin", "start": 136, "end": 148, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "tranexamic", "start": 156, "end": 166, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Low endoscopy bleeding risk in patients with congenital bleeding disorders. Haemophilia A and haemophilia B, von Willebrand disease (VWD), factor VII deficiency and factor XI deficiency are congenital bleeding disorders predisposing to bleeding during invasive procedures. The ageing population of people with congenital bleeding disorders will likely increasingly require gastrointestinal endoscopy. The bleeding risk postgastrointestinal endoscopy and optimal prophylactic treatment regimens are not well described. ### methods We performed a retrospective chart review at the McGill University Health Centre. Adult patients with haemophilia A or B, VWD, FVII deficiency and FXI deficiency who underwent gastrointestinal endoscopic procedures were included. Bleeding prophylaxis included combinations of plasma-derived factor ( VWD ) or recombinant factor ( haemophilia A and haemophilia B ) , desmopressin and/or tranexamic acid . Our primary outcome was the 72-hour postendoscopy bleeding rate. ### results One hundred and four endoscopies were performed in 48 patients. Haemophilia A (45.3% of endoscopies) was the most common bleeding disorder, followed by VWD (38.5%), FXI deficiency (8.7%), haemophilia B (4.8%) and FVII deficiency (2.9%). All patients were reviewed by the Haemophilia Treatment Center with peri-procedure treatment protocols put in place as required. The overall 72-hour bleeding rate was 0.96%, confidence interval (CI) 95% (0.17%-5.25%). The colonoscopic postpolypectomy bleeding rate was 1/21 (4.8%, CI 95% (0.9%-22.7%)) in comparison with the general population rate of 0.3%-10% for high-risk endoscopy (including colonoscopic polypectomy). ### conclusion To the best of our knowledge, this is the largest study describing patients with inherited bleeding disorders undergoing gastrointestinal endoscopy. The bleeding risk is not significantly higher to the general population when haemostatically managed by a team experienced in bleeding disorders.", "source": "https://pubmed.ncbi.nlm.nih.gov/30748066/"}
{"doc_id": "d9994cfb89299e8c4c4c6f0130d9189b", "sentence": "Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel , we suggest that physicians should consider possible predictive risk factors for overall survival , individual 's treatment priorities , and the differing safety profiles .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 44, "end": 55, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "capecitabine", "start": 61, "end": 73, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "bevacizumab", "start": 117, "end": 128, "token_start": 15, "token_end": 16}, {"span_id": 3, "text": "paclitaxel", "start": 134, "end": 144, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1\u00b704; 97\u00b75% repeated CI [RCI] -\u221e to 1\u00b769). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. ### methods In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR \u22651\u00b733) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. ### findings Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30\u00b72 months (95% CI 25\u00b76-32\u00b76 months) versus 26\u00b71 months (22\u00b73-29\u00b70), respectively. The stratified HR was 1\u00b702 (97\u00b75% RCI -\u221e to 1\u00b726; repeated p=0\u00b70070), indicating non-inferiority. The unstratified Cox model (HR 1\u00b713 [97\u00b75% RCI -\u221e to 1\u00b739]; repeated p=0\u00b7061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. ### interpretation bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel , we suggest that physicians should consider possible predictive risk factors for overall survival , individual 's treatment priorities , and the differing safety profiles . ### funding Roche.", "source": "https://pubmed.ncbi.nlm.nih.gov/27501767/"}
{"doc_id": "90111cf0d99ec6681021ea333de19ace", "sentence": "The combination of ixabepilone and bevacizumab was well tolerated , with modest activity in second - or later-line mRCC , but it is not recommended as a therapy without further clinical development .", "spans": [{"span_id": 0, "text": "ixabepilone", "start": 19, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bevacizumab", "start": 35, "end": 46, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Phase II Multi-Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma. Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. ### background Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. ### methods We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m ### results The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2-54). The median follow-up was 36.4 months (range 23.5-96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9-10.6) and the median OS was 15.0 months (95% CI, 11.3-28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). ### conclusion The combination of ixabepilone and bevacizumab was well tolerated , with modest activity in second - or later-line mRCC , but it is not recommended as a therapy without further clinical development . Alternative combinations with these agents could be explored in future studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/28679644/"}
{"doc_id": "2ce0bf4cbd6f3d346eb3e1ad0fac2e63", "sentence": "Eligible patients with unresectable MPM , without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression , stratified by number of cycles ( < 6 or 6 ) , cis- or carboplatin containing regimen , and histology .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 97, "end": 107, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "platinum", "start": 112, "end": 120, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "pemetrexed", "start": 175, "end": 185, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "carboplatin", "start": 260, "end": 271, "token_start": 44, "token_end": 45}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Randomized Study of Maintenance Pemetrexed Versus Observation for Treatment of Malignant Pleural Mesothelioma: CALGB 30901. The role of maintenance therapy for malignant pleural mesothelioma (MPM) is unknown. We performed a randomized phase II trial to determine if continuation of pemetrexed after first-line pemetrexed and platinum would improve progression-free survival (PFS). ### Patients And Methods Eligible patients with unresectable MPM , without disease progression following 4 to 6 cycles of pemetrexed and platinum were randomized 1:1 to observation or continuation of pemetrexed until progression , stratified by number of cycles ( < 6 or 6 ) , cis- or carboplatin containing regimen , and histology . Study size was calculated based on the assumption that observation would produce a median PFS of 3 months and pemetrexed would yield median PFS of 6 months. ### results A total of 72 patients were registered from December 2010 to June 2016. The study closed early after 53 patients were randomized; 49 eligible (22 on the observation arm and 27 on the pemetrexed arm) were included in the analysis. The median PFS was 3 months (95% confidence interval [CI], 2.6-11.9 months) on observation and 3.4 months (95% CI, 2.8-9.8 months) on pemetrexed (hazard ratio [HR], 0.99; 95% CI, 0.51-1.90; P\u00a0= .9733). The median overall survival (OS) was 11.8 months (95% CI, 9.3-28.7 months) for observation, and 16.3 months (95% CI, 10.5-26.0 months) for pemetrexed (HR, 0.86; 95% CI, 0.44-1.71; P\u00a0= .6737). Grade 3 or 4 toxicities on the pemetrexed arm included anemia (8%), lymphopenia (8%), neutropenia (4%), and fatigue (4%). A higher baseline level of soluble mesothelin-related peptide was associated with worse PFS (HR, 1.86; 95% CI, 1.00-3.46; P\u00a0= .049). ### conclusion Maintenance pemetrexed following initial pemetrexed and platinum chemotherapy does not improve PFS in patients with MPM.", "source": "https://pubmed.ncbi.nlm.nih.gov/32727707/"}
{"doc_id": "d8228db05effe17e695057b6931e7251", "sentence": "A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan , plus a median time to progression of 4.1 months , a tumour response rate of 22.9 % and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events ( any grade 3 or grade 4 adverse event ) than cetuximab monotherapy .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 84, "end": 93, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "irinotecan", "start": 99, "end": 109, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "cetuximab", "start": 229, "end": 238, "token_start": 41, "token_end": 42}, {"span_id": 3, "text": "irinotecan", "start": 259, "end": 269, "token_start": 45, "token_end": 46}, {"span_id": 4, "text": "cetuximab", "start": 369, "end": 378, "token_start": 64, "token_end": 65}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). ### Data Sources Searches of main electronic databases were conducted in April and May 2005. ### Review Methods For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. ### results Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3/4 adverse events. The independent health economic assessment suggests that the cost-effectiveness of bevacizumab plus IFL is unlikely to be better than pound 46,853 per life-year gained (LYG); the cost-utility of bevacizumab plus IFL is unlikely to be better than pound 62,857 per quality-adjusted life-year (QALY) gained. The cost-effectiveness of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 84,607 per LYG; the cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan , plus a median time to progression of 4.1 months , a tumour response rate of 22.9 % and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events ( any grade 3 or grade 4 adverse event ) than cetuximab monotherapy . The single arm study of cetuximab plus irinotecan reported a median OS duration of 8.4 months, a median time to progression of 2.9 months and a tumour response rate of 15.2%. The cost-effectiveness model suggested that the expected survival duration of patients receiving cetuximab plus irinotecan is 0.79 years (9.5 months) when the proposed continuation rule is applied. In order for cetuximab plus irinotecan to achieve a cost-utility ratio of pound 30,000 per QALY gained, treatment with cetuximab plus irinotecan must provide an additional 0.65 life years (7.8 months) over treatment with active/best supportive care, implying that survival in the active/best supportive care group must be 0.14 life years (1.7 months) or less. ### conclusions The trials indicate that bevacizumab in combination with 5-FU/FA, and bevacizumab in combination with IFL, is clinically effective in comparison to standard chemotherapy options for the first-line treatment of metastatic CRC. The health economic analysis suggests that the marginal cost-utility of bevacizumab plus IFL versus IFL is unlikely to be better than pound 62,857 per QALY gained, and the marginal cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. There is no direct evidence to demonstrate whether cetuximab in combination with irinotecan improves health-related quality of life or OS in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA, although the evidence on tumour response rates suggests that cetuximab plus irinotecan has some clinical activity. While it is difficult to suggest whether cetuximab represents value for money, indirect comparisons suggest that the incremental cost-utility of cetuximab plus irinotecan is unlikely to be better than pound 30,000 per QALY gained. This review highlights a number of areas for further research, including clarifying the true impact of first-line bevacizumab in combination with irinotecan and/or infusional 5-FU/FA, without subsequent bevacizumab treatment following disease progression, on OS in patients with metastatic CRC who are representative of the typical population of CRC patients in England and Wales. Further research concerning the impact of therapies on health-related quality of life is essential.", "source": "https://pubmed.ncbi.nlm.nih.gov/17346499/"}
{"doc_id": "6f7f62aa1e5b1817104f828c34afc946", "sentence": "Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane , with about 27 % of patients having an objective response and 40 % of patients achieving durable disease control .", "spans": [{"span_id": 0, "text": "pertuzumab", "start": 63, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "trastuzumab", "start": 79, "end": 90, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study. T-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2 ### Patients And Methods Eligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. ### results Of 445 patients with HER2 ### conclusions Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane , with about 27 % of patients having an objective response and 40 % of patients achieving durable disease control .", "source": "https://pubmed.ncbi.nlm.nih.gov/31735691/"}
{"doc_id": "a56f01a9aeaba193912053d4079ba9ad", "sentence": "Dapagliflozin seemed to play a role in accelerating the patient 's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide .", "spans": [{"span_id": 0, "text": "Dapagliflozin", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "furosemide", "start": 197, "end": 207, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention. A 48-year-old female was admitted to our hospital presenting with a chief complaint of progressive swelling because of diabetic nephrotic syndrome. Dapagliflozin seemed to play a role in accelerating the patient 's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide . Our experience emphasizes a potential novel approach to overcoming loop diuretic resistance using this agent among some subsets of type 2 diabetic subjects complicated with severe volume accumulation. We believe that combination treatment consisting of dapagliflozin and furosemide may produce diuretic synergy via sequential nephron blockade. The accumulation of more experience with additional cases similar to ours requires continuous and careful attention.", "source": "https://pubmed.ncbi.nlm.nih.gov/26609216/"}
{"doc_id": "2b25d51f8c4a7f7cd32adf4f78458da5", "sentence": "PA combination of goserelin and tamoxifen in patients with relapsed ovarian cancer can not be recommended as standard therapy , but may result in long-term survival in individual patients .", "spans": [{"span_id": 0, "text": "goserelin", "start": 18, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "tamoxifen", "start": 32, "end": 41, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combined treatment with goserelin and tamoxifen in patients with advanced chemotherapy resistant ovarian cancer. The purpose of this study was to determine the response in patients with recurrent, chemotherapy-resistant ovarian cancer to a combination of the LHRH-analog goserelin and tamoxifen. ### Patients And Methods Twenty-five patients with recurrent, chemotherapy resistant ovarian cancer received a combination of goserelin and tamoxifen until clinical or serological evidence of progression as measured by serum CA-125 levels. Suppression of LH, FSH and prolactin levels in this group were compared with a second group of ten patients treated with decapeptyl for the same indication. ### results The combination was well tolerated. The median progression free survival amounted to five (range 2-96+) months and overall survival to eight (range 3-96+) months. One of the responding patients is still alive without progression at 8 years. With this combination the median levels of LH and FSH were markedly suppressed, to respectively 2.6% and 3.7% of baseline values. With decapeptyl the LH levels were also suppressed, but the resulting FSH levels were significantly higher. PA combination of goserelin and tamoxifen in patients with relapsed ovarian cancer can not be recommended as standard therapy , but may result in long-term survival in individual patients .", "source": "https://pubmed.ncbi.nlm.nih.gov/10629663/"}
{"doc_id": "7385613d0a7b2b60cf472517e778e6d6", "sentence": "In previous analyses of the MURANO study , fixed-duration venetoclax plus rituximab ( VenR ) resulted in improved progression-free survival ( PFS ) compared with bendamustine plus rituximab ( BR ) in patients with relapsed or refractory chronic lymphocytic leukemia ( CLL ) .", "spans": [{"span_id": 0, "text": "venetoclax", "start": 58, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "rituximab", "start": 74, "end": 83, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "bendamustine", "start": 162, "end": 174, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "rituximab", "start": 180, "end": 189, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study.  In previous analyses of the MURANO study , fixed-duration venetoclax plus rituximab ( VenR ) resulted in improved progression-free survival ( PFS ) compared with bendamustine plus rituximab ( BR ) in patients with relapsed or refractory chronic lymphocytic leukemia ( CLL ) . At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. ### Patients And Methods Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. ### results Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( ### conclusion Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.", "source": "https://pubmed.ncbi.nlm.nih.gov/32986498/"}
{"doc_id": "9c4c2f5c9efc3983bbdf6e974ac0c8cf", "sentence": "The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats .", "spans": [{"span_id": 0, "text": "atorvastatin", "start": 71, "end": 83, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "amlodipine", "start": 88, "end": 98, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination therapy of atorvastatin and amlodipine inhibits sympathetic nervous system activation and improves cognitive function in hypertensive rats. A previous study has demonstrated that orally administered atorvastatin reduces sympathetic nervous system (SNS) activation via an anti-oxidant in the rostral ventrolateral medulla (RVLM) of hypertensive rats, whereas amlodipine did not. Furthermore, several previous reports have suggested that atorvastatin or amlodipine improves cognitive dysfunction during hypertension. The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats . ### Methods And Results Stroke-prone spontaneously hypertensive rats (SHRSPs), as a hypertensive model with sympathoexcitation, were divided into 4 groups; a combination of atorvastatin and amlodipine-treated (COM), atorvastatin-treated (ATR), amlodipine-treated (AML), hydralazine-treated (HYD), and vehicle-treated SHRSPs (VEH). After treatment for 28 days, the mean blood pressure did not change in ATR rats, and was reduced to the similar levels in COM, AML, and HYD rats. However, SNS activation and oxidative stress in the RVLM were significantly lower only in COM than in ATR, AML, HYD, and VEH rats. Cognitive performance and manganese-superoxide dismutase activity in the hippocampus were significantly higher, and oxidative stress in the hippocampus was significantly lower in COM than in VEH, AML, and HYD rats to a greater extent than in ATR rats. ### conclusions A combination of atorvastatin and amlodipine causes sympathoinhibition via an anti-oxidant in the RVLM and improves cognitive dysfunction via an anti-oxidant in the hippocampus in hypertensive rats, independent of the blood pressure-lowering effect.", "source": "https://pubmed.ncbi.nlm.nih.gov/22664571/"}
{"doc_id": "afcdd9616aa1ce5039d88e604c970fc4", "sentence": "Active treatment consisted of hydrochlorothiazide ( 25 - 50 mg/day ) plus triamterene ( 50 - 100 mg/day ) with the addition of alpha-methyldopa ( 0.5 - 2.0 g/day ) in one-third of the patients .", "spans": [{"span_id": 0, "text": "hydrochlorothiazide", "start": 30, "end": 49, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "triamterene", "start": 74, "end": 85, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "alpha-methyldopa", "start": 127, "end": 143, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Is a high serum cholesterol level associated with longer survival in elderly hypertensives? The relationship between serum total cholesterol, measured at randomization, and mortality was investigated in 822 patients, who were followed for an average of 3.1 years in a double-blind trial, conducted by the European Working Party on High Blood Pressure in the Elderly. Serum cholesterol, measured at randomization, was 0.54 mmol/l higher in women than in men, and declined with increasing age in both men (0.028 mmol/l per year) and women (0.036 mmol/l per year). During follow-up on randomized treatment, cholesterol fell by a similar amount with placebo (0.11 mmol/l per year) and with active treatment (0.14 mmol/l per year). Active treatment consisted of hydrochlorothiazide ( 25 - 50 mg/day ) plus triamterene ( 50 - 100 mg/day ) with the addition of alpha-methyldopa ( 0.5 - 2.0 g/day ) in one-third of the patients . Serum total cholesterol, measured at randomization, was independently and inversely correlated with total (P = 0.03), non-cardiovascular (P = 0.03) and cancer (P = 0.04) mortality during follow-up on double-blind treatment. Total and non-cardiovascular mortality were also negatively correlated with haemoglobin and body weight at randomization.", "source": "https://pubmed.ncbi.nlm.nih.gov/2170516/"}
{"doc_id": "0f2ad9e7460bb0d985ca9e8945d14421", "sentence": "Eight days treatment with 15 \u03bcM clozapine increased adipogenesis by 37.4 % and 50 \u03bcM risperidone increased adipogenesis by 26.5 % during 3T3-L1 cell differentiation accompanied by increased SREBP-1 , PPAR\u03b3 , C/EBP\u03b1 , LDLR and Adiponectin gene expression .", "spans": [{"span_id": 0, "text": "clozapine", "start": 32, "end": 41, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "risperidone", "start": 85, "end": 96, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Berberine inhibits SREBP-1-related clozapine and risperidone induced adipogenesis in 3T3-L1 cells. Weight gain is a common and potentially serious complication associated with the treatment of second generation antipsychotics such as clozapine and risperidone. Increased peripheral adipogenesis via the SREBP-1 pathway could be one critical mechanism responsible for antipsychotic drug-induced weight gain. berberine, a botanical alkaloid, has been shown in our previous studies to inhibit adipogenesis in cell and animal models. MTT was used to determine the cytotoxic effects of clozapine and risperidone in combination with berberine. Differentiation of 3T3-L1 cells was monitored by Oil-Red-O staining and the expression of SREBP-1 and related proteins was determined by real-time RT-PCR and western blotting. The results showed that neither clozapine nor risperidone, alone or in combination with berberine had significant effects on cell viability. Eight days treatment with 15 \u03bcM clozapine increased adipogenesis by 37.4 % and 50 \u03bcM risperidone increased adipogenesis by 26.5 % during 3T3-L1 cell differentiation accompanied by increased SREBP-1 , PPAR\u03b3 , C/EBP\u03b1 , LDLR and Adiponectin gene expression . More importantly, the addition of 8\u2009\u03bcM berberine diminished the induction of adipogenesis almost completely accompanied by down-regulated mRNA and protein expression levels of SREBP-1-related proteins. These encouraging results may lead to the use of berberine as an adjuvant to prevent weight gain during second generation antipsychotic medication.", "source": "https://pubmed.ncbi.nlm.nih.gov/20564506/"}
{"doc_id": "11b193003411ca34e04b6ed68cb26b97", "sentence": "It is predicted that patients suffering from both VL and cardiac disorders ( atrial fibrillation ) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome .", "spans": [{"span_id": 0, "text": "warfarin", "start": 136, "end": 144, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "miltefosine", "start": 210, "end": 221, "token_start": 32, "token_end": 33}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Analysis of sequence, structure of GAPDH of Leishmania donovani and its interactions. Drug resistance acquired by Leishmania donovani (Ldv) is a major problem in the treatment and control of visceral leishmaniasis (VL). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a major glycolytic enzyme has been targeted as is found in other protozoan which cause diseases like sleeping sickness. GAPDH gene of Ldv (AG83 strain) was amplified, sequenced, and modeled on the basis of crystal structure of Leishmania mexicana. The model of the Ldv GAPDH exhibited NAD-binding domain with Rossmann folding. Virtual screening of different experimentally proved compounds with the crystal and the modeled structures of GAPDH of Leishmania strains revealed diverse binding affinities of different compounds. Comparison of binding affinities (based on different programs) of compounds revealed that discovery studio v2.5 (Ligandfit) was able to predict the most hit compounds, the best hit compounds against GAPDH of Leishmania strains are hydrazine, vetrazine, and benzyl carbazate. It is predicted that patients suffering from both VL and cardiac disorders ( atrial fibrillation ) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome .", "source": "https://pubmed.ncbi.nlm.nih.gov/22830998/"}
{"doc_id": "8cc0b55cf48eb3e5e082a769a6810117", "sentence": "If concomitant therapy is absolutely necessary , the dose of digoxin should be halved prior to initiating dronedarone .", "spans": [{"span_id": 0, "text": "digoxin", "start": 61, "end": 68, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "dronedarone", "start": 106, "end": 117, "token_start": 17, "token_end": 18}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Chronic Digoxin Toxicity Precipitated by Dronedarone. To report the case of a patient who presented with chronic symptoms attributable to dronedarone-induced digoxin toxicity. A review of the literature is also provided. ### Case Summary This case report details a case of a 77-year-old male patient who presented to the hospital with multiple ambiguous symptoms that lasted several weeks. The patient was later hospitalized for symptoms of chronic digoxin toxicity, including prolonged nausea, diarrhea, weakness, and lack of appetite. The patient had a long history of digoxin use for control of his atrial fibrillation but experienced signs and symptoms of toxicity only after the addition of dronedarone. ### discussion Both the Naranjo and Drug Interaction Probability Scales indicated a \"probable\" relationship between the development of digoxin toxicity and dronedarone. Due to a p-glycoprotein-mediated interaction, dronedarone is able to decrease the renal clearance of digoxin, thus putting patients at risk for potentially fatal digoxin toxicity. ### conclusion This is the second case report detailing dronedarone-induced digoxin toxicity and the first to focus on chronic digoxin toxicity. The presentation, possible causes, and drug-drug interactions associated with digoxin toxicity are described. This report aims to increase clinicians' awareness of this possible complication. It is recommended that digoxin be discontinued prior to initiating dronedarone. If concomitant therapy is absolutely necessary , the dose of digoxin should be halved prior to initiating dronedarone . digoxin plasma levels should be monitored closely, with frequent patient evaluation for signs and symptoms of digoxin toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/24687541/"}
{"doc_id": "6ef05076decf475feae87638cf32e457", "sentence": "Stable isotope labelling by amino acids in cell culture ( SILAC ) coupled to high-resolution mass spectrometry ( MS ) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 218, "end": 229, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "etoposide", "start": 233, "end": 242, "token_start": 37, "token_end": 38}], "rels": [], "paragraph": "Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer. Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture ( SILAC ) coupled to high-resolution mass spectrometry ( MS ) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide . The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/26022350/"}
{"doc_id": "d4e201d429bd505cd797e095cf81cb5c", "sentence": "All patients received neoadjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil , or cyclophosphamide , doxorubicin , vincristine , and prednisone .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 52, "end": 68, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "doxorubicin", "start": 71, "end": 82, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "fluorouracil", "start": 89, "end": 101, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "cyclophosphamide", "start": 107, "end": 123, "token_start": 14, "token_end": 15}, {"span_id": 4, "text": "doxorubicin", "start": 126, "end": 137, "token_start": 16, "token_end": 17}, {"span_id": 5, "text": "vincristine", "start": 140, "end": 151, "token_start": 18, "token_end": 19}, {"span_id": 6, "text": "prednisone", "start": 158, "end": 168, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "POS", "spans": [3, 4, 5, 6], "is_context_needed": true}], "paragraph": "Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. To determine outcomes in local-regional control, disease-free survival, and overall survival in patients with locally advanced breast cancer (LABC) who present with ipsilateral supraclavicular metastases and who are treated with combined-modality therapy. ### Patients And Methods Seventy patients with regional stage IV LABC, which is defined by our institution as LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease, received treatment on three prospective trials of neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy with cyclophosphamide , doxorubicin , and fluorouracil , or cyclophosphamide , doxorubicin , vincristine , and prednisone . Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection (ALND) or segmental mastectomy and ALND before or after irradiation. Patients with no response to neoadjuvant chemotherapy were treated with surgery and/or radiotherapy. After completion of local therapy, chemotherapy was continued for four to 15 cycles, followed by radiotherapy. Patients older than 50 years who had estrogen receptor-positive tumors received tamoxifen for 5 years. ### results Median follow-up was 11.6 years (range, 4.8 to 22.6 years). Disease-free survival rates at 5 and 10 years were 34% and 32%, respectively. The median disease-free survival was 1.9 years. Overall survival rates at 5 and 10 years were 41% and 31%, respectively. The median overall survival was 3.5 years. The overall response rate (partial and complete responses) to induction chemotherapy was 89%. No treatment-related deaths occurred. ### conclusion Patients with ipsilateral supraclavicular metastases but no other evidence of distant metastases warrant therapy administered with curative intent, ie, combined-modality therapy consisting of chemotherapy, surgery, and radiotherapy. Patients with ipsilateral supraclavicular metastases should be included in the stage IIIB category of the tumor-node-metastasis classification because their clinical course and prognosis are similar to those of patients with stage IIIB LABC.", "source": "https://pubmed.ncbi.nlm.nih.gov/11157012/"}
{"doc_id": "910846208d0afa4265c6666870b32a77", "sentence": "Chemotherapy consisted of ( 1 ) fluorouracil ( 5-FU ) , ( 2 ) 5-FU variations , ( 3 ) 5-FU plus oxaliplatin , ( 4 ) 5-FU plus irinotecan , or ( 5 ) oral fluoropyrimidine-based regimens .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 32, "end": 44, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "oxaliplatin", "start": 96, "end": 107, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "irinotecan", "start": 126, "end": 136, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "The predictive and prognostic value of sex in early-stage colon cancer: a pooled analysis of 33,345 patients from the ACCENT database. To compare long-term outcomes between men and women in a large cohort of clinical trial participants with early-stage colon cancer, specifically by examining whether the prognostic effect of sex varies based on age, stage of disease, and type of adjuvant therapy received. ### methods A pooled analysis of individual patient data from 33,345 patients with colon cancer enrolled in 24 phase III studies of various adjuvant systemic therapies was conducted. Chemotherapy consisted of ( 1 ) fluorouracil ( 5-FU ) , ( 2 ) 5-FU variations , ( 3 ) 5-FU plus oxaliplatin , ( 4 ) 5-FU plus irinotecan , or ( 5 ) oral fluoropyrimidine-based regimens . The primary endpoint was disease-free survival; secondary endpoints included overall survival and time to recurrence. Stratified Cox models were used to assess the effect of sex on outcomes. Multivariate models were used to assess adjusted effects and to explore the interaction among sex and other factors. ### results A total of 18,244 (55%) men and 15,101 (45%) women were included. In the entire cohort, the median age was 61 years; 91% (24,868) were white; 31% (10,347) and 69% (22,964) had stage I/II and III disease, respectively. Overall, men had inferior prognoses when compared with women for time to recurrence (hazard ratio [HR] 1.05 [95% CI, 1.01-1.09]) and other endpoints after adjusting for age, stage, and treatment. Sex was not a predictive factor of treatment efficacy (P for interaction between sex and treatment when adjusting for age and stage were .40, .67, and .77 for disease-free survival, overall survival, and time to recurrence, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older patients when adjusting for stage and treatment (HR 1.08 in age \u2264 65 years vs. HR 1.18 in age > 65 years; interaction P = .016 for disease-free survival). The stage of disease and type of adjuvant regimen did not modify the prognostic value of sex. ### conclusions Sex is a modest independent prognostic marker for patients with early-stage colon cancer, particularly in older patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/23810482/"}
{"doc_id": "29c3333193035b03fd398adb1e27f8b0", "sentence": "To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile , including lipoprotein(a ) levels , and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia ( serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl , respectively , and serum triglyceride level > 200 mg/dl ) .", "spans": [{"span_id": 0, "text": "fenofibrate", "start": 53, "end": 64, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "atorvastatin", "start": 69, "end": 81, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia.  To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile , including lipoprotein(a ) levels , and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia ( serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl , respectively , and serum triglyceride level > 200 mg/dl ) . ### methods This was a 16-week, open-label, parallel-design study conducted in our lipid clinic. After a 6-week dietary baseline phase, we implemented a treatment phase, during which patients received 10 mg/day atorvastatin (n = 45) or 200 mg/day micronized fenofibrate (n = 46) for 16 weeks. Patients were assigned to one of the drugs in sequential orders. Serum lipid profiles, including levels of lipoprotein(a) and fibrinogen, as well as muscle and liver enzymes, were measured during screening, and during weeks -4, -2, 0, 8, and 16 of the treatment period. ### results atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol, whereas fenofibrate was more effective at lowering levels of triglycerides, and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1. However, micronized fenofibrate could significantly decrease plasma fibrinogen levels, whereas atorvastatin evoked a small increase. ### conclusion Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia. However, there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels.", "source": "https://pubmed.ncbi.nlm.nih.gov/10353071/"}
{"doc_id": "e4a6ef4ca14cebe5c45a8d9177702e13", "sentence": "Comparison of brimonidine with latanoprost in the adjunctive treatment of glaucoma . ALPHAGAN/XALATAN Study Group .", "spans": [{"span_id": 0, "text": "brimonidine", "start": 14, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "latanoprost", "start": 31, "end": 42, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Comparison of brimonidine with latanoprost in the adjunctive treatment of glaucoma . ALPHAGAN/XALATAN Study Group . This study compared brimonidine with latanoprost as adjunctive therapy for the treatment of open-angle glaucoma and ocular hypertension. ### background Patients with open-angle glaucoma or ocular hypertension often require >1 medication to achieve control of intraocular pressure (IOP). Both brimonidine and latanoprost effectively lower IOP, but no previously reported clinical trials have directly compared these agents as adjunctive therapy. ### methods This was a prospective, randomized, investigator-masked, multicenter, parallel-design clinical trial. Forty patients (69 study eyes) with uncontrolled IOP of < or =34 mm Hg while using a topical beta-blocker plus dorzolamide or pilocarpine were randomly assigned to receive either brimonidine 0.2% BID or latanoprost 0.005% QD over 6 months as adjunctive therapy. Tolerability was assessed by reports of adverse events, and efficacy was determined by reduction in IOP from baseline. Clinical success was defined as the achievement of a > or =15% reduction in IOP from baseline. ### results There were no significant between-group differences in any demographic variable. Most patients in each group were white, had open-angle glaucoma, and were being treated with a nonselective beta-blocker and dorzolamide. When brimonidine or latanoprost was used as an adjunctive agent with a beta-blocker and dorzolamide or pilocarpine, the rates of clinical success at month 1 were 85% (17/20 patients) with brimonidine versus 65% (13/20 patients) with latanoprost (P = 0.144). Overall mean IOP reduction at month 1 was 4.60+/-0.62 mm Hg (22.8%; P < 0.001) with brimonidine and 3.43+/-0.62 mm Hg (17.2%; P < 0.001) with latanoprost, with no significant differences between groups (P = 0.219). Among the patients with an inadequate IOP-lowering response (<15% reduction from baseline), the mean IOP reduction was 0.36+/-0.66 mm Hg with latanoprost (n = 7) and 0.50+/-2.18 mm Hg with brimonidine (n = 3). brimonidine and latanoprost had comparable IOP-lowering efficacy in patients receiving concomitant pilocarpine therapy (mean change in IOP of -4.23 mm Hg vs -3.75 mm Hg, P = 0.173). In patients concurrently treated with dorzolamide, brimonidine produced a mean change in IOP of -5.29 mm Hg, compared with a mean change of -3.21 mm Hg in the latanoprost group (P = 0.159). Both brimonidine and latanoprost were well tolerated. Few adverse events leading to discontinuation were observed with either drug regimen (n = 2 with brimonidine; n = 0 with latanoprost). ### conclusions Both brimonidine 0.2% BID and latanoprost 0.005% QD were well-tolerated and reduced IOP in most patients when used as third-line adjunctive therapy. However, clinical success was achieved by 17 of 20 patients (85%) who received brimonidine, compared with 13 of 20 patients (65%) who received latanoprost (P = 0.144). These results suggest that brimonidine 0.2% BID may be more reliable than latanoprost 0.005% QD as adjunctive therapy for glaucoma and ocular hypertension.", "source": "https://pubmed.ncbi.nlm.nih.gov/10823361/"}
{"doc_id": "303f2c71e88e108784acc3cd4ce0255c", "sentence": "Pretreatment with inhaled N(2)O can reduce the pain associated with propofol and rocuronium injection .", "spans": [{"span_id": 0, "text": "propofol", "start": 68, "end": 76, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "rocuronium", "start": 81, "end": 91, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Effect of nitrous oxide inhalation on pain after propofol and rocuronium injection. This prospective, double-blind, placebo-controlled study was designed to determine the efficacy of nitrous oxide (N(2)O) in alleviating the pain that followed sequential injection of propofol and rocuronium. ### methods A total of 205 adult patients (age, 18-68 years) received one of the following combinations: NaCl and 100 % O(2) (group C); 0.5 mg/kg lidocaine and 100 % O(2) (group L); NaCl and a mixture of 67 % N(2)O/O(2) (group N); or 0.5 mg/kg lidocaine and a mixture of 67 % N(2)O/O(2) (group LN). Vein occlusion was released after 1 min, and 5 ml propofol was injected over 10 s. Pain was evaluated on a visually enlarged, laminated, numeric rating (0-10) scale. The remainder of the induction dose of propofol (with a 3-ml bolus of normal saline and 0.6 mg/kg rocuronium) was then injected. The response to the rocuronium injection was assessed with a four-point scale (0-3). ### results The incidence and severity of pain from the propofol injection in groups L, N, and LN were significantly lower than those in group C (P < 0.001). Frequency and intensity of the withdrawal response were significantly less in groups N and LN than in groups C and L (no response, P < 0.001; severe response, P < 0.001). ### conclusions Pretreatment with inhaled N(2)O can reduce the pain associated with propofol and rocuronium injection . Moreover, N(2)O (with or without lidocaine) is more effective than lidocaine alone in reducing rocuronium-related withdrawal reactions associated with sequential injection of propofol and rocuronium.", "source": "https://pubmed.ncbi.nlm.nih.gov/23982855/"}
{"doc_id": "ee8733c65a403048ff5bcc9f2ac1b28b", "sentence": "To further these observations , we discovered that the bromodomain PHD finger transcription factor subunit ( BPTF ) of the nucleosome remodeling factor ( NURF ) promotes resistance to doxorubicin , etoposide and paclitaxel in the 4T1 breast tumor cell line .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 184, "end": 195, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "etoposide", "start": 198, "end": 207, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "paclitaxel", "start": 212, "end": 222, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Autophagy Dependent Sensitization of Triple Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor. Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations , we discovered that the bromodomain PHD finger transcription factor subunit ( BPTF ) of the nucleosome remodeling factor ( NURF ) promotes resistance to doxorubicin , etoposide and paclitaxel in the 4T1 breast tumor cell line . BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (Top2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacological inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231 but not ER positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased Top2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of Top2 poisons, preventing the resolution of Top2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small molecule inhibitors to enhance the effectiveness of Top2-targeted cancer chemotherapeutic drugs. Implications: These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.", "source": "https://pubmed.ncbi.nlm.nih.gov/33811160/"}
{"doc_id": "ea2e6eff96dd615782bafae123dd6423", "sentence": "We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens : CBV ( cyclophosphamide , carmustine and etoposide ; n = 16 ) , BEAM ( carmustine , etoposide , cytarabine and melphalan ; n = 36 ) and BEAC ( carmustine , etoposide , cytarabine and cyclophosphamide ; n = 77 ) .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 123, "end": 139, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "carmustine", "start": 142, "end": 152, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "etoposide", "start": 157, "end": 166, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "carmustine", "start": 187, "end": 197, "token_start": 34, "token_end": 35}, {"span_id": 4, "text": "etoposide", "start": 200, "end": 209, "token_start": 36, "token_end": 37}, {"span_id": 5, "text": "cytarabine", "start": 212, "end": 222, "token_start": 38, "token_end": 39}, {"span_id": 6, "text": "melphalan", "start": 227, "end": 236, "token_start": 40, "token_end": 41}, {"span_id": 7, "text": "carmustine", "start": 259, "end": 269, "token_start": 49, "token_end": 50}, {"span_id": 8, "text": "etoposide", "start": 272, "end": 281, "token_start": 51, "token_end": 52}, {"span_id": 9, "text": "cytarabine", "start": 284, "end": 294, "token_start": 53, "token_end": 54}, {"span_id": 10, "text": "cyclophosphamide", "start": 299, "end": 315, "token_start": 55, "token_end": 56}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "POS", "spans": [3, 4, 5, 6], "is_context_needed": true}, {"class": "POS", "spans": [8, 9, 10, 7], "is_context_needed": true}], "paragraph": "Comparison of CBV, BEAM and BEAC high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non-Hodgkin lymphoma: Efficacy and toxicity. Limited data are available to guide the choice of conditioning regimen before autologous hematopoietic stem cell transplantation (AHSCT) for patients with lymphoma. ### methods We analyzed 129 non-Hodgkin lymphoma patients who underwent AHSCT from 1996 to 2013 using the most common regimens : CBV ( cyclophosphamide , carmustine and etoposide ; n = 16 ) , BEAM ( carmustine , etoposide , cytarabine and melphalan ; n = 36 ) and BEAC ( carmustine , etoposide , cytarabine and cyclophosphamide ; n = 77 ) . ### results At a median follow-up of 42.5 months, the estimated 5-year overall survival for the CBV, BEAM and BEAC groups was 68.8%, 77.8% and 81.8%, respectively (P = 0.584). The estimated 5-year progression-free survival in the CBV group (43.8%) was relatively inferior to the BEAM (66.7%) and BEAC (67.5%) groups, but the differences were not significant (P = 0.403). Grade 2 or higher mucositis, diarrhea and fever were relatively more common in the BEAM group (P < 0.05). No differences were observed in the time to hematopoietic recovery and the duration of hospitalization. The amount of transfused platelet was significantly less in the CBV. ### conclusion CBV, BEAM and BEAC regimens are all optional high-dose chemotherapy before AHSCT for NHL patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/28101911/"}
{"doc_id": "5113a643f92fbbea92632b15fc9e50a1", "sentence": "Early Prostate-Specific Antigen ( PSA ) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer .", "spans": [{"span_id": 0, "text": "Abiraterone", "start": 95, "end": 106, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "Enzalutamide", "start": 111, "end": 123, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Early Prostate-Specific Antigen ( PSA ) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer . The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC \u2264 12 months and Eastern Cooperative Oncology Group Performance Status \u2265 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks-particularly in patients with a modest effect of ADT and poor performance status.", "source": "https://pubmed.ncbi.nlm.nih.gov/33573172/"}
{"doc_id": "bbc050f999f763343619808bea2a3824", "sentence": "Several chemotherapy drugs are active in SCCHN , most notably the platinum compounds , taxanes , fluorouracil ( 5-FU ) , methotrexate and cetuximab .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 97, "end": 109, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "methotrexate", "start": 121, "end": 133, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "cetuximab", "start": 138, "end": 147, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Management of recurrent head and neck cancer: recent progress and future directions. The incidence of squamous cell carcinoma of the head and neck (SCCHN) is on the rise in the US despite a drop in cigarette smoking rates. Much of this rise is due to the increasing incidence of SCCHN attributable to human papillomavirus (HPV). HPV-related SCCHN has a high cure rate, which contributes to the stable death rates despite the increased incidence. Up to half of patients with SCCHN will develop recurrence. For these patients, the first clinical decision is whether the recurrence is potentially treatable for cure, or is incurable. For those deemed potentially curable, surgical or radiation-based therapies, or both, are undertaken. For those who have incurable recurrences, the goals are palliation and possibly prolongation of life - average survivals are in the range of 6-12 months depending on the type of recurrence and other factors. Several chemotherapy drugs are active in SCCHN , most notably the platinum compounds , taxanes , fluorouracil ( 5-FU ) , methotrexate and cetuximab . Approximately 10-25% of patients will respond to treatment with one of these drugs. The response rate is higher for combinations such as a platinum plus a taxane, a platinum plus 5-FU, a combination of the three, or one of more of these drugs plus cetuximab. Combination chemotherapy has not been shown to prolong survival over single-agent therapy, with the exception of the addition of cetuximab to a platinum and 5-FU combination. A number of orally bioavailable tyrosine kinase inhibitors have been tested or are undergoing trials in SCCHN. None of these has as yet been shown to be more effective than the currently available drugs. For patients with recurrences who are undergoing active therapy, and especially for those for whom further therapy is no longer appropriate or is declined, strict attention is necessary to palliation of pain, oral and airway issues, and to nutrition, speech, and social and psychological issues.", "source": "https://pubmed.ncbi.nlm.nih.gov/21861540/"}
{"doc_id": "b49696c4425245043d701994c68666a9", "sentence": "Dexamethasone , cytarabine , ifosfamide , and cisplatin as salvage therapy in non-Hodgkin lymphoma .", "spans": [{"span_id": 0, "text": "Dexamethasone", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cytarabine", "start": 16, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "ifosfamide", "start": 29, "end": 39, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "cisplatin", "start": 46, "end": 55, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Dexamethasone , cytarabine , ifosfamide , and cisplatin as salvage therapy in non-Hodgkin lymphoma . The authors conducted a phase II study to evaluate a new combination of chemotherapeutic drugs that includes dexamethasone, cytarabine, ifosfamide, and cisplatin as salvage therapy in non-Hodgkin lymphoma after prior exposure to both adriamycin and etoposide. All drugs were administered intravenously over 4 consecutive days. The daily dose of dexamethasone was 20 mg twice daily. The maximal daily doses of cytarabine, ifosfamide, and cisplatin were 75 mg/m2, 1,200 mg/m2, and 20 mg/m2, respectively. Cycles were repeated every 3 weeks. A total of 31 patients were entered in the trial. Thirty patients were evaluable for response. A complete response was seen in 11 patients (37%), and a partial response was noted in six patients (20%). A significantly higher complete response rate was seen in patients with relapsing non-Hodgkin lymphoma compared with those who failed to achieve a complete response with the last chemotherapy (10/14 vs. 1/16; p < 0.013). A complete response continues in two patients who received consolidation with high-dose chemotherapy for more than 49 months and more than 60 months for each patient. Median time to treatment failure and median survival were 3.3 months and 7.5 months, respectively, for the entire group and 11 months and 30 months, respectively, for complete responders. Myelosuppression was pronounced but was usually of short duration. Neutropenic fever developed in 13 patients (42%) and in 15 of 96 cycles (16%). Platelet transfusions were required in seven patients (23%). There was one drug-related death associated with myelotoxicity. Nonhematologic toxicity was not dose limiting. The authors conclude that dexamethasone, cytarabine, ifosfamide, and cisplatin is active and a relatively tolerable regime for patients with non-Hodgkin lymphoma previously treated with adriamycin and etoposide.", "source": "https://pubmed.ncbi.nlm.nih.gov/10025380/"}
{"doc_id": "f42c0f1b9c9ec6d9b76b4adbc90ce6b9", "sentence": "Cost-effectiveness of ribociclib plus letrozole", "spans": [{"span_id": 0, "text": "ribociclib", "start": 22, "end": 32, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "letrozole", "start": 38, "end": 47, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Cost-effectiveness of ribociclib plus letrozole The global burden of breast cancer (BC) is high, especially in advanced stages. CDK 4/6 inhibitors represent a paradigm shift in the treatment of advanced BC HR+/HER2-, given the clinically and statistically significant gain in overall survival associated with this new class of medications. Nevertheless, as an innovation, the incorporation of these drugs impacts healthcare budgets, requiring cost-effectiveness analyses for decision-making. The aim of this study was to evaluate the cost-effectiveness of ribociclib plus letrozole compared with palbociclib plus letrozole or letrozole as monotherapy for first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic BC (aBC) from a Brazilian private healthcare system perspective. ### methods A model including progression-free survival (PFS), progressed disease, and death health states was used to simulate lifetime costs and outcomes. PFS and overall survival were derived from the MONALEESA-2 trial (lifetime horizon). Healthcare costs included drug acquisition and monitoring, subsequent therapies, adverse events, and end-of-life costs. Effectiveness was measured in quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were performed. ### results The total cost of treatment with ribociclib plus letrozole was USD 72,091.82 ### conclusions As demonstrated by the cost-effectiveness dominance over palbociclib, ribociclib results in savings when used as first-line treatment in postmenopausal women with HR+/HER2- aBC, warranting incorporation in the private healthcare system.", "source": "https://pubmed.ncbi.nlm.nih.gov/33948121/"}
{"doc_id": "76d6e9b5067c942e1d7906a02971927e", "sentence": "We investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1 .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 24, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "gemcitabine", "start": 39, "end": 50, "token_start": 5, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "In vitro effects of lapatinib with gemcitabine for pancreatic cancer cells.  We investigated whether lapatinib plus gemcitabine has synergistic or antagonistic effects on the pancreatic cancer cell lines MiaPaca-2 and PANC-1 . Furthermore, the changes of gemcitabine sensitivity-related genes by lapatinib treatment were examined. ### methodology The effects of lapatinib, gemcitabine, and combined treatment with both agents on cell viability were examined by methyl thiazolyl tetrazolium analysis. Synergy between lapatinib and gemcitabine was assessed by median effect analysis. The mRNA amounts of human equilibrative nucleoside transporter (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit M1 (RRM1) genes were measured by quantitative real-time polymerase chain reaction in cells exposed to lapatinib for 48 h, as compared with untreated cells. ### results No synergistic effects were observed with combined treatment in either cell line. In contrast, antagonistic effects occurred on MiaPaca-2 cells with the two agents. Specific changes in gemcitabine sensitivity-related genes induced by lapatinib were not detected in either MiaPaca-2 or PANC-1. ### conclusions lapatinib may not enhance the anti-tumor effects of gemcitabine for pancreatic cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/23933942/"}
{"doc_id": "7026e25992d70427b64362230b605bb3", "sentence": "Gal(beta1 - 3)Galbeta1-methyl ( disaccharide ) and GalNAc(beta1 - 4)GlcA(beta1 - 3)GalNAc(beta1 - 4 ) GlcA(beta1 - 3)GalNAc(pentasaccharide ) were used respectively as acceptors of [14C]GlcA from UDP-[14C]GlcA. Distributions of the two GlcA transferase activities in the sucrose-density-gradient fractions were compared with each other and with the previously reported distribution of the activities of Gal transferases ( UDP-Gal to ovalbumin , and to xylose of the proteochondroitin linkage region ) and GalNAc ( N-acetylgalactosamine ) transferase II of chondroitin polymerization .", "spans": [{"span_id": 0, "text": "xylose", "start": 452, "end": 458, "token_start": 63, "token_end": 64}, {"span_id": 1, "text": "chondroitin", "start": 556, "end": 567, "token_start": 78, "token_end": 79}], "rels": [], "paragraph": "Subcellular co-localization and potential interaction of glucuronosyltransferases with nascent proteochondroitin sulphate at Golgi sites of chondroitin synthesis. Microsomal membranes from chick embryo epiphyseal cartilage were fractionated by equilibrium sucrose-density-gradient centrifugation and assayed for GlcA (glucuronic acid) transferase I (the enzyme that transfers GlcA from UDP-GlcA to Gal-Gal-Xyl of proteochondroitin linkage region), for comparison with GlcA transferase II (the GlcA transferase of chondroitin polymerization). Gal(beta1 - 3)Galbeta1-methyl ( disaccharide ) and GalNAc(beta1 - 4)GlcA(beta1 - 3)GalNAc(beta1 - 4 ) GlcA(beta1 - 3)GalNAc(pentasaccharide ) were used respectively as acceptors of [14C]GlcA from UDP-[14C]GlcA. Distributions of the two GlcA transferase activities in the sucrose-density-gradient fractions were compared with each other and with the previously reported distribution of the activities of Gal transferases ( UDP-Gal to ovalbumin , and to xylose of the proteochondroitin linkage region ) and GalNAc ( N-acetylgalactosamine ) transferase II of chondroitin polymerization . The linkage-region GlcA transferase I had a dual Golgi distribution similar to that of chondroitin-polymerizing GlcA transferase II and distinctly different from the distribution of linkage-region Gal transferases I and II, which were found exclusively in the heavier fractions. Solubilized GlcA transferase I was partly purified by sequential use of Q-Sepharose, heparin-Sepharose and wheatgerm agglutinin-agarose and was accompanied at each step by some of the GlcA transferase II activity. Both GlcA transferase I and II bound to the Q-Sepharose as though they were highly anionic. However, treatment with chondroitin ABC lyase eliminated the binding while markedly decreasing enzyme stability. The enzyme activities could not be reconstituted by adding chondroitin or chondroitin pentasaccharide to the chondroitin ABC lyase-treated enzymes. Incubation of the partly purified enzymes with both UDP-GlcA and UDP-GalNAc resulted in a 40-fold greater incorporation than with just one sugar nucleotide, indicating the presence of bound, nascent proteochondroitin serving as the acceptor for chondroitin polymerization. These results, together with the membrane co-localization, indicate that GlcA transferase I and GlcA transferase II occur closely together with nascent proteochondroitin at the site of synthesis and that this complex with the nascent proteochondroitin stabilizes both enzymes during purification.", "source": "https://pubmed.ncbi.nlm.nih.gov/9405295/"}
{"doc_id": "6d427c9e01e1e8a4826839198fa2af7f", "sentence": "No significant changes of endothelium-independent dilation were observed with both drugs ( from 17.10+/-2.4 % to 18.14+/-3.76 % and from 18.73+/-4.07 % to 17.46+/-4.27 % during nifedipine and hydrochlorothiazide , respectively , NS ) .", "spans": [{"span_id": 0, "text": "nifedipine", "start": 177, "end": 187, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "hydrochlorothiazide", "start": 192, "end": 211, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension. off aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 microg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1+/-3% at baseline to 6.5+/-4.5% at 6 months and to 8.12+/-4. 6% at 12 months; P<0.001 by ANOVA), concomitant with blood pressure reduction (from 162+/-24/102+/-13 mm Hg to 141+/-12/89+/-6 mm Hg and to 141+/-9/89+/-6 mm Hg; P<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2+/-4.8 at baseline to 15.5+/-4.7 at 6 months and 16.8+/-5.9% at 12 months; P=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5+/-6.18% at baseline to 9. 45+/-3.94%, P<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15+/-5.28% at baseline to 4.69+/-4.34%, NS). No significant changes of endothelium-independent dilation were observed with both drugs ( from 17.10+/-2.4 % to 18.14+/-3.76 % and from 18.73+/-4.07 % to 17.46+/-4.27 % during nifedipine and hydrochlorothiazide , respectively , NS ) . Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.", "source": "https://pubmed.ncbi.nlm.nih.gov/9931168/"}
{"doc_id": "7a76285b62b9c23acaeb7d96cf4c1b8d", "sentence": "The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable , but the clinical activity was not sufficient to warrant further testing .", "spans": [{"span_id": 0, "text": "pantoprazole", "start": 69, "end": 81, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "docetaxel", "start": 87, "end": 96, "token_start": 13, "token_end": 14}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pantoprazole Affecting Docetaxel Resistance Pathways via Autophagy (PANDORA): Phase II Trial of High Dose Pantoprazole (Autophagy Inhibitor) with Docetaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC). Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. ### Materials And Methods Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m ### results Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (\u226513/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. ### conclusion The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. ### Implications For Practice To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable , but the clinical activity was not sufficient to warrant further testing . The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.", "source": "https://pubmed.ncbi.nlm.nih.gov/30952818/"}
{"doc_id": "0e887d3051881c9eb2e97aff4e8b454c", "sentence": "Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir .", "spans": [{"span_id": 0, "text": "saquinavir", "start": 32, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "lopinavir", "start": 47, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "saquinavir", "start": 101, "end": 111, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir. To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. ### design Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. ### methods Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. ### results Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). lopinavir levels were similar to historical data. ### conclusion Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir . This boosted double PI combination could be an effective option for patients with limited RTI options.", "source": "https://pubmed.ncbi.nlm.nih.gov/15090803/"}
{"doc_id": "ba57e1b08c300abc4c30ff284a79ac02", "sentence": "Clopidogrel administration significantly reduces the likelihood of recurrent CATE compared with aspirin in cats ; both drugs were well tolerated .", "spans": [{"span_id": 0, "text": "Clopidogrel", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "aspirin", "start": 96, "end": 103, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Secondary prevention of cardiogenic arterial thromboembolism in the cat: The double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). To determine if clopidogrel administration is associated with a reduced likelihood of recurrent cardiogenic arterial thromboembolism (CATE) in cats compared to aspirin administration. Secondary aims were to determine if clopidogrel administration had an effect on the composite endpoint of recurrent CATE and cardiac death and to identify adverse effects of chronic clopidogrel or aspirin therapy. ### animals Seventy-five cats that survived a CATE event. ### methods Multicenter, double-blind, randomized, positive-controlled study. Cats were assigned to clopidogrel (18.75 mg/cat PO q 24 h) or aspirin (81 mg/cat PO q 72 h). Kaplan-Meier survival curves were created for each endpoint and the log rank test performed to compare treatment groups with respect to time to event and the likelihood of the event occurring. ### results The mean age of all cats was 8.0 \u00b1 3.5 yr and 57/75 (76%) were male (p < 0.001); 62/75 (83%) were mixed breed with the remainder including Persian, Abyssinian, American Shorthair, Bengal, Birman, Himalayan, Maine Coon, Ragdoll, Snowshoe, and Sphynx breeds. Only 15% (11/75) of cats had a history of heart disease recorded prior to the CATE event. clopidogrel administration was associated with significantly reduced likelihood of recurrent CATE compared to aspirin (p = 0.024) and had a longer median time to recurrence [443 (95% CI 185-990) days vs. 192 (95% CI 62-364) days, respectively]. clopidogrel was also associated with a significantly reduced likelihood of the composite endpoint of recurrent CATE or cardiac death (p = 0.033) with a longer median time to event [346 (95% CI 146-495) days vs. 128 (95% CI 58-243) days]. ### conclusions Clopidogrel administration significantly reduces the likelihood of recurrent CATE compared with aspirin in cats ; both drugs were well tolerated .", "source": "https://pubmed.ncbi.nlm.nih.gov/26776588/"}
{"doc_id": "f23bcffeb3185e2f6c8931118c169096", "sentence": "In recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated , such as sorafenib , lenvatinib , and sunitinib .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 151, "end": 160, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "lenvatinib", "start": 163, "end": 173, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "sunitinib", "start": 180, "end": 189, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Sorafenib and Sunitinib for the Treatment of Metastatic Thyroid Cancer of Follicular Origin: A 7-Year Single-Centre Experience. Radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is a rare form of DTC which poses a therapeutic challenge due to the scarcity of effective treatment options. In recent years several tyrosine kinase inhibitors targeting specific molecular pathways involved in its pathogenesis have been investigated , such as sorafenib , lenvatinib , and sunitinib . These appear to be associated with improved progression-free survival (PFS). ### objectives We aim to describe our experience with sorafenib and sunitinib in the treatment of RAI-refractory metastatic DTC and to evaluate and compare their efficacy and adverse effect profiles. ### method A total of 28 patients with RAI-refractory metastatic DTC were included - 26 had first-line treatment with sorafenib (8 subsequently switched to sunitinib, most due to disease progression) and 2 with sunitinib. We evaluated PFS and best radiological response achieved with each agent as primary endpoints. The secondary objective was to describe adverse effects and safety profile. ### results Mean PFS was 10.8 months with sorafenib and 6 months with sunitinib as a second-line treatment. Best overall response was partial remission (PR) with either agent - PR rate of 30.7% with sorafenib and 37.5% with second-line sunitinib. All treatment courses had registered adverse effects and 13.9% justified definitive treatment cessation. ### conclusions sorafenib and sunitinib appear to be effective treatment options in delaying disease progression of patients with RAI-refractory metastatic DTC, with an acceptable safety profile. Interestingly, sunitinib appears to show some efficacy even in patients who experience disease progression on sorafenib.", "source": "https://pubmed.ncbi.nlm.nih.gov/31768337/"}
{"doc_id": "1340b6ccb9e588be0096065a7dbffdfd", "sentence": "By passage 25 and thereafter , the selected cells were resistant to doxorubicin , etoposide , mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1 , MRP1 , MRP2 and breast cancer resistance protein .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 68, "end": 79, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "etoposide", "start": 82, "end": 91, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "mitoxantrone", "start": 94, "end": 106, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells. U-937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P-glycoprotein (Pgp), encoded by the multidrug-resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug-resistance-associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin-resistant cell lines were selected. Both drug-resistant cell lines upregulated the MVP mRNA level 1.5-fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug-selected cells. MVP induction is therefore the rate-limiting step for vault particle formation in U-937 cells. By passage 25 and thereafter , the selected cells were resistant to doxorubicin , etoposide , mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1 , MRP1 , MRP2 and breast cancer resistance protein . In summary, U-937 doxorubicin-selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant.", "source": "https://pubmed.ncbi.nlm.nih.gov/11774257/"}
{"doc_id": "b584eb44c6c157bad2207e9da0ce15a9", "sentence": "The in vitro antibacterial activity of zidovudine alone and in combination with ciprofloxacin was investigated .", "spans": [{"span_id": 0, "text": "zidovudine", "start": 39, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "ciprofloxacin", "start": 80, "end": 93, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "In vitro activity of zidovudine alone and in combination with ciprofloxacin against Salmonella and Escherichia coli.  The in vitro antibacterial activity of zidovudine alone and in combination with ciprofloxacin was investigated . zidovudine showed a good activity against Escherichia coli and Salmonella (MIC range 0.5-8 micrograms/ml and 1.5-62 micrograms/ml respectively) isolated from biological samples of HIV-infected patients. These strains proved to be extremely susceptible to ciprofloxacin alone. The interaction between zidovudine and ciprofloxacin ranged from additive activity to indifference. No antagonism was observed: the FIC index for every combination resulted < or = 1.5. The addition of AZT 1 mg/l (clinically achievable plasma concentration after therapeutic doses of 1200 mg/day) did not affect the bactericidal activity of ciprofloxacin; on the contrary, in some cases we observed an increase of bactericidal effect of the quinolone. These data have to be considered in patients with AIDS who can be treated concomitantly with zidovudine and ciprofloxacin.", "source": "https://pubmed.ncbi.nlm.nih.gov/8364519/"}
{"doc_id": "f2861595996d83b4c3c73e885a009998", "sentence": "This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 161, "end": 177, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "prednisolone", "start": 201, "end": 213, "token_start": 29, "token_end": 30}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[A case of primary antiphospholipid antibody syndrome with severe nephrotic syndrome showing remarkable endothelial cell damage in the capillary lumen]. A 25-year-old woman complained of anasarca and was admitted to Sakura National hospital on the presumptive diagnosis of nephrotic syndrome with 10.7 g of 24-hour urinary protein. At first, lupus nephritis with antiphospholipid antibody syndrome was suspected because of prolongation of APTT, existence of lupus anticoagulant and elevation of serum anticardiolipin antibody titer (IgM) in addition to positive ANA, lymphocytopenia and the biologically false positive test for syphilis (BFPTS). On day 28 of hospitalization, renal biopsy findings revealed severe endocapillary cell damage, such as swelling and proliferation of endothelial cells, fragmentation and double contour of the basement membrane walls, which were located only in the capillary lumens with a few thrombi. Immunofluorescent micrography revealed the absence of specific immunoglobulin or complement deposit. Therefore, the diagnosis of lupus nephritis was negated as these findings were suggestive of characteristic glomerulopathy due to primary antiphospholipid antibody syndrome. She was treated initially with oral prednisolone 60 mg and intravenous infusion of heparin 20,000 units daily. Moreover, cyclophosphamide 750 mg was administered intravenously as pulse therapy on day 13 as her serum level of CH50 had fallen suddenly, and hemodialysis was necessary because her renal function had deteriorated and she was suffering from cough and orthopnea with overhydratin. After the combined therapy, BFPTS disappeared and APTT returned to the normal range: dialysis treatment was not required further after the 4th hemodialysis. Thereafter, renal function improved and complete remission of nephrotic syndrome was obtained. This patient was a case of primary antiphospholipid antibody syndrome in which endothelial cell damage was located exclusively in the capillary lumens and pulse cyclophosphamide therapy in addition to prednisolone and anticoagulant was effective . We present this instructive case to promote understanding of the pathogenesis of primary antiphospholipid antibody syndrome.", "source": "https://pubmed.ncbi.nlm.nih.gov/9198367/"}
{"doc_id": "b735fb903e9b00efcf84b11b8bfce9e3", "sentence": "Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution .", "spans": [{"span_id": 0, "text": "Vancomycin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gentamicin", "start": 15, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "streptomycin", "start": 83, "end": 95, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Antibiotic prophylaxis in neurosurgery. A randomized controlled trial. A randomized trial was performed to support the contention that prophylactic antibiotics can reduce the incidence of postoperative neurosurgical wound infections. The regime outlined by Malis was followed. Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution . Patients were randomly assigned to two groups: control and treated. The infection rate in the control group was 3.5% and in the treated group 0.5%.", "source": "https://pubmed.ncbi.nlm.nih.gov/6368765/"}
{"doc_id": "b0e281e2e21137034cbcfb125ee8f931", "sentence": "We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines .", "spans": [{"span_id": 0, "text": "foretinib", "start": 66, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "lapatinib", "start": 80, "end": 89, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines. Melanoma is an aggressive cancer type with a high mortality rate and an elevated resistance to conventional treatment. Recently, promising new tools for anti-melanoma targeted therapy have emerged including inhibitors directed against frequently overexpressed receptors of growth factors implicated in the progression of this cancer. The ineffectiveness of single-targeted therapy prompted us to study the efficacy of treatment with a combination of foretinib, a MET (hepatocyte growth factor receptor) inhibitor, and gefitinib or lapatinib, EGFR (epidermal growth factor receptor) inhibitors. We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines . This combination of inhibitors significantly decreased Akt and Erk phosphorylation, while the drugs used independently were insufficient. Additionally, after treatment with pairs of inhibitors, cells became larger, with more pronounced stress fibers and abnormally shaped nuclei. We also noticed the appearance of polyploid cells and massive enrichment in the G2/M phase. Therefore, combination treatment was much more effective against melanoma cells than a single-targeted approach. Based on our results, we conclude that both EGFR and MET receptors might be effective targets in melanoma therapy. However, variation in their levels in patients should be taken into consideration.", "source": "https://pubmed.ncbi.nlm.nih.gov/29719603/"}
{"doc_id": "aff964519fe19b2506eced45b9c9d22a", "sentence": "Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy ( RR=0.88 , 95 % CI=0.64 - 1.21 , p=0.43 ) .", "spans": [{"span_id": 0, "text": "metronidazole", "start": 31, "end": 44, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "vancomycin", "start": 73, "end": 83, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "A meta-analysis of metronidazole and vancomycin for the treatment of Clostridium difficile infection, stratified by disease severity. The aim of this meta-analysis was to compare the efficacy of metronidazole and vancomycin for the treatment of Clostridium difficile infection, especially to investigate which agent was superior for treating either mild or severe C. difficile infection. A meta-analysis of randomized controlled trials and cohort studies identified in Pubmed, Embase, and the Cochrane Library was conducted. Four randomized controlled trials and two cohort studies involving 1218 patients were included in this meta-analysis. metronidazole was inferior to vancomycin for treating C. difficile infection in terms of both initial clinical cure rates (risk ratio, RR=0.91, 95% confidence interval, CI=0.84-0.98, p=0.02) and sustained cure rates (RR=0.88, 95% CI=0.82-0.96, p=0.003). For mild C. difficile infection, the efficacy of metronidazole and vancomycin resulted in similar clinical cure rates (RR=0.94, 95% CI=0.84-1.04, p=0.21) and sustained cure rates (RR=0.93, 95% CI=0.83-1.05, p=0.26). For severe C. difficile infection the efficacy of vancomycin was superior to metronidazole in terms of clinical cure rates (RR=0.81, 95% CI=0.69-0.95, p=0.009), whereas sustained cure rates were similar (RR=0.86, 95% CI=0.72-1.02, p=0.08). Regarding microbiological cure metronidazole therapy was as effective as vancomycin therapy ( RR=0.88 , 95 % CI=0.64 - 1.21 , p=0.43 ) . Recurrence rates with metronidazole and vancomycin for both mild C. difficile infection (RR=0.95, 95% CI=0.56-1.60, p=0.85) and severe C. difficile infection (RR=1.27, 95% CI=0.85-1.91, p=0.25) were not different. Likewise, no difference in all-cause mortality was found as well (RR=0.87, 95% CI=0.56-1.35, p=0.53). In conclusion, vancomycin provides improved initial clinical and sustained cure rates in patients with C. difficile infection compared with metronidazole, especially in patients with severe C. difficile infection. In view of these data, vancomycin may be considered first line therapy for severe C. difficile infection.", "source": "https://pubmed.ncbi.nlm.nih.gov/26001980/"}
{"doc_id": "fc00a893900f4703d0e0b6f310b9f548", "sentence": "During the infusion protocol used in clinical practice , etoposide , cytarabine and daunorubicine were stable and compatible with the various materials present in the infusion sets and extension tubing ( polyvinyl chloride , polyethylene ) and catheters ( silicone ) .", "spans": [{"span_id": 0, "text": "etoposide", "start": 57, "end": 66, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "cytarabine", "start": 69, "end": 79, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Stability and compatibility of a mixture of the anti-cancer drugs etoposide, cytarabine and daunorubicine for infusion. We evaluated (i) the stability of a mixture of the three anti-cancer agents used for the treatment of leukemia, namely etoposide, cytarabine and daunorubicine, in 5% glucose, and (ii) its compatibility towards various materials during an infusion protocol as performed for therapeutic purposes in hospital practice. etoposide and cytarabine were assayed by high-performance liquid chromatography with a C18 type column and UV detection. daunorubicine was assayed by visible spectrophotometry. The stability study showed all three anti-cancer drugs to be stable in 5% glucose solution, both alone and mixed. Best conservation was obtained by keeping bottles containing the mixture in the dark at room temperature. During the infusion protocol used in clinical practice , etoposide , cytarabine and daunorubicine were stable and compatible with the various materials present in the infusion sets and extension tubing ( polyvinyl chloride , polyethylene ) and catheters ( silicone ) . Observed variations in concentration did not exceed 10% of initial concentrations of each drug, though we would advocate changing infusion sets and extension tubing daily.", "source": "https://pubmed.ncbi.nlm.nih.gov/7651971/"}
{"doc_id": "9b61fc81ffb14fa9cd2564d54a1b505a", "sentence": "Following knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 116, "end": 127, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "etoposide", "start": 146, "end": 155, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Annexin A2 could enhance multidrug resistance by regulating NF-\u03baB signaling pathway in pediatric neuroblastoma. Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance. ### methods We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo. ### results First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2 ) using shRNA , we demonstrate enhanced drug sensitivity for doxorubicin ( 2.77-fold ) and etoposide ( 7.87-fold ) compared with control . Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-\u03baB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo. ### conclusion Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB.", "source": "https://pubmed.ncbi.nlm.nih.gov/28814318/"}
{"doc_id": "52ecae189b7c12c1e7263aef53247fc4", "sentence": "Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality .", "spans": [{"span_id": 0, "text": "amiodarone", "start": 22, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "carvedilol", "start": 37, "end": 47, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "[Correction of baroreflex sensitivity impairment and efficacy of prevention of sudden arrhythmic death in patients with postinfarction left ventricular dysfunction]. Baroreflex sensitivity was assessed in 287 patients with history of myocardial infarction and left ventricular ejection fraction < or =40% by phenylephrine test and was found to be depressed (4.44+/-0.38 ms/mm Hg). Repeat study in 3, 6 and 12 months revealed substantial improvement of baroreflex sensitivity in patients treated with perindopril especially when it was combined with amiodarone, metoprolol, bisoprolol and carvedilol but not with atenolol. Combined therapy with amiodarone and carvedilol provided greatest reduction of sudden arrhythmic and total mortality . Superiority of combination of amiodarone with lipophilic beta-adrenoblocker over monotherapy had been anticipate but was not confirmed in any of large prospective studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/15477784/"}
{"doc_id": "4b882f10fc1a53ea41c3d37160f7c40a", "sentence": "Efficacy of paclitaxel , carboplatin , and bevacizumab for cervical cancer : A protocol for systematic review and meta-analysis .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 12, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "carboplatin", "start": 25, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "bevacizumab", "start": 43, "end": 54, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Efficacy of paclitaxel , carboplatin , and bevacizumab for cervical cancer : A protocol for systematic review and meta-analysis . Cervical cancer (CC) is a very common and malignant tumor in female population. Although a variety of single medications are reported to treat this condition, they all have limited efficacy. Previous studies have reported the combination of paclitaxel, carboplatin, and bevacizumab (PCB) can be used for the treatment of patients with CC effectively. However, no systematic review has explored its efficacy and safety. This study will address its efficacy and safety systematically and comprehensively. ### methods The following electronic databases will be retrieved from their inceptions to the January 1, 2020 to identify all potential associated studies: MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, Google scholar, and Chinese Biomedical Literature Database. We will include randomized controlled trials (RCTs) of adult women (\u226518 years) with CC globally. Eligible interventions will target any forms of PCB. The study methodological quality of all included studies will be appraised using Cochrane risk of bias tool. Statistical analysis will be undertaken using RevMan 5.3 software. In addition, we will perform a narrative synthesis to describe quality and content of the evidence. ### results This study will summarize recent evidence and provide quality evidence for the efficacy and safety of PCB on CC. ### conclusion The findings of this study will seek to identify the efficacy and safety of PCB and suggest future directions for research efforts targeting CC among this population. ### Systematic Review Registration INPLASY202040195.", "source": "https://pubmed.ncbi.nlm.nih.gov/32541479/"}
{"doc_id": "21c7c9267a761f7e54194cae09a35820", "sentence": "The eradication rate of C. trachomatis in baseline-positive patients at the first follow-up visit in the azithromycin group was 96 % with one persistent case , and 100 % in the doxycycline group .", "spans": [{"span_id": 0, "text": "azithromycin", "start": 105, "end": 117, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "doxycycline", "start": 177, "end": 188, "token_start": 31, "token_end": 32}], "rels": [], "paragraph": "Single-dose oral azithromycin versus seven-day doxycycline in the treatment of non-gonococcal urethritis in males. One hundred and twenty male patients with signs and symptoms compatible with non-gonococcal urethritis were enrolled in a prospective-randomized study to compare the efficacy and safety of a single oral-dose of 1 g azithromycin and a seven-day course of 100 mg doxycycline twice-daily. Clinical examination and culture samples for Chlamydia trachomatis were performed before and approximately 8, 15 and 35 days after starting treatment. Both treatment groups were comprised of 30 chlamydia-positive patients evaluable for efficacy. The eradication rate of C. trachomatis in baseline-positive patients at the first follow-up visit in the azithromycin group was 96 % with one persistent case , and 100 % in the doxycycline group . After about two weeks, there were two re-occurrences in the azithromycin group, resulting in a cumulative eradication rate of 90% with three culture-positive cases. The corresponding figure in the doxycycline group was still 100%, but there were leucocytes present in the urethral smear of two patients who later proved to be true culture-positive re-occurrences. After about five weeks, there was an additional re-occurrence in the azithromycin group leading to a cumulative eradication rate of 87%, while two re-occurrences in the doxycycline group gave a cumulative eradication rate of 93%. There was no statistically significant difference in efficacy between the single-dose azithromycin and seven-day course of doxycycline in the treatment of patients with chlamydial urethritis.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/8396091/"}
{"doc_id": "c47d83d7eec4a7d07750de608807d10e", "sentence": "For example , the overall objective response rate of 9.5 % with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients , but toxicity , notably fatigue , lead to discontinuation in 38 % of patients .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 77, "end": 86, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "pemetrexed", "start": 117, "end": 127, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "docetaxel", "start": 131, "end": 140, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example , the overall objective response rate of 9.5 % with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients , but toxicity , notably fatigue , lead to discontinuation in 38 % of patients . Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and \"traps\" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.", "source": "https://pubmed.ncbi.nlm.nih.gov/17634832/"}
{"doc_id": "00169f308f6bab3a5793ce3491c6817f", "sentence": "Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 78, "end": 87, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "erlotinib", "start": 187, "end": 196, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "sorafenib", "start": 201, "end": 210, "token_start": 29, "token_end": 30}, {"span_id": 3, "text": "sorafenib", "start": 244, "end": 253, "token_start": 38, "token_end": 39}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI). To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. ### Patients And Methods Patients with progressive refractory NSCLC who had previously benefitted from erlotinib ( objective response or stable disease > 8weeks ) were randomized to receive treatment with either erlotinib and sorafenib ( 400 mg orally twice daily ) or sorafenib alone . Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. ### results Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. ### conclusions These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804.", "source": "https://pubmed.ncbi.nlm.nih.gov/29110854/"}
{"doc_id": "11e266d33694244478184960a4f5ca71", "sentence": "In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment .", "spans": [{"span_id": 0, "text": "aflibercept", "start": 28, "end": 39, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "irinotecan", "start": 121, "end": 131, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "5-fluorouracil", "start": 136, "end": 150, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer. Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. aflibercept , a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs. ### Areas Covered A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described. ### Expert Opinion In this challenging field , aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment . Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/25988772/"}
{"doc_id": "a552828060f67274a59cce5e784f3492", "sentence": "The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 26, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "carboplatin", "start": 39, "end": 50, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "etoposide", "start": 80, "end": 89, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Paclitaxel, carboplatin, and oral etoposide in the treatment of small cell lung cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is active in previously untreated patients with small cell lung cancer (SCLC). We evaluated the toxicity and efficacy of a 1-hour infusion of paclitaxel added to a combination regimen of carboplatin and etoposide in a phase II trial for the treatment of patients with SCLC. Thirty-eight patients with previously untreated SCLC were treated with paclitaxel 135 mg/m2 (1-hour intravenous infusion), day 1; carboplatin at area under the concentration-time curve of 5, day 1; and oral etoposide 100 and 50 mg (alternating days), days 1 to 10. Treatment cycles were repeated every 21 days for a total of four courses. Patients with limited-stage disease received radiation therapy (4,500 cGy in 25 fractions) concurrently with the last two courses of chemotherapy. This outpatient combination was easily tolerated. Grade 3 or 4 leukopenia was experienced in only 8% of courses; grades 3 and 4 thrombocytopenia and anemia were also infrequent. Nonhematologic toxicity was uncommon, with the exception of transient esophagitis, which occurred in six of 15 patients (grade 3 in five patients, grade 4 in one) receiving concurrent chemoradiotherapy. Of 35 evaluable patients, 29 (83%) achieved a response to treatment. The complete response rate was 29% (40% in patients with limited-stage disease). Median survival was 7 months for patients with extensive-stage disease and 17 months in limited-stage patients. Prophylactic whole brain irradiation was not used, and seven patients developed brain metastases as their initial site of relapse. The combination of 1-hour paclitaxel , carboplatin , and extended oral schedule etoposide is feasible and well tolerated at the doses administered in this phase II trial . This treatment was highly active and the results are comparable to other standard regimens. Increased doses of both paclitaxel and carboplatin could probably be tolerated and are currently being evaluated. Precise definition of the role of paclitaxel in the treatment of SCLC will require randomized studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/9007113/"}
{"doc_id": "17f4d7217cc41ed7afdf6e8ca2189f9d", "sentence": "In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 59, "end": 69, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "gemcitabine", "start": 82, "end": 93, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment. Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard , we have synthesized Pem-PEG-Gem , wherein pemetrexed ( Pem ) and gemcitabine ( Gem ) are conjugated to a heterobifunctional polyethylene glycol ( PEG ) polymer for the effective treatment of Non-Small Cell Lung Cancer ( NSCLC ) . Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/25968494/"}
{"doc_id": "ec8c0a2aee1447c50afd5943b55779e9", "sentence": "After the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved .", "spans": [{"span_id": 0, "text": "artesunate", "start": 52, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "mefloquine", "start": 67, "end": 77, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "An 11-year-old boy with Plasmodium falciparum malaria and dengue co-infection. Malaria and dengue fever are major mosquito-borne public health problems in tropical countries. The authors report a malaria and dengue co-infection in an 11-year-old boy who presented with sustained fever for 10 days. The physical examination revealed a flushed face, injected conjunctivae and left submandibular lymphadenopathy. His peripheral blood smear showed few ring-form trophozoites of Plasmodium falciparum. His blood tests were positive for dengue NS-1 antigen and IgM antibody, and negative for IgG antibody. After the initiation of antimalarial treatment with artesunate and mefloquine , his clinical condition gradually improved . However, he still had low-grade fever that persisted for 6 days. Finally, he recovered well without fluid leakage, shock or severe bleeding. This case report emphasises that early recognition and concomitant treatment of malaria and dengue co-infection in endemic areas can improve clinical outcome and prevent serious complications.", "source": "https://pubmed.ncbi.nlm.nih.gov/24692379/"}
{"doc_id": "997f3bcc47d7e8eb59d59b8932623751", "sentence": "For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors .", "spans": [{"span_id": 0, "text": "vinblastine", "start": 85, "end": 96, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "ifosfamide", "start": 99, "end": 109, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "cisplatin", "start": 116, "end": 125, "token_start": 20, "token_end": 21}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Update on malignant ovarian germ cell tumors. The evolution of therapy for malignant ovarian germ cell tumors has been one of the true success stories in oncology. This article reviews the major advances in this field, with emphasis on more recent developments. During the past two decades, the nomenclature and histologic criteria for the major histologic subtypes have been standardized. Although the role of secondary debulking is uncertain, it probably has merit in selected patients. The use of second-look laparotomy should be limited as much as possible. Chemotherapeutic regimens have evolved to the current \"gold standard\"--the combination of bleomycin, etoposide, and cisplatin, with overall disease-free survival rates of greater than 95%. For patients with metastatic dysgerminoma, chemotherapy has replaced radiation therapy as the treatment of choice. For those few patients who do not respond to first-line therapy , the combination of vinblastine , ifosfamide , and cisplatin is the most popular regimen for the subset of platinum-sensitive tumors . For those with platinum-resistant tumors, dose intensification with autologous bone marrow rescue or Phase II drugs are being investigated. Studies on the late effects of treatment reveal that reproductive potential can be preserved in most young patients. In summary, although the progress in this field has been phenomenal, small incremental advances will continue to occur during the 1990s.", "source": "https://pubmed.ncbi.nlm.nih.gov/8381708/"}
{"doc_id": "24ae80413b3dd00b228c2faee29db136", "sentence": "Antibiotic treatment was changed to imipenem/cilastatin , piperacillin , gentamicin , clarithromycin , erythromycin , and minocycline .", "spans": [{"span_id": 0, "text": "piperacillin", "start": 58, "end": 70, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "gentamicin", "start": 73, "end": 83, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "clarithromycin", "start": 86, "end": 100, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "erythromycin", "start": 103, "end": 115, "token_start": 13, "token_end": 14}, {"span_id": 4, "text": "minocycline", "start": 122, "end": 133, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "[Legionella pneumonia successfully treated despite late diagnosis]. Status asthmaticus developed in a 72-year-old man who was being treated with oral prednisolone for severe persistent asthma. The dosage of prednisolone was increased, and amikacin was injected to treat pneumonia that had developed in the right lung. Progressive pulmonary infiltrates, respiratory compromise, and hypoxemia developed, and the patient eventually required mechanical ventilation. Antibiotic treatment was changed to imipenem/cilastatin , piperacillin , gentamicin , clarithromycin , erythromycin , and minocycline . Liver injury developed. More than one month after the patient was admitted, Legionella pneumonia was diagnosed. levofloxacin (400 mg/day) was then given orally, in combination with injected imipenem/cilastatin. Liver function did not deteriorate, and the pneumonia resolved. Most diagnoses of Legionnaires' disease are made retrospectively by examination of serum. In this case, antibiotics active against Legionella pneumophila had been used before the diagnosis was established, which probably contributed to the patient's recovery. When aminoglycosides or beta-lactam antibiotics are ineffective, administration of agents effective against Legionnaires' disease should be considered.", "source": "https://pubmed.ncbi.nlm.nih.gov/9234637/"}
{"doc_id": "62665fef62b1b254a8c360ec1c84a862", "sentence": "Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) .", "spans": [{"span_id": 0, "text": "vandetanib", "start": 29, "end": 39, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "5-FU", "start": 199, "end": 203, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "paclitaxel", "start": 240, "end": 250, "token_start": 46, "token_end": 47}, {"span_id": 3, "text": "carboplatin", "start": 295, "end": 306, "token_start": 63, "token_end": 64}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection. Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. ### methods Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib ( planned dosing levels of 100 , 200 , and 300 mg ) with concomitant daily radiotherapy ( 1.8 Gy/d , 45 Gy total ) and chemotherapy , consisting of infusional 5-FU ( 225 mg/m/d over 96 h , weekly ) , paclitaxel ( 50 mg/m , days 1 , 8 , 15 , 22 , 29 ) and carboplatin ( AUC of 5 , days 1 , 29 ) . ### results A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. ### conclusions vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.", "source": "https://pubmed.ncbi.nlm.nih.gov/26986978/"}
{"doc_id": "dfc6b9441ddfd8b86ebcd3331ee8783d", "sentence": "Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 25, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "toremifene", "start": 61, "end": 71, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer . To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer. ### Materials And Methods Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212). ### results The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms. ### conclusion The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/7595707/"}
{"doc_id": "d404a0a64aefa9b15e1c76f398b14335", "sentence": "Eighteen patients received chemotherapy including etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( n = 13 ) and cyclophosphamide , doxorubicin , vincristine , and prednisone ( n = 2 ) .", "spans": [{"span_id": 0, "text": "etoposide", "start": 50, "end": 59, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "prednisone", "start": 62, "end": 72, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "vincristine", "start": 75, "end": 86, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "cyclophosphamide", "start": 89, "end": 105, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "doxorubicin", "start": 112, "end": 123, "token_start": 14, "token_end": 15}, {"span_id": 5, "text": "and cyclophospha", "start": 139, "end": 155, "token_start": 21, "token_end": 22}, {"span_id": 6, "text": "e , doxorub", "start": 158, "end": 169, "token_start": 23, "token_end": 24}, {"span_id": 7, "text": "n , vincris", "start": 172, "end": 183, "token_start": 25, "token_end": 26}, {"span_id": 8, "text": "and predni", "start": 190, "end": 200, "token_start": 28, "token_end": 29}], "rels": [], "paragraph": "HIV-associated plasmablastic lymphoma in the era of HAART: a single-center experience of 21 patients. Patients with HIV infection have an increased risk of developing plasmablastic lymphoma (PBL). In this study, we reviewed the clinicopathologic features of PBL in HIV+ patients in the era of HAART from a single health center. ### design Retrospective study. ### methods The morphologic, immunophenotypic, and clinical features were reviewed in these HIV+ patients with PBL and univariate analysis was employed to determine the survival prognosis. ### results During the interval of 1 January 2008 to 30 December 2018, we identified 95 HIV+ patients with aggressive non-Hodgkin B-cell lymphomas. Among these patients, there were 21 (22%) patients with PBL (19 men and two women; median age: 45 years). Seven patients had PBL at their initial HIV diagnosis and 14 developed PBL after a median interval of 7.7 months of HIV diagnosis. Lymph nodes (n\u200a=\u200a10), oral cavity/sinonasal mass (n\u200a=\u200a6), and rectal masses (n\u200a=\u200a5) were the common involved sites, and five of 15 (33%) had bone marrow involvement. Lymphoma cells were immunoreactive for MUM-1/IRF4 (100%), CD138 (90%), CD45 (63%), CD79a (47%), and CD30 (25%). Proliferation rate assessed by Ki67 was at least 90% in 18 of 20 cases. Eighteen patients received chemotherapy including etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( n = 13 ) and cyclophosphamide , doxorubicin , vincristine , and prednisone ( n = 2 ) . With a median follow-up time of 19 months, nine out of 17 patients died. Bone marrow involvement was associated with a poorer overall survival (median: 4.7 months, P\u200a=\u200a0.015). ### conclusion PBL is the second most common type of aggressive lymphoma and often presents in lymph nodes of patients with poorly controlled HIV infection. Bone marrow involvement is associated with a poorer outcome.", "source": "https://pubmed.ncbi.nlm.nih.gov/32889849/"}
{"doc_id": "e0bf205b5f4f7b0aef116d39aeca8d51", "sentence": "The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin .", "spans": [{"span_id": 0, "text": "verapamil", "start": 28, "end": 37, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "doxorubicin", "start": 139, "end": 150, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "doxorubicin", "start": 249, "end": 260, "token_start": 35, "token_end": 36}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Inhibitory effects of a calcium antagonist on ornithine decarboxylase induction in pancreatic cancer cell lines.  The calcium channel blocker verapamil has been previously shown to augment the chemosensitivity of pancreatic adenocarcinoma cell lines to doxorubicin by mechanisms other than changes in the intracellular accumulation , retention , or metabolism of doxorubicin . Because of our interest in polyamine biosynthesis and metabolism and the known involvement of calcium in the induction of ornithine decarboxylase (ODC) by serum refeeding of cultured cells, the effects of verapamil on the serum-stimulated ODC activity in two hamster pancreatic adenocarcinoma cell lines were examined. In plateau phase well-differentiated (WD) PaCa and poorly differentiated (PD) PaCa cells, a dose-dependent inhibition of the 4-h serum induction of ODC was seen at concentrations of 1, 5, and 10 microM verapamil. At the higher concentrations of verapamil, the inhibition of ODC induction was comparable to that achieved with 5 mM alpha-difluoromethylornithine (DFMO, a specific enzyme inhibitor of ODC) and greater than that seen with 2 mM EGTA plus calcium-depleted serum. Log phase PD PaCa cells, included for comparison, showed less ODC induction with serum and lesser degrees of inhibition of the response to serum refeeding with verapamil, DFMO, and calcium depletion. No direct inhibition of the ODC enzyme was found when verapamil was added at the time the activity was measured. Based on our present data, a possible influence of intracellular calcium pools in the verapamil effect on ODC activity is unclear. Nevertheless, the present findings suggest that verapamil's effects on cytotoxicity may be mediated (at least in part) by inhibition of the serum-mediated induction of ODC.", "source": "https://pubmed.ncbi.nlm.nih.gov/1780323/"}
{"doc_id": "243ff1340b156e1ef82da5cce81b3564", "sentence": "The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 82, "end": 91, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "irinotecan", "start": 95, "end": 105, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Current status of second-line therapy for metastatic colorectal cancer. Decisions regarding the optimal systemic therapy for patients with metastatic colorectal cancer (CRC) have become more complex with the identification and development of multiple effective agents for this disease. Multiple treatment options are now available in the second-line setting for patients with metastatic CRC who have progressed despite prior chemotherapy. The exact choice of second-line therapy depends on the first-line treatment that was administered. irinotecan as a salvage therapy for patients with metastatic CRC who have progression following front-line 5-fluorouracil (5-FU)-based therapies was confirmed in a number of phase II/III studies. Many patients who received irinotecan/5-FU-based therapy as first-line treatment benefit from the combination of oxaliplatin and 5-FU/leucovorin (FOLFOX) in terms of response, time to progression, and relief of tumor-related symptoms. Other considerations include the integration of targeted therapies into chemotherapy regimens. The results of a randomized phase II trial have demonstrated that the addition of cetuximab to irinotecan in patients with irinotecan-resistant tumors represents another active treatment option for these patients . The activity of bevacizumab as part of second-line therapy is currently under investigation and results from phase III trials are expected within the next year. In summary, the availability of 5 drugs that are active in CRC provides us, for the first time, with choice--and dilemma--regarding optimal second-line therapy in patients with metastatic CRC.", "source": "https://pubmed.ncbi.nlm.nih.gov/15212701/"}
{"doc_id": "4cc8adfb245b330491b730ea1b5e7855", "sentence": "Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide .", "spans": [{"span_id": 0, "text": "digoxin", "start": 66, "end": 73, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "flecainide", "start": 78, "end": 88, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Direct fetal administration of adenosine for the termination of incessant supraventricular tachycardia. Adenosine terminates supraventricular reentry tachycardia safely and effectively in the pediatric age group. ### case The recurrence of pretreated incessant tachycardia led to severe hydrops in a 28-week-old fetus. The tachycardia was terminated instantly with direct fetal administration of adenosine via the umbilical vein. Normal heart rate and rhythm were then preserved temporarily with digoxin and flecainide . ### conclusion Direct fetal adenosine administration might be helpful in the treatment of fetal reentry tachycardias if the sinus rhythm achieved quickly can be preserved by long-acting antiarrhythmic drugs. Such a combined therapeutic approach might be especially advantageous in hydropic fetuses.", "source": "https://pubmed.ncbi.nlm.nih.gov/7724143/"}
{"doc_id": "524028001d20085596cb36bbd3d78092", "sentence": "A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 42, "end": 52, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "capecitabine", "start": 73, "end": 85, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer . The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine. ### Patients And Methods One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed. ### results The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics. ### conclusions irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/15939714/"}
{"doc_id": "087b5adc35235f9ed99914b77d097379", "sentence": "The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime .", "spans": [{"span_id": 0, "text": "vancomycin", "start": 76, "end": 86, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "TZP", "start": 91, "end": 94, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "vancomycin", "start": 210, "end": 220, "token_start": 34, "token_end": 35}, {"span_id": 3, "text": "cefepime", "start": 225, "end": 233, "token_start": 36, "token_end": 37}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Incidence of Nephrotoxicity Among Pediatric Patients Receiving Vancomycin With Either Piperacillin-Tazobactam or Cefepime: A Cohort Study. Recent studies in adults have found an incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin and piperacillin-tazobactam (TZP) that is greater than that expected with either medication alone. The purpose of this study was to determine whether combination therapy with vancomycin and TZP is associated with an incidence of AKI in pediatric patients higher than that in those on combination therapy with vancomycin and cefepime . ### methods We performed a retrospective single-center matched-cohort study of pediatric patients who received vancomycin in combination with TZP or cefepime between January 2015 and June 2016. The patients were matched according to chronic disease, age, sex, and number of concomitant nephrotoxic medications at the time of combination antibiotic therapy. The primary outcome was incidence of AKI. Secondary outcomes included differences between groups in time to AKI, resolution of AKI, and effect of vancomycin trough levels on the incidence of nephrotoxicity. Conditional logistic regression was used to compare categorical and continuous variables between treatment groups. Conditional Poisson regression was used to assess the association between AKI and treatment groups. Stratified log-rank tests and Cox proportional hazards models with shared frailty were used to compare the times to AKI according to treatment group. ### results Two hundred twenty-eight matched patients were included. AKI developed in 9 (7.9%) of 114 and 33 (28.9%) of 114 patients in the cefepime and TZP groups, respectively (P < .001). Type of combination therapy remained a significant predictor for AKI in multivariate conditional Poisson analysis in which adjustments were made for age, sex, use of concomitant nephrotoxins, and vancomycin dose (relative risk, 2.5 [95% confidence interval, 1.1-5.8]; P = .03). AKI developed almost 3 times sooner in the TZP group than in the cefepime group (hazard ratio, 2.9 [95% confidence interval, 1.3-6.1]; P = .006). Sensitivity analyses in which adjustment was made for antibiotic indication in addition to the aforementioned variables and excluding those with gastrointestinal infection revealed similar results. ### conclusion Among hospitalized children at our institution, combination therapy with vancomycin and TZP was associated with an incidence of AKI higher than that associated with vancomycin and cefepime.", "source": "https://pubmed.ncbi.nlm.nih.gov/29590376/"}
{"doc_id": "2ebb8341a08c839141f8b65e95691777", "sentence": "In patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option .", "spans": [{"span_id": 0, "text": "etoposide", "start": 53, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "doxorubicin", "start": 65, "end": 76, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "cisplatin", "start": 79, "end": 88, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "mitotane", "start": 94, "end": 102, "token_start": 13, "token_end": 14}, {"span_id": 4, "text": "gemcitabine", "start": 115, "end": 126, "token_start": 18, "token_end": 19}, {"span_id": 5, "text": "capecitabine", "start": 142, "end": 154, "token_start": 21, "token_end": 22}, {"span_id": 6, "text": "streptozotocin", "start": 174, "end": 188, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [4, 5], "is_context_needed": false}, {"class": "POS", "spans": [4, 6], "is_context_needed": false}], "paragraph": "Adrenocortical carcinoma: current treatment options. In this article, we focus on the current and future treatment options for adrenocortical carcinoma (ACC). ### Recent Findings Radical surgery remains the only curative treatment for ACC. Recent reports showed a longer overall survival (OS) in patients with high risk of recurrence treated with adjuvant mitotane; the time in target range (14-20\u200amg/l) is related to low risk of relapse both in adjuvant and in palliative setting. In patients who experience disease progression after etoposide , doxorubicin , cisplatin with mitotane ( EDP-M ) , gemcitabine and metronomic capecitabine , or the less used streptozotocin , represent a second-line chemotherapy option . temozolomide can be employed as a third-line chemotherapy. To date, unsatisfactory results have been obtained on the efficacy of targeted therapies. Clinical trials are ongoing to evaluate the efficacy of tyrosine kinase and immune checkpoint inhibitors. ### summary ACC is a rare disease with a poor prognosis. The main therapy is represented by radical surgery conducted by an expert surgeon. Adjuvant mitotane has to be started in patients with high risk of recurrence. In patients with inoperable disease, the scheme EDP-M is the most employed. Few data are available on second-line and third-line chemotherapy in patients with disease progression after EDP-M. Currently, the role of targeted therapies is under evaluation.", "source": "https://pubmed.ncbi.nlm.nih.gov/33186181/"}
{"doc_id": "a73e44b782d98aba7c53f394543442eb", "sentence": "We conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect .", "spans": [{"span_id": 0, "text": "ropivacaine", "start": 17, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "epinephrine", "start": 145, "end": 156, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effects of regional anesthesia with ropivacaine on arterial pressure and heart rate in healthy subjects. The anesthetic, ropivacaine, has been used extensively in clinical practice, but few studies have evaluated this long-acting local anesthetic in dentistry. In this study we evaluated the effects of ropivacaine alone and ropivacaine + vasoconstrictor on the cardiovascular system when used as a dental anesthetic in volunteers. Thirty-two healthy subjects received two consecutive infiltrations of 1.8 ml of either 0.75% ropivacaine or ropivacaine + epinephrine into the pterygomandibular region. Pain sensation, numbness of the lip, arterial pressure, heart rate, and electrocardiogram changes were monitored for 2 h. The onset of anesthesia was 10 min after the injection and lasted for more than 2 h, and numbness of the lip lasted for approximately 8 h. ropivacaine alone did not cause significant changes in the cardiovascular parameters, but ropivacaine + epinephrine caused a transient increase in arterial pressure and heart rate 2 min postinjection. We conclude that ropivacaine alone injected into the pterygomandibular region does not affect the cardiovascular system and that the addition of epinephrine has no beneficial effect . This finding may be relevant to dentists endeavoring to find an anesthetic of minimal cardiovascular risk to produce regional anesthesia for long-lasting procedures without the need of a vasoconstrictor.", "source": "https://pubmed.ncbi.nlm.nih.gov/16460338/"}
{"doc_id": "f2416fdc4c1df1164e8dae3932989427", "sentence": "The next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol .", "spans": [{"span_id": 0, "text": "ethionamide", "start": 33, "end": 44, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "rifampin", "start": 71, "end": 79, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "capreomycin", "start": 82, "end": 93, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "kanamycin", "start": 96, "end": 105, "token_start": 15, "token_end": 16}, {"span_id": 4, "text": "streptomycin", "start": 108, "end": 120, "token_start": 17, "token_end": 18}, {"span_id": 5, "text": "ethambutol", "start": 125, "end": 135, "token_start": 19, "token_end": 20}, {"span_id": 6, "text": "ansamycin", "start": 59, "end": 68, "token_start": 9, "token_end": 10}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": true}], "paragraph": "Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs? The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method. All the species tested were resistant to isoniazid and pyrazinamide. In general, clofazimine and d-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M. chelonei which were resistant to both drugs, and the M. szulgai and M. terrae complex which was resistant to d-cycloserine. The next broad-spectrum drug was ethionamide , followed by ansamycin , rifampin , capreomycin , kanamycin , streptomycin and ethambutol . Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M. xenopi, M. gordonae and M. fortuitum whereas M. kansasii and M. gastri were sensitive to ofloxacin only. When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M. kansasii, M. gastri and M. xenopi; 6/13 for M. gordonae; 5/13 for M. marinum; 3/13 for M. szulgai; 2/13 for M. fortuitum; 1/13 for the M. avium, M. scrofulaceum, M. simiae, and M. terrae complex, and none of the 13 in the case of M. chelonei. These results are discussed in relation to the multiple drug resistance of atypical mycobacteria. We conclude that the critical concentrations of drugs established for M. tuberculosis are not appropriate for atypical mycobacteria.", "source": "https://pubmed.ncbi.nlm.nih.gov/1303690/"}
{"doc_id": "d920c61f16550899ca4f42c2889ece9a", "sentence": "Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 20, "end": 29, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "capecitabine", "start": 34, "end": 46, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer . The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). ### Methods And Patients Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. ### results The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. ### conclusions capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/18208793/"}
{"doc_id": "e8983bc29117201dac2cf3304550dfe5", "sentence": "Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma .", "spans": [{"span_id": 0, "text": "ibrutinib", "start": 23, "end": 32, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "venetoclax", "start": 56, "end": 66, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma.  Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma . Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. ### methods We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. ### results The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%). ### conclusions In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).", "source": "https://pubmed.ncbi.nlm.nih.gov/29590547/"}
{"doc_id": "72408996cbbac6460db21f6e3b784e67", "sentence": "The chloroethylating nitrosoureas ( lomustine , fotemustine , cystemustine ( BCNU ) and methylating agents temozolomide ( TMZ ) , dacarbazine ( DTIC ) , procarbazine ) have documented activity in metastatic malignant melanoma with single agent response rates of 15 - 25 % .", "spans": [{"span_id": 0, "text": "lomustine", "start": 36, "end": 45, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "temozolomide", "start": 107, "end": 119, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "dacarbazine", "start": 130, "end": 141, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "procarbazine", "start": 153, "end": 165, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance.  The chloroethylating nitrosoureas ( lomustine , fotemustine , cystemustine ( BCNU ) and methylating agents temozolomide ( TMZ ) , dacarbazine ( DTIC ) , procarbazine ) have documented activity in metastatic malignant melanoma with single agent response rates of 15 - 25 % . Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/11007934/"}
{"doc_id": "e3d4c7e46a39af27f2f034cd9243dfe4", "sentence": "The population growth rate was adversely influenced by exposure to chlortetracycline , sulfamethazine , or sulfathiazole in water fleas , but reduction in population size was not expected .", "spans": [{"span_id": 0, "text": "chlortetracycline", "start": 67, "end": 84, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "sulfamethazine", "start": 87, "end": 101, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "sulfathiazole", "start": 107, "end": 120, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Risk assessment of chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin in aquatic environment: are the current environmental concentrations safe? To understand potential risks of major pharmaceutical residues in waters, we evaluated ecotoxicities of five major veterinary pharmaceuticals, i.e., chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin, which have been frequently detected in freshwater environment worldwide. We conducted acute and chronic toxicity tests using two freshwater invertebrates (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). In general, D. magna exhibited greater sensitivity than M. macrocopa, and chronic reproduction was the most sensitive endpoints for both organisms. The population growth rate was adversely influenced by exposure to chlortetracycline , sulfamethazine , or sulfathiazole in water fleas , but reduction in population size was not expected . In O. latipes, the tested pharmaceuticals affected several reproduction related endpoints including time to hatch and growth. Based on the toxicity values from the present study and literature, algae appeared to be the most sensitive organism, followed by Daphnia and fish. Hazard quotients derived from measured environmental concentrations (MECs) and predicted no effect concentrations (PNECs) for erythromycin and oxytetracycline exceeded unity, suggesting that potential ecological effects at highly contaminated sites cannot be ruled out. Long-term consequences of veterinary pharmaceutical contamination in the environment deserve further investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/22711548/"}
{"doc_id": "f7fbf1b752fc2876bf34e69b16299d34", "sentence": "A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 106, "end": 116, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "paclitaxel", "start": 164, "end": 174, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "carboplatin", "start": 179, "end": 190, "token_start": 32, "token_end": 33}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients. The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6 . The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.", "source": "https://pubmed.ncbi.nlm.nih.gov/11488525/"}
{"doc_id": "836dfe1a21ffa42a19c4d829208f22f1", "sentence": "Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor .", "spans": [{"span_id": 0, "text": "Ticlopidine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "clopidogrel", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "The antiplatelet effects of ticlopidine and clopidogrel.  Ticlopidine and clopidogrel achieve antiplatelet effects by inhibiting the binding of adenosine 5'-disphosphate to its platelet receptor . ticlopidine was first shown to decrease major events compared with placebo or aspirin in patients with stroke or recent transient ischemic attack. Randomized studies in patients undergoing coronary artery stenting have shown that ticlopidine reduces the risk for subacute stent thrombosis compared with warfarin-based regimens. Smaller studies have also shown this drug to have benefit during follow-up in patients with unstable angina, peripheral arterial disease, saphenous vein coronary bypass grafts, and diabetic retinopathy. clopidogrel was recently approved by the U.S. Food and Drug Administration for the reduction of ischemic events in patients with recent myocardial infarction, stroke, or peripheral arterial disease (incidence, 5.32% per year compared with 5.83% per year for aspirin; P = 0.043) with no added risk for neutropenia. The combination of clopidogrel and aspirin, as well as the utility of clopidogrel in other patient populations and in stenting, requires further study. ticlopidine and clopidogrel seem to have beneficial effects compared with aspirin (the current standard) in a broad range of patients. These observations highlight the importance of antiplatelet therapy in cardiovascular disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/9735068/"}
{"doc_id": "cceb9a88a83ca29198d7e218b0ba2623", "sentence": "Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer .", "spans": [{"span_id": 0, "text": "Irinotecan", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gemcitabine", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Irinotecan plus gemcitabine induces both radiographic and CA 19 - 9 tumor marker responses in patients with previously untreated advanced pancreatic cancer . This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. ### Patients And Methods Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. ### results Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). ### conclusion irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.", "source": "https://pubmed.ncbi.nlm.nih.gov/11870159/"}
{"doc_id": "b157235272b3fb888e30df30a0f83408", "sentence": "The patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 46, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "doxorubicin", "start": 65, "end": 76, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "vincristine", "start": 79, "end": 90, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "prednisone", "start": 97, "end": 107, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Lymphomatoid granulomatosis. Successful treatment with CHOP combination chemotherapy. A patient with lymphomatoid granulomatosis is reported. The patient was treated with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisone as initial management immediately after diagnosis . She obtained a complete remission and remains free of disease 3 1/2 years from the time of diagnosis. The favorable outcome in this patient may be related to her initial limited disease or to the use of initial intensive chemotherapy; nonetheless, the generally unfavorable prognosis of this disease appears to mandate early trials of intensive therapy in most patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/6546471/"}
{"doc_id": "690144b77124fc39135f75139b0a789f", "sentence": "To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature .", "spans": [{"span_id": 0, "text": "linezolid", "start": 76, "end": 85, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "methadone", "start": 90, "end": 99, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Serotonin syndrome due to co-administration of linezolid and methadone. Serotonin syndrome (SS), a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors, may be caused by a single drug or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. To our knowledge , we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature .", "source": "https://pubmed.ncbi.nlm.nih.gov/28956544/"}
{"doc_id": "ef60ba55b695c1599db590f25a7eabc7", "sentence": "Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene .", "spans": [{"span_id": 0, "text": "ipilimumab", "start": 78, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "vemurafenib", "start": 201, "end": 212, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Vemurafenib  for the treatment of melanoma. Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents ; ipilimumab , a humanized , IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) and vemurafenib , a BRAF ( v-raf murine sarcoma viral oncogene homolog B1 ) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene . ### Areas Covered The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading 'vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma. ### Expert Opinion vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research.", "source": "https://pubmed.ncbi.nlm.nih.gov/23094782/"}
{"doc_id": "9946a786a927a415bf77bbafa138aa28", "sentence": "Anesthetized rats received a single intravenous injection of epinephrine ( 25 , 50 , or 100 mcg/kg ) ; matched cohorts were pretreated with phentolamine ( 100 mcg/kg ) ; n = 5 for each of the six treatment groups .", "spans": [{"span_id": 0, "text": "epinephrine", "start": 61, "end": 72, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "phentolamine", "start": 140, "end": 152, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Epinephrine induces rapid deterioration in pulmonary oxygen exchange in intact, anesthetized rats: a flow and pulmonary capillary pressure-dependent phenomenon. Previous studies indicate epinephrine adversely affects arterial oxygenation when administered in a rat model of local anesthetic overdose. The authors tested whether epinephrine alone exerts similar effects in the intact animal. ### methods Anesthetized rats received a single intravenous injection of epinephrine ( 25 , 50 , or 100 mcg/kg ) ; matched cohorts were pretreated with phentolamine ( 100 mcg/kg ) ; n = 5 for each of the six treatment groups . Arterial pressure and blood gases were measured at baseline, 1 and 10 min after epinephrine administration. Pulmonary capillary pressures during epinephrine infusion with normal and increased flows were measured in an isolated lung preparation. ### results epinephrine injection in the intact animal caused hypoxemia, hypercapnia, and acidosis at all doses. Arterial oxygen tension was reduced within 1 min of injection. Hyperlactatemia occurred by 10 min after 50 and 100 mcg/kg. Rate pressure product was decreased by 10 min after 100 mcg/kg epinephrine. Pretreatment with phentolamine attenuated these effects except at 100 mcg/kg epinephrine. In the isolated lung preparation, epinephrine in combination with increased pulmonary flow increased pulmonary capillary pressure and lung water. ### conclusions Bolus injection of epinephrine in the intact, anesthetized rat impairs pulmonary oxygen exchange within 1 min of treatment. Effects were blunted by \u03b1-adrenergic receptor blockade. Edema occurred in the isolated lung above a threshold pulmonary capillary pressure when epinephrine treatment was coupled with an increase in pulmonary flow. These results potentially argue against using traditional doses of epinephrine for resuscitation, particularly in the anesthetized patient.", "source": "https://pubmed.ncbi.nlm.nih.gov/22902967/"}
{"doc_id": "422758913c79dd8028aaaa6c7e96e8fd", "sentence": "Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy .", "spans": [{"span_id": 0, "text": "Ipilimumab", "start": 98, "end": 108, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "Nivolumab", "start": 111, "end": 120, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "Ipilimumab", "start": 125, "end": 135, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "Chemotherapy", "start": 138, "end": 150, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Pharmacological interventions for melanoma: Comparative analysis using bayesian meta-analysis. We conducted a network meta-analysis in order to compare different strategies for managing melanoma patients. Electronic databases were searched for eligible randomized trials that compared different strategies in efficacy and tolerability. Five interventions were associated with a significant improvement in PFS over chemotherapy (all HR < 1): ipilimumab, tremelimumab, nivolumab, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. Three interventions exhibited significantly improved OS results over chemotherapy ( all HR < 1 ): Ipilimumab , Nivolumab and Ipilimumab + Chemotherapy . Four interventions were superior to chemotherapy in CR and PR (all OR > 1): nivolumab, pembrolizumab 10 mg/kg, pembrolizumab 2 mg/kg and ipilimumab + nivolumab. However, the other seven interventions were associated with an increased risk of pruritus compared to chemotherapy (all OR > 1). ipilimumab, tremelimumab, ipilimumab + nivolumab and ipilimumab + Chemotherapy might result in a higher risk of diarrhea compared to chemotherapy (all OR > 1). Immune checkpoint therapy or combined interventions might be more effective than chemotherapy for managing melanoma patients. However, chemotherapy appears to be more tolerable than these combined strategies with respect to adverse events.", "source": "https://pubmed.ncbi.nlm.nih.gov/27764796/"}
{"doc_id": "438f02449febdb538919b85102dab9ea", "sentence": "The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 105, "end": 116, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "cyclophosphamide", "start": 121, "end": 137, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "paclitaxel", "start": 163, "end": 173, "token_start": 23, "token_end": 24}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Criterion validity of Medicare chemotherapy claims in Cancer and Leukemia Group B breast and lung cancer trial participants. To determine the accuracy with which Medicare claims data measure chemotherapy use in elderly Medicare beneficiaries with cancer, we performed a criterion validation study. We compared gold-standard clinical trial data for 175 elderly cancer patients treated in two Cancer and Leukemia Group B (CALGB) breast and lung cancer trials (i.e., 45 from trial 9344 and 130 from trial 9730) with contemporaneous ambulatory and in-patient Medicare health insurance claims data from Centers for Medicare and Medicaid Services (CMS). The breast trial participants studied were those elderly enrolled between 1995 and 1997 and treated with doxorubicin and cyclophosphamide or this combination with paclitaxel . The lung trial participants studied were those elderly enrolled between 1998 and 2000 and treated with paclitaxel and carboplatin or paclitaxel alone. Comparing CALGB data with Medicare claims, we found the crude sensitivity for chemotherapy administration was 93% (95% confidence interval [CI] = 88% to 96%). Individual chemotherapy agents had similarly high sensitivities, ranging from 81% (95% CI = 70% to 89%) for carboplatin to 91% (95% CI = 79% to 98%) for cyclophosphamide. Agent-specific specificities were 100%. CMS data reliably captured repeat administration of chemotherapy to within one cycle. Administrative Medicare claims data appear to be a valid source of information for chemotherapy administered to elderly Medicare beneficiaries with cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/16030306/"}
{"doc_id": "ae2ba8df041969a9a318e41ab57be3d2", "sentence": "The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities .", "spans": [{"span_id": 0, "text": "bleomycin", "start": 50, "end": 59, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "etoposide", "start": 62, "end": 71, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "doxorubicin", "start": 74, "end": 85, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "cyclophosphamide", "start": 88, "end": 104, "token_start": 12, "token_end": 13}, {"span_id": 4, "text": "vincristine", "start": 107, "end": 118, "token_start": 14, "token_end": 15}, {"span_id": 5, "text": "procarbazine", "start": 121, "end": 133, "token_start": 16, "token_end": 17}, {"span_id": 6, "text": "prednisone", "start": 140, "end": 150, "token_start": 19, "token_end": 20}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4, 5, 6], "is_context_needed": true}], "paragraph": "PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.  The intensive polychemotherapy regimen eBEACOPP ( bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone in escalated doses ) is very active in patients with advanced-stage Hodgkin 's lymphoma , albeit at the expense of severe toxicities . Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. ### methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8\u2008\u00d7\u2008eBEACOPP in total) or eBEACOPP with rituximab (8\u2008\u00d7\u2008R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8\u2008\u00d7\u2008eBEACOPP) or experimental treatment with two additional cycles (4\u2008\u00d7\u2008eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6\u2008\u00d7\u2008eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6\u2008\u00d7\u2008eBEACOPP and patients with negative PET-2 were randomly assigned to 6\u2008\u00d7\u2008eBEACOPP (standard) or 4\u2008\u00d7\u2008eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs \u226545 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m ### findings Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89\u00b77% (95% CI 85\u00b74-94\u00b70) with eBEACOPP and 88\u00b71% (83\u00b75-92\u00b77) with R-eBEACOPP (log-rank p=0\u00b746). Patients with negative PET-2 randomly assigned to either 8\u2008\u00d7\u2008eBEACOPP or 6\u2008\u00d7\u2008eBEACOPP (n=504) or 4\u2008\u00d7\u2008eBEACOPP (n=501) had 5-year progression-free survival of 90\u00b78% (95% CI 87\u00b79-93\u00b77) and 92\u00b72% (89\u00b74-95\u00b70), respectively (difference 1\u00b74%, 95% CI -2\u00b77 to 5\u00b74). 4\u2008\u00d7\u2008eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8\u2008\u00d7\u2008eBEACOPP or 6\u2008\u00d7\u2008eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8\u2008\u00d7\u2008eBEACOPP group, three [1%] in the 8\u2008\u00d7\u2008R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8\u2008\u00d7\u2008eBEACOPP or 6\u2008\u00d7\u2008eBEACOPP group). ### interpretation The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. ### funding Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.", "source": "https://pubmed.ncbi.nlm.nih.gov/29061295/"}
{"doc_id": "c63002cc4497bdfb032257bcd9cf54cc", "sentence": "Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments .", "spans": [{"span_id": 0, "text": "bexarotene", "start": 112, "end": 122, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "denileukin diftitox", "start": 128, "end": 147, "token_start": 20, "token_end": 22}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Interventions for mycosis fungoides. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. ### objectives To assess the effects of interventions for mycosis fungoides in all stages of the disease. ### Search Methods We searched the following databases up to January 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), and LILACS (from 1982). We also checked reference lists of included studies for further references to relevant RCTs. We searched online trials registries for further references to unpublished trials and undertook a separate search for adverse effects of interventions for mycosis fungoides in non-RCTs in MEDLINE in May 2011. ### Selection Criteria Randomised controlled trials (RCTs) of interventions for mycosis fungoides in people with any stage of the disease. At least 90% of participants in the trials must have been diagnosed with mycosis fungoides (Alibert-Bazin-type). ### Data Collection And Analysis Two authors independently assessed eligibility and methodological quality for each study and carried out data extraction. We resolved any disagreement by discussion. Primary outcomes were the impact on quality of life and the safety of interventions. When available, we reported on our secondary outcomes, which were the improvement or clearance of skin lesions, disease-free intervals, survival rates, relapse rates, and rare adverse effects. When possible, we combined homogeneous studies for meta-analysis. We used The Cochrane Collaboration's 'Risk of bias' tool to assess the internal validity of all included studies in six different domains. ### Main Results The review included 14 RCTs involving 675 participants, covering a wide range of interventions. Eleven of the included trials assessed participants in clinical stages IA to IIB only (please see Table 1 for definitions of these stages).Internal validity was considerably low in studies with a high or unclear risk of bias. The main reasons for this were low methodological quality or missing data, even after we contacted the study authors, and a mean dropout rate of 26% (0% to 72%). Study size was generally small with a minimum of 4 and a maximum of 103 participants. Only one study provided a long enough follow-up for reliable survival analysis.Included studies assessed topical treatments, such as imiquimod, peldesine, hypericin, nitrogen mustard, as well as intralesional injections of interferon-\u03b1 (IFN-\u03b1). The light therapies investigated included psoralen plus ultraviolet A light (PUVA), extracorporeal photopheresis (photochemotherapy), and visible light. Oral treatments included acitretin, bexarotene, and methotrexate. Treatment with parenteral systemic agents consisted of denileukin diftitox; a combination of chemotherapy and electron beam radiation; and intramuscular injections of active transfer factor. Nine studies evaluated therapies by using an active comparator; five were placebo-controlled RCTs.Twelve studies reported on common adverse effects, while only two assessed quality of life. None of these studies compared the health-related quality of life of participants undergoing different treatments. Most of the reported adverse effects were attributed to the interventions. Systemic treatments , and here in particular a combined therapeutic regimen of chemotherapy and electron beam , bexarotene , or denileukin diftitox , showed more adverse effects than topical or skin-directed treatments .In the included studies, clearance rates ranged from 0% to 83%, and improvement ranged from 0% to 88%. The meta-analysis combining the results of 2 trials comparing the effect of IFN-\u03b1 and PUVA versus PUVA alone showed no significant difference in the relative risk of clearance: 1.07 (95% confidence interval 0.87 to 1.31). None of the included studies demonstrated a significant increase in disease-free intervals, relapse, or overall survival. ### Authors Conclusions This review identified trial evidence for a range of different topical and systemic interventions for mycosis fungoides. Because of substantial heterogeneity in design, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be established on the basis of the included RCTs. Taking into account the possible serious adverse effects and the limited availability of efficacy data, topical and skin-directed treatments are recommended first, especially in the early stages of disease. More aggressive therapeutic regimens may show improvement or clearance of lesions, but they also result in more adverse effects; therefore, they are to be considered with caution. Larger studies with comparable, clearly-defined end points for all stages of mycosis fungoides, and a focus on safety, quality of life, and duration of remission as part of the outcome measures, are necessary.", "source": "https://pubmed.ncbi.nlm.nih.gov/22972128/"}
{"doc_id": "cb3f244bc027dd4d8edb28f71cbb3533", "sentence": "The incident number of the infected mice was significantly different among groups with different drugs and doses : 2/60 , 16/60 , 10/60 and 10/60 in the groups of Changqing capsule , spiramycin , pyrimethamine and azithromycin respectively ( P < 0.05 ) .", "spans": [{"span_id": 0, "text": "spiramycin", "start": 183, "end": 193, "token_start": 32, "token_end": 33}, {"span_id": 1, "text": "pyrimethamine", "start": 196, "end": 209, "token_start": 34, "token_end": 35}, {"span_id": 2, "text": "azithromycin", "start": 214, "end": 226, "token_start": 36, "token_end": 37}], "rels": [], "paragraph": "[In vitro effect of combined traditional Chinese medicine (Changqing capsule) on the tachyzoites of Toxoplasma gondii]. To detect the in vitro effect of the traditional Chinese medicine on the tachyzoites of Toxoplasma gondii. ### methods Supernatant (1.5 ml) of different doses of the traditional Chinese medicine (Changqing capsule) was collected by normal saline immersion and 2.5 x 10(4) Toxoplasma gondii tachyzoites were added in each paste well for 8 hours. spiramycin, pyrimethamine and azithromycin in different doses were used as controls. Normal saline was used as negative control. Mice were inoculated with drug-treated tachyzoites intraperitoneally or intragastrically. The normal mice were subcultured after 8 days for 3 generations. ### results The incident number of the infected mice was significantly different among groups with different drugs and doses : 2/60 , 16/60 , 10/60 and 10/60 in the groups of Changqing capsule , spiramycin , pyrimethamine and azithromycin respectively ( P < 0.05 ) . No mice were found incident in groups of high and medium dose Changqing capsule while 2 out of 20 found sick in the low dose group (P < 0.05). The subculture observation showed that 2 and 1 mice in the first generation of the low dose Changqing capsule group inoculated intraperitonelly and intragastrically were found infected respectively. 2 mice of the second generation in low dose spiramycin group and 1 mouse of the third generation in low dose pyrimethamine group were also found infected. ### conclusion The in vitro killing effect of the Changqing capsule on the tachyzoites of Toxoplasma gondii is better than the current clinical drugs and shows a positive correlation with the dosages.", "source": "https://pubmed.ncbi.nlm.nih.gov/16866146/"}
{"doc_id": "c4282f342c8740913c7239c8d24b0a85", "sentence": "In total , seven different interventions ( Chloroquine , Mefloquine , Mefloquine artesunate , Proguanil , Pyrimethamine , Sulfadoxine-pyrimethamine , Sulfadoxine-pyrimethamine amodiaquine ) were evaluated in 912 children with SCD .", "spans": [{"span_id": 0, "text": "Chloroquine", "start": 43, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Mefloquine", "start": 57, "end": 67, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "Mefloquine", "start": 70, "end": 80, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "artesunate", "start": 81, "end": 91, "token_start": 12, "token_end": 13}, {"span_id": 4, "text": "Proguanil", "start": 94, "end": 103, "token_start": 14, "token_end": 15}, {"span_id": 5, "text": "Pyrimethamine", "start": 106, "end": 119, "token_start": 16, "token_end": 17}, {"span_id": 6, "text": "amodiaquine", "start": 176, "end": 187, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Safety and effectiveness of antimalarial therapy in sickle cell disease: a systematic review and network meta-analysis. About 80% of all reported sickle cell disease (SCD) cases in children anually are recorded in Africa. Although malaria is considered a major cause of death in SCD children, there is limited data on the safety and effectiveness of the available antimalarial drugs used for prophylaxis. Also, previous systematic reviews have not provided quantitative measures of preventive effectiveness. The purpose of this research was to conduct a systematic review and meta-analysis of the available literature to determine the safety and effectiveness of antimalarial chemoprophylaxis used in SCD patients. ### methods We searched in PubMed, Medline, CINAHL, POPLine and Cochrane library, for the period spanning January 1990 to April 2018. We considered randomized or quasi-randomized controlled trials comparing any antimalarial chemoprophylaxis to, 1) other antimalarial chemoprophylaxis, 2) placebo or 3) no intervention, in SCD patients. Studies comparing at least two treatment arms, for a minimum duration of three months, with no restriction on the number of patients per arm were reviewed. The data were extracted and expressed as odds ratios. Direct pairwise comparisons were performed using fixed effect models and the heterogeneity assessed using the I-square. ### results Six qualified studies that highlighted the importance of antimalarial chemoprophylaxis in SCD children were identified. In total , seven different interventions ( Chloroquine , Mefloquine , Mefloquine artesunate , Proguanil , Pyrimethamine , Sulfadoxine-pyrimethamine , Sulfadoxine-pyrimethamine amodiaquine ) were evaluated in 912 children with SCD . Overall, the meta-analysis showed that antimalarial chemoprophylaxis provided protection against parasitemia and clinical malaria episodes in children with SCD. Nevertheless, the risk of hospitalization (OR\u2009=\u20090.72, 95% CI\u2009=\u20090.267-1.959; I ### conclusion The data shows that antimalarial prophylaxis reduces the incidence of clinical malaria in children with SCD. However, there was no difference between the occurrence of adverse events in children who received placebo and those who received prophylaxis. This creates an urgent need to assess the efficacy of new antimalarial drug regimens as potential prophylactic agents in SCD patients. ### Systematic Review Registration PROSPERO (CRD42016052514).", "source": "https://pubmed.ncbi.nlm.nih.gov/30541465/"}
{"doc_id": "566beddae5f4a864547e3dd6650f5e85", "sentence": "We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib , carfilzomib , or ixazomib .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 101, "end": 111, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "carfilzomib", "start": 114, "end": 125, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "ixazomib", "start": 131, "end": 139, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Identification\u00a0of\u00a0Long\u00a0Non-Coding\u00a0RNAs Deregulated\u00a0in\u00a0Multiple\u00a0Myeloma\u00a0Cells\u00a0Resistant\u00a0to Proteasome\u00a0Inhibitors. While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib , carfilzomib , or ixazomib . Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM.", "source": "https://pubmed.ncbi.nlm.nih.gov/27782060/"}
{"doc_id": "6357d2a470758a4d5aea49835ba7b900", "sentence": "However , we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group .", "spans": [{"span_id": 0, "text": "valsartan", "start": 126, "end": 135, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "amlodipine", "start": 157, "end": 167, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART. The valsartan amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However , we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group . There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.", "source": "https://pubmed.ncbi.nlm.nih.gov/21993491/"}
{"doc_id": "3d1bf519d3d919348aa6eab2ae11a2bd", "sentence": "Effects of chloroquine , mefloquine and quinine on natural killer cell activity in vitro .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 11, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "mefloquine", "start": 25, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "quinine", "start": 40, "end": 47, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Effects of chloroquine , mefloquine and quinine on natural killer cell activity in vitro . Natural killer (NK) cell activity against K 562 target cells was inhibited by pharmacological concentrations of chloroquine, mefloquine and quinine. The most potent were mefloquine and quinine. The drug-induced inhibition of the NK cell activity was abolished by addition of alpha-interferon (IF) or interleukin 2 (Il-2); preincubation of mononuclear cells with IF or Il-2 followed by addition of anti-malarial drugs decreased the inhibitory effects of the drugs. The drug-induced inhibition of the NK cell activity was not dependent on the presence of monocytes. Using monocyte depleted Percoll fractionated NK cell enriched populations in a single cell agarose assay, it was shown that the inhibitory effects of mefloquine, but not of chloroquine and quinine were due to an inhibition of the formation of effector/target cell conjugates.", "source": "https://pubmed.ncbi.nlm.nih.gov/2431633/"}
{"doc_id": "dd4bbac74556ad8a14b439a38da022bd", "sentence": "Fulvestrant ( intramuscular injection 250 mg month(-1 ) ) was found to be at least as effective as anastrozole ( orally 1 mg day(-1 ) ) for time to progression ( 5.5 vs 4.1 months , respectively ( hazard ratio ( HR ): 0.95 ; 95.14 % confidence interval ( CI ) , 0.82 - 1.10 ; P=0.48 ) ) and objective response 19.2 vs 16.5 % , respectively ; treatment difference 2.75 % ; 95.14 % CI , -2.27 to 9.05 % ; P=0.31 ) .", "spans": [{"span_id": 0, "text": "Fulvestrant", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "anastrozole", "start": 99, "end": 110, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: results from clinical trials. fulvestrant ('Faslodex') is a new type of endocrine treatment--an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects. Early efficacy data from phase I/II trials have demonstrated fulvestrant to be effective and well tolerated. Two randomised phase III trials have compared the efficacy of fulvestrant and the aromatase inhibitor, anastrozole, in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy. Fulvestrant ( intramuscular injection 250 mg month(-1 ) ) was found to be at least as effective as anastrozole ( orally 1 mg day(-1 ) ) for time to progression ( 5.5 vs 4.1 months , respectively ( hazard ratio ( HR ): 0.95 ; 95.14 % confidence interval ( CI ) , 0.82 - 1.10 ; P=0.48 ) ) and objective response 19.2 vs 16.5 % , respectively ; treatment difference 2.75 % ; 95.14 % CI , -2.27 to 9.05 % ; P=0.31 ) . More recently, fulvestrant has also been shown to be noninferior to anastrozole in terms of overall survival, with median time to death being 26.4 months in fulvestrant-treated patients and 24.2 months in those treated with anastrozole (HR: 0.97; 95% CI, 0.78-1.21; P=0.82). In a further randomised phase III trial, fulvestrant was compared with tamoxifen as first-line therapy for advanced disease in postmenopausal women. In the overall population, efficacy differences favoured tamoxifen and noninferiority of fulvestrant could not be ruled out. In the prospectively defined subset of patients with ER-positive and/or progesterone receptor-positive disease, there was no statistically significant difference between fulvestrant and tamoxifen. This paper reviews the efficacy and tolerability results from these trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/15094759/"}
{"doc_id": "267cd5b262efa4d0f40eeeab4d4e304c", "sentence": "Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 62, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "trastuzumab", "start": 279, "end": 290, "token_start": 59, "token_end": 60}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients. Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. ### methods We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. ### results Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [ adjusted hazard ratio ( aHR ) = 1.02 , 95 % confidence interval ( CI ) 1.00 - 1.04 ; p = 0.05 ] , metastasis ( aHR = 2.66 ; 95 % CI 1.36 - 5.20 ; p < 0.01 ) , and concomitant trastuzumab ( aHR = 4.08 ; 95 % CI 2.31 - 7.21 ; p\u2009<\u20090.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2\u00a0years (without substantial change from about 9\u00a0months)and 20.2% at 2\u00a0years (without substantial change from about 15\u00a0months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. ### conclusions Susceptibility to chemotherapy-induced cardiotoxicity within 2\u00a0years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9\u00a0months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15\u00a0months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/32468335/"}
{"doc_id": "9b8558943abd223f38c55dac03ee9082", "sentence": "Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 100, "end": 110, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "carboplatin", "start": 125, "end": 136, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Preliminary results of a dose-finding study of paclitaxel and carboplatin in patients with advanced non-small cell lung cancer. This ongoing phase I study sought to establish the maximum tolerated dose of the combination of carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. paclitaxel was administered as a 3-hour intravenous infusion. The carboplatin infusion was administered over 30 minutes immediately afterward. Patients were assigned sequentially to one of eight treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 185 mg/m2 and from 230 to 350 mg/m2, respectively. Twenty-four patients have been treated to date , and the maximum tolerated dose has been reached at paclitaxel 185 mg/m2 and carboplatin 350 mg/m2 . The combination has an excellent safety profile, with only a few, short-lasting episodes of neutropenia observed and no evidence of infection. At the doses tested, thrombocytopenia has not occurred.", "source": "https://pubmed.ncbi.nlm.nih.gov/9007129/"}
{"doc_id": "5af37444c8364f62af66ab7987da2456", "sentence": "FAB M5 was significantly more sensitive than FAB M4 to most drugs frequently used in AML , as indicated by the following ratios of median sensitivities : the anthracyclines ( 2.6- to 3.2-fold ) , mitoxantrone ( 12.5-fold ) , etoposide ( 8.7-fold ) , and cytarabine ( 2.9-fold ) .", "spans": [{"span_id": 0, "text": "mitoxantrone", "start": 196, "end": 208, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "etoposide", "start": 225, "end": 234, "token_start": 40, "token_end": 41}, {"span_id": 2, "text": "cytarabine", "start": 254, "end": 264, "token_start": 46, "token_end": 47}], "rels": [], "paragraph": "Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia. Determining in vitro drug resistance may reveal clinically relevant information in childhood leukemia. Using the methyl-thiazol-tetrazolium assay, the resistance of untreated leukemic cells to 21 drugs was compared in 128 children with acute myeloid leukemia (AML) and 536 children with acute lymphoblastic leukemia (ALL). The differences between 3 French-American-British (FAB) types (M1/M2, M4, and M5) were also compared. AML was significantly more resistant than ALL to the following drugs, as noted by the median resistance: glucocorticoids (greater than 85-fold), vincristine (4.4-fold), L-asparaginase (6.9-fold), anthracyclines (1.8- to 3.4-fold), mitoxantrone (2.6-fold), etoposide (4.9-fold), platinum analogues (2.4- to 3.4-fold), ifosfamide (3.5-fold), and thiotepa (3.9-fold). For cytarabine and thiopurines, the median LC50 values (the drug concentration that kills 5% of the cells) were equal. Also, busulfan, amsacrine, teniposide, and vindesine showed no significant differences, but the numbers were smaller, and the median LC50 values were 1.3- to 5.2-fold higher in AML. None of the drugs demonstrated greater cytotoxicity in AML. FAB M5 was significantly more sensitive than FAB M4 to most drugs frequently used in AML , as indicated by the following ratios of median sensitivities : the anthracyclines ( 2.6- to 3.2-fold ) , mitoxantrone ( 12.5-fold ) , etoposide ( 8.7-fold ) , and cytarabine ( 2.9-fold ) . For etoposide and cytarabine (5.4- and 3.4-fold, respectively) FAB M5 was also significantly more sensitive than FAB M1/M2. FAB M5 was equally sensitive to L-asparaginase and vincristine as ALL. Only 15% of the AML samples were \"intermediately\" sensitive to glucocorticoids, mainly in FAB M1/M2. The poorer prognosis of childhood AML is related to resistance to a large number of drugs. Within AML, FAB M5 had a distinct resistance pattern. These resistance profiles may be helpful in the rational design of further treatment protocols. (Blood. 2000;96:2879-2886)", "source": "https://pubmed.ncbi.nlm.nih.gov/11023525/"}
{"doc_id": "76f53d15b6627c4c13e14f047a241f67", "sentence": "[ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] .", "spans": [{"span_id": 0, "text": "Aztreonam", "start": 2, "end": 11, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "gentamicin", "start": 15, "end": 25, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "piperacillin", "start": 40, "end": 52, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "[ Aztreonam or gentamicin combined with piperacillin as empiric antibiotic therapy during neutropenia of patients with hematologic diseases ] . Fourty-two febrile episodes of 32 patients with hematologic disease during neutropenia were treated with two randomly assigned antibiotic combinations of either piperacillin plus gentamicin or piperacillin plus aztreonam. Eleven of the 22 febrile episodes treated with piperacillin plus gentamicin and 12 of the 20 febrile episodes treated with piperacillin plus aztreonam responded. Addition of cefamandole to non-responders improved the outcome in 2 of the 16 febrile episodes. Mean nadir leucocyte count, age, sex, and underlying disease were not significantly different in both groups. Side effects were tolerable in both groups, although 1 patient treated with piperacillin plus gentamicin showed severe renal impairment. piperacillin plus aztreonam is as effective as piperacillin plus gentamicin as an empiric antibiotic combination in the treatment of febrile episodes with hematologic disease during neutropenia.", "source": "https://pubmed.ncbi.nlm.nih.gov/1402071/"}
{"doc_id": "c8c3eefd188ec9458a1b50c453b92dfb", "sentence": "The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man .", "spans": [{"span_id": 0, "text": "salbutamol", "start": 68, "end": 78, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "digoxin", "start": 106, "end": 113, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effect of salbutamol on digoxin pharmacokinetics. A single dose of the beta 2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a beta 2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man . Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 micrograms.kg-1.h-1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i.v. injection of digoxin 15 micrograms.kg-1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0-6 h was 15% lower during salbutamol infusion than during saline infusion. salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/1618253/"}
{"doc_id": "f6650ee92d2f6ba1fb001d64344a260b", "sentence": "Mecamylamine reversed the effects of nicotine on SHR performance .", "spans": [{"span_id": 0, "text": "Mecamylamine", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "nicotine", "start": 37, "end": 45, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Nicotine-induced behavioral sensitization in an adult rat model of attention deficit/hyperactivity disorder (ADHD). Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90\u00b0 rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance . These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD.", "source": "https://pubmed.ncbi.nlm.nih.gov/27363925/"}
{"doc_id": "a2471412eb546f1cfa6a282660907512", "sentence": "The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis .", "spans": [{"span_id": 0, "text": "leflunomide", "start": 42, "end": 53, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "cyclosporin", "start": 58, "end": 69, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis .", "source": "https://pubmed.ncbi.nlm.nih.gov/8907592/"}
{"doc_id": "bd6411f1a1b7f41d6e10153cd2202962", "sentence": "In the metastatic setting , FOLFIRINOX ( folinic acid , 5-fluorouracil , irinotecan , and oxaliplatin ) , and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival .", "spans": [{"span_id": 0, "text": "folinic", "start": 41, "end": 48, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "5-fluorouracil", "start": 56, "end": 70, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "irinotecan", "start": 73, "end": 83, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "oxaliplatin", "start": 90, "end": 101, "token_start": 15, "token_end": 16}, {"span_id": 4, "text": "nab-paclitaxel", "start": 110, "end": 124, "token_start": 19, "token_end": 20}, {"span_id": 5, "text": "gemcitabine", "start": 130, "end": 141, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [4, 5], "is_context_needed": true}], "paragraph": "Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting , FOLFIRINOX ( folinic acid , 5-fluorouracil , irinotecan , and oxaliplatin ) , and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival . Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state-of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed.", "source": "https://pubmed.ncbi.nlm.nih.gov/25824606/"}
{"doc_id": "53a14a119d41a911324fb13bb24c206b", "sentence": "Patients in arm 1 ( n = 88 ) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 50, "end": 60, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "carboplatin", "start": 65, "end": 76, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "gemcitabine-based", "start": 106, "end": 123, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE-compliant study. We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE-compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 ( n = 88 ) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy . Patients in arm 2 (n\u200a=\u200a90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P\u200a=\u200a0.003]) as well as 5-year OS (34.1% and 18.9% [P\u200a=\u200a0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P\u200a=\u200a0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/28002342/"}
{"doc_id": "09afedc0b9034c5961cc31e111f44242", "sentence": "In patients receiving digoxin and propafenone simultaneously , the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity .", "spans": [{"span_id": 0, "text": "digoxin", "start": 22, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "propafenone", "start": 34, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "digoxin", "start": 100, "end": 107, "token_start": 15, "token_end": 16}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Interaction between digoxin and propafenone. The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously , the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity .", "source": "https://pubmed.ncbi.nlm.nih.gov/2911842/"}
{"doc_id": "f12072676087f8e74c862655cba32504", "sentence": "To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib ( LAP ) in combination with an aromatase inhibitor ( AI ) and trastuzumab ( TRA ) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive ( HER2 + ) mBC .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 78, "end": 87, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "AI", "start": 141, "end": 143, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "trastuzumab", "start": 150, "end": 161, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis. Breast cancer is the uncontrolled, abnormal growth of malignant breast tissue affecting predominantly women. Metastatic breast cancer (mBC) is an advanced stage of the disease when the disease has spread beyond the original organ. Hormone receptor status and human epidermal growth factor 2 (HER2) status are two predictive factors that are taken into consideration when estimating the prognosis of patients with breast cancer. ### objectives To review the clinical effectiveness and cost-effectiveness evidence base for lapatinib ( LAP ) in combination with an aromatase inhibitor ( AI ) and trastuzumab ( TRA ) in combination with an AI for the first-line treatment of patients who have hormone receptor-positive (HR+)/human epidermal growth factor 2-positive ( HER2 + ) mBC . ### Data Sources Relevant electronic databases and websites, including MEDLINE, EMBASE and the Cochrane Library, were searched until May 2010. Further data were derived from the manufacturers' submissions for LAP + AI and TRA + AI. ### Review Methods A systematic review of the clinical effectiveness and cost-effectiveness of LAP + AI and TRA + AI was undertaken. As it was deemed inappropriate to compare LAP + AI with TRA + AI, two separate assessments of cost-effectiveness versus AIs alone were undertaken. ### results Three trials were included in the systematic review [the patient populations of the efficacy and safety of lapatinib combined with letrozole (EGF30008) trial, the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) trial and the efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) trial]. As a result of differences in the exclusion criteria and because one trial was halted prematurely, comparisons across trials were believed to be inappropriate and meta-analysis was not possible. Individually, however, the findings from the trials all suggest that LAP + AI or TRA + AI results in improved progression-free survival and/or time to progression when compared with AIs alone. The trials do not show a statistically significant benefit in terms of overall survival. Two separate economic analyses were conducted based on the completed trials; neither LAP + AI nor TRA + AI was found to be cost-effective when compared with AI monotherapy. ### limitations Because of differences in the EGF30008 and the TAnDEM trials, the Assessment Group believes the indirect comparisons analyses conducted by the manufacturers are inappropriate and, for the same reason, chooses not to compare LAP + AI with TRA + AI in an economic evaluation. ### conclusions LAP + AI and TRA + AI appear to be clinically more effective than AI monotherapy, but neither is cost-effective compared with AIs alone. It was not possible to compare LAP + AI with TRA + AI. Future research should include research into treating mBC in the HR+/HER2+ population who are not TRA (or LAP) naive and into comparing the clinical effectiveness of AIs as monotherapy in patients with HER2+ and human epidermal growth factor 2-negative breast cancer. ### funding The National Institute for Health Research Technology Assessment programme.", "source": "https://pubmed.ncbi.nlm.nih.gov/22152751/"}
{"doc_id": "5291c1729be9df2b8b65f392854410de", "sentence": "Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass , our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance .", "spans": [{"span_id": 0, "text": "nateglinide", "start": 31, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "vildagliptin", "start": 47, "end": 59, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination therapy with nateglinide and vildagliptin improves postprandial metabolic derangements in Zucker fatty rats. Postprandial metabolic derangements are one of the risk factors of cardiovascular disease in humans. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial metabolic derangements. In this study, we investigated the potential utility of combination therapy with vildagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial metabolic derangements in Zucker Fatty (ZF) rats, an animal model of obesity with insulin resistance. ZF rats fed twice daily with or without high fat diet (HFD) were given vehicle, 50 mg/kg of nateglinide, 10 mg/kg of vildagliptin, or both for 6 weeks. Combination therapy with nateglinide and vildagliptin for 2 weeks ameliorated postprandial hyperglycemia, hypertriglyceridemia, and elevation of free fatty acid in ZF rats fed with HFD. 6-week treatment with nateglinide and vildagliptin not only increased hepatic levels of phosphorylated forkhead box protein 1A (FOXO1A), but also reduced triglyceride contents in the liver. Combination therapy also prevented the loss of pancreatic islet mass in ZF rats fed with HFD. These observations demonstrate that combination therapy with nateglinide and vildagliptin may improve postprandial metabolic derangements probably by ameliorating early phase of insulin secretion and hepatic insulin resistance, respectively, in ZF rats fed with HFD. Since combination therapy with nateglinide and vildagliptin restored the decrease in pancreatic beta cell mass , our present findings suggest that combination therapy could be a promising therapeutic strategy for postprandial dysmetabolism associated with obese and insulin resistance .", "source": "https://pubmed.ncbi.nlm.nih.gov/20625970/"}
{"doc_id": "e9bc93e6cd607f5ce2ab6d592ba99266", "sentence": "Paclitaxel , doxorubicin , tamoxifen , erlotinib , gefitinib , temozolomide , and methotrexate are among therapeutic agents whose efficacy is influenced by the expression of H19 .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 13, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "tamoxifen", "start": 27, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "erlotinib", "start": 39, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "gefitinib", "start": 51, "end": 60, "token_start": 8, "token_end": 9}, {"span_id": 5, "text": "temozolomide", "start": 63, "end": 75, "token_start": 10, "token_end": 11}, {"span_id": 6, "text": "methotrexate", "start": 82, "end": 94, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "The role of H19 lncRNA in conferring chemoresistance in cancer cells. H19 is an oncofetal transcript with crucial roles in the development and progression of several neoplastic cells. With anti-apoptotic, pro-proliferative, and pro-migratory functions, H19 affects the carcinogenic process from different functional points. In addition, H19 has central roles in the induction of chemoresistance in breast cancer, lung cancer, glioma, liver cancer, and other types of cancers. Induction of EMT, activation of oncogenic signaling pathways, and changes in the tumor microenvironment are among mechanisms of participation of H19 in chemoresistance. Paclitaxel , doxorubicin , tamoxifen , erlotinib , gefitinib , temozolomide , and methotrexate are among therapeutic agents whose efficacy is influenced by the expression of H19 . In the present paper, we discuss the impact of H19 in conferring resistance to chemotherapeutic agents in different cancers.", "source": "https://pubmed.ncbi.nlm.nih.gov/33667788/"}
{"doc_id": "a28fce0214516827c33a6acc9a87f898", "sentence": "Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide , vincristine and etoposide and also randomised to receive , on disease progression , either second line chemotherapy ( methotrexate and doxorubicin ) or symptomatic treatment only .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 96, "end": 112, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "vincristine", "start": 115, "end": 126, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "etoposide", "start": 131, "end": 140, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "methotrexate", "start": 233, "end": 245, "token_start": 34, "token_end": 35}, {"span_id": 4, "text": "doxorubicin", "start": 250, "end": 261, "token_start": 36, "token_end": 37}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [3, 4], "is_context_needed": true}], "paragraph": "Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. A total of 610 patients with small cell lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide , vincristine and etoposide and also randomised to receive , on disease progression , either second line chemotherapy ( methotrexate and doxorubicin ) or symptomatic treatment only . In the whole study 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial chemotherapy the response rate (complete and partial responses) after four courses of treatment was 61% with no significant increase in patients receiving eight courses (63%). In those randomised to receive relapse chemotherapy the response rate was improved slightly for those who had originally received four courses of chemotherapy (25.6%) over those receiving eight (18.7%). The overall results show that of the four possible treatment randomizations, four courses of chemotherapy alone is inferior in terms of overall survival (30 weeks median survival) to the other three treatment options (39 weeks median survival, P less than 0.01). In patients responding to initial chemotherapy the disadvantage of four courses of chemotherapy alone was apparent (median survival of 40 weeks versus 49 weeks, P = 0.003) but not if drug treatment was given on relapse. The study shows that limiting treatment to four courses of chemotherapy alone is associated with inferior survival, but this is not the case if chemotherapy is given at relapse.", "source": "https://pubmed.ncbi.nlm.nih.gov/2540788/"}
{"doc_id": "241b3b811402f79bbd36216dd0287f70", "sentence": "Amisulpride demonstrated a greater improvement in BPRS total scores ( P<0.05 ) and PANSS negative subscores ( P=0.0001 ) than haloperidol after 12 months of treatment in chronic schizophrenic patients with acute exacerbations .", "spans": [{"span_id": 0, "text": "Amisulpride", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "haloperidol", "start": 126, "end": 137, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Amisulpride: a review of its efficacy in schizophrenia. To assess the efficacy of the new atypical antipsychotic drug, amisulpride. ### method Studies comparing the efficacy of amisulpride with that of haloperidol and risperidone, respectively, are reviewed. Outcome measures were Clinical Global Impression, Brief Psychiatric Rating Scale (BPRS), and Positive And Negative Symptom Scale (PANSS) scores. ### results amisulpride was at least as effective as haloperidol and risperidone in the improvement of positive symptoms, and significantly more efficacious than haloperidol in reducing PANSS negative subscores (P=0.038) in patients with acute exacerbations. Amisulpride demonstrated a greater improvement in BPRS total scores ( P<0.05 ) and PANSS negative subscores ( P=0.0001 ) than haloperidol after 12 months of treatment in chronic schizophrenic patients with acute exacerbations . ### conclusion amisulpride can thus be considered for use as first-line treatment of acute and chronic schizophrenia.", "source": "https://pubmed.ncbi.nlm.nih.gov/10823307/"}
{"doc_id": "24bf61baac10caa2ceda2cdbe17c973c", "sentence": "In patients with acute cholecystitis , ampicillin plus tobramycin , cefoperazone and piperacillin had clinical cure rates of 85 , 95 and 95 per cent , respectively .", "spans": [{"span_id": 0, "text": "ampicillin", "start": 39, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "tobramycin", "start": 55, "end": 65, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "cefoperazone", "start": 68, "end": 80, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "piperacillin", "start": 85, "end": 97, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Antibiotics in infections of the biliary tract. The combination of a penicillin and an aminoglycoside has been recommended as the initial treatment of choice for patients with infections of the biliary tract. However, elderly, septic, patients with jaundice have a high incidence of renal problems. For this reason, amingolycoside treatment of these patients must be reevaluated as newer less nephrotoxic agents become available. We, therefore, performed a prospective, randomized trial of ampicillin plus tobramycin, cefoperazone and piperacillin in patients with biliary tract infections. During a 20 month period, 106 patients with acute cholecystitis (53) or cholangitis (53), or both, received one of these antibiotic regimens for a minimum of five days. In patients with acute cholecystitis , ampicillin plus tobramycin , cefoperazone and piperacillin had clinical cure rates of 85 , 95 and 95 per cent , respectively . In patients with cholangitis, however, cure rates for the three regimens were 85, 56 (p less than 0.05 versus ampicillin plus tobramycin) and 60 per cent (not significant versus ampicillin plus tobramycin), respectively. Moreover, 13 per cent of the patients receiving cefoperazone had an increased prothrombin time and three of 39 patients receiving this antibiotic had clinical problems with bleeding. Nephrotoxicity was greatest in patients with cholangitis receiving ampicillin plus tobramycin, 10 per cent, as compared with 3 per cent in those who did not receive an aminoglycoside. This difference, however, was not statistically significant. It was concluded that piperacillin should be considered for antibiotic management of patients with acute cholecystitis and that further studies are necessary in patients with cholangitis to determine whether or not newer agents should replace penicillin and aminoglycoside combinations.", "source": "https://pubmed.ncbi.nlm.nih.gov/3310282/"}
{"doc_id": "03ac9f494ca93f526d5d08ad0531741a", "sentence": "A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 51, "end": 61, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "docetaxel", "start": 69, "end": 78, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "pemetrexed", "start": 152, "end": 162, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "docetaxel", "start": 177, "end": 186, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "An evaluation of pemetrexed in second-line treatment of non-small cell lung cancer. pemetrexed is a novel antifolate antimetabolite that targets multiple folate-dependent enzymatic pathways and inhibits multiple enzymes involved in purine and pyrimidine synthesis. Its targets include pathways that, when amplified, are associated with reduced efficacy in conventional cytotoxic agents. As second-line treatment for advanced non-small cell lung cancer, (NSCLC) pemetrexed, when administered with folic acid and vitamin B12, has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel. A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel . Newer targeted therapies, especially the epidermal growth factor receptor inhibitors gefitinib and erlotinib, have produced conflicting results and have only been compared with best supportive care and placebo. They should be compared directly to pemetrexed as second-line therapy in large, randomised studies of patients with advanced NSCLC. For patients with advanced recurrent NSCLC and good performance status who progress after first-line chemotherapy, pemetrexed should be considered as a new standard of care.", "source": "https://pubmed.ncbi.nlm.nih.gov/16318436/"}
{"doc_id": "f25d84924710d85834c20bd5df3dceea", "sentence": "Tazobactam has inhibitory activity , and therefore protects piperacillin against Richmond and Sykes types II , III , IV and V beta-lactamases , staphylococcal penicillinase and extended-spectrum beta-lactamases .", "spans": [{"span_id": 0, "text": "Tazobactam", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "piperacillin", "start": 60, "end": 72, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase-producing bacteria. Tazobactam has inhibitory activity , and therefore protects piperacillin against Richmond and Sykes types II , III , IV and V beta-lactamases , staphylococcal penicillinase and extended-spectrum beta-lactamases . However, tazobactam has only species-specific activity against class I chromosomally-mediated enzymes. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia and Enterococcus faecium. Consistent with its in vitro activity, preliminary clinical data indicate that the fixed combination of piperacillin/tazobactam (dose ratio 8:1) is effective in the treatment of moderate to severe polymicrobial infections, including intra-abdominal, skin and soft-tissue and lower respiratory tract infections. In limited comparative trials, piperacillin/tazobactam demonstrated equivalent or better efficacy than standard comparator regimens in these infections. piperacillin/tazobactam in combination with an aminoglycoside was effective in the empirical treatment of fever in patients with neutropenia and compared favourably with ceftazidime in combination with an aminoglycoside, although second-line therapy with a glycopeptide antibiotic may be indicated in unresponsive episodes. Data from phase III trials indicate that piperacillin/tazobactam has a tolerability profile typical of a penicillin agent. piperacillin/tazobactam provides a broad spectrum of antibacterial activity in a convenient single formulation suitable for use in the treatment of polymicrobial infections. Possible limitations concern its restricted activity against class I beta-lactamases, enzymes that are becoming increasingly important in the nosocomial environment. Combined therapy with an aminoglycoside may be necessary in more serious infections.", "source": "https://pubmed.ncbi.nlm.nih.gov/7514977/"}
{"doc_id": "4d7d05a563202fd48c05ee58a0d965ac", "sentence": "The diagnosis was stage IIIA HHV-8-LBL , and he was treated with 6 cycles of R-EPOCH ( rituximab , etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) infusion chemotherapy .", "spans": [{"span_id": 0, "text": "rituximab", "start": 87, "end": 96, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "etoposide", "start": 99, "end": 108, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "vincristine", "start": 111, "end": 122, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "doxorubicin", "start": 125, "end": 136, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "cyclophosphamide", "start": 139, "end": 155, "token_start": 25, "token_end": 26}, {"span_id": 5, "text": "prednisone", "start": 162, "end": 172, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "Human Herpesvirus Type 8-associated Large B-cell Lymphoma: A Nonserous Extracavitary Variant of Primary Effusion Lymphoma in an\u00a0HIV-infected Man: A Case Report and Review\u00a0of\u00a0the Literature. Primary effusion lymphoma (PEL) is a rare non-Hodgkin lymphoma subtype primarily seen in human immunodeficiency virus (HIV)-infected individuals with low CD4(+) cell counts and elevated HIV viral loads. It has always been associated with human herpesvirus type 8 (HHV-8) and in 80% of cases has also been associated with Epstein-Barr virus (EBV). Less commonly, PEL has presented in patients with advanced age and other conditions associated with an altered immunity, including malignancy, liver cirrhosis, and immunosuppressive medications. It is a tumor of B-cell lineage; however, it shows a \"null\" phenotype, rarely expressing pan-B cell surface antigens. It will usually express CD45, CD30, CD38, CD138, and MUM1 and is characterized by lymphomatous effusions in body cavities but not lymphadenopathy. It is an aggressive lymphoma, with an average median survival of\u00a0< 1 year. HHV-8-associated large B-cell lymphoma (HHV-8-LBL) is a second variant of PEL that is both solid and extracavitary. It has immunoblastic and/or anaplastic morphologic features and a distinct immunohistochemical staining pattern. It could also have a different clinical presentation than that of classic PEL. ### Materials And Methods We describe the case of a 57-year-old HIV-infected man who presented with a slow-growing and asymptomatic abdominal mass. Examination of an excisional biopsy specimen showed malignant large cells with prominent cytoplasm that were positive for pan-B cell antigen CD20, HHV-8, and EBV and negative for CD138, CD10, BCL-6, CD3, and CD30. The Ki-67 labeling index was 90%. The diagnosis was stage IIIA HHV-8-LBL , and he was treated with 6 cycles of R-EPOCH ( rituximab , etoposide , vincristine , doxorubicin , cyclophosphamide , and prednisone ) infusion chemotherapy . At 12 months after treatment, he was in complete remission. We also performed a Medline and Embase search to better understand the clinical findings of our patient and the unique attributes of HHV-8-LBL. Focusing our search on English language studies, we identified 83 cases of HHV-8-LBL without an effusion component. We compared these 83 cases with 118 reported cases of classic PEL. ### results The median age of the patients with HHV-8-LBL was 41 years (range, 24-77), and 96% of the cases were associated with HIV. The median age of the patients with classic PEL was 41 years (range, 26-86), and 96% of the cases were associated with HIV. Of those with HHV-8-LBL, 31 of 61 (51%) had a pre-existing diagnosis of acquired immunodeficiency syndrome (AIDS) and 47 of 63 (75%) were coinfected with EBV. In contrast, 69 of 96 patients (72%) with classic PEL had a pre-existing AIDS diagnosis and 40 of 49 (82%) were coinfected with EBV. The mean CD4(+) count of the HHV-8-LBL patients was 256 cells/\u03bcL (range, 18-1126 cells/\u03bcL) compared with 139 cells/\u03bcL (range, 2-557 cells/\u03bcL) in the classic PEL patients. The median survival time for both groups was similar at 5.5 months (range, 25 days to\u00a0\u2265 25 months) for patients with HHV-8-LBL and 4 months (range, 2 days to\u00a0\u2265 113 months) for those with classic PEL. More patients with HHV-8-LBL were alive at the last follow-up point (59% vs. 18%). The percentage of patients achieving complete remission was 54% (30 of 56) and 36% (32 of 89) for HHV-8-LBL and classic PEL, respectively. ### conclusion Our patient's high CD4(+) cell count, the lack of a pre-existing AIDS diagnosis, and the excellent response to chemotherapy highlights that HHV-8-LBL might have distinct clinical features and possibly a better response to chemotherapy than classic PEL. HHV-8-LBL should be included in the differential diagnosis of HIV patients with solid lesions. It is essential that patients' Centers for Disease Control and Prevention HIV clinical status and HIV viral load at the diagnosis of PEL and HHV-8-LBL be reported and that the reported clinical results include longer term follow-up data. Only then will a more complete clinical picture of this little-appreciated and little-understood PEL variant be defined.", "source": "https://pubmed.ncbi.nlm.nih.gov/27234438/"}
{"doc_id": "05844fac1ef40cc8323e39504e4af8e5", "sentence": "Our objective was to define the maximum tolerated dose of an escalating dose of ifosfamide in combination with a fixed dose of doxorubicin supported by granulocyte colony-stimulating factor ( Neupogen ) .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 80, "end": 90, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "doxorubicin", "start": 127, "end": 138, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I study of ifosfamide and doxorubicin with recombinant human granulocyte colony-stimulating factor in stage IV breast cancer.  Our objective was to define the maximum tolerated dose of an escalating dose of ifosfamide in combination with a fixed dose of doxorubicin supported by granulocyte colony-stimulating factor ( Neupogen ) . Eighteen women with stage IV breast cancer were enrolled in a Phase I study of an escalating dose of ifosfamide (1.2 g/m2/day for 5 days-2.75 g/m2/day for 5 days) with doxorubicin 20 mg/m2/day for 3 days. Granulocyte colony-stimulating factor was used at 5 microgram/kg on day 6 until hematological recovery. Prophylactic antibiotics were also used. The maximum tolerated dose of ifosfamide in combination with doxorubicin was 2.75 g/m2/day for 5 days. The objective response rate was 83% with a complete response rate of 33% (6/18 patients); the median time to treatment failure was 11.5 months. The median survival has not been reached and will exceed 18 months. We concluded that the recommended dose of ifosfamide in combination with doxorubicin is 2.5 g/m2/day for 5 days. This combination shows promise in stage IV breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/9815972/"}
{"doc_id": "05030f04e3fe94ee28f0a39f5bb787cd", "sentence": "A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer .", "spans": [{"span_id": 0, "text": "pegfilgrastim", "start": 73, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "Filgrastim", "start": 120, "end": 130, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A combined analysis of two pivotal randomized trials of a single dose of pegfilgrastim per chemotherapy cycle and daily Filgrastim in patients with stage II-IV breast cancer . This combined, retrospective analysis compared once-per-chemotherapy-cycle pegfilgrastim with daily filgrastim in breast cancer patients undergoing myelosuppressive chemotherapy enrolled in two similarly designed, randomized, double-blind, pivotal trials. On day 2 of each chemotherapy cycle, a single subcutaneous (SC) injection of pegfilgrastim [either 6 mg (n=77) or 100 microg/kg (n=149)] was administered, or daily filgrastim SC injections (5 microg/kg/day; n=222) were initiated and continued until either absolute neutrophil count (ANC) > or =10 x 10(9)/l after the expected nadir or for up to 14 days, whichever occurred first. Individually, each of these trials demonstrated that a single pegfilgrastim injection per cycle is as effective at reducing the duration of severe neutropenia as daily injections of filgrastim. Clinical efficacy data from the two trials were combined for analysis (n=448). The risk of febrile neutropenia (FN; absolute neutrophil count <0.5 x 10(9)/l with fever > or =38.2 degrees C) was significantly lower [11% vs 19%, respectively; relative risk = 0.56 (95% confidence interval: 0.35, 0.89)] in patients receiving pegfilgrastim than for those receiving filgrastim. Trends towards lower risks of hospitalization and intravenous anti-infective use were also observed. These observations were consistent irrespective of risk factors, including age, disease stage, performance status and prior treatment. Pegfilgrastim may offer patients more effective protection against neutropenic complications of chemotherapy with fewer injections and less disruption to their lives.", "source": "https://pubmed.ncbi.nlm.nih.gov/12684649/"}
{"doc_id": "27c978e08bc33f86686d1c1ae90f631c", "sentence": "[ Nilotinib in patients with chronic myeloid leukemia without response to imatinib ] .", "spans": [{"span_id": 0, "text": "Nilotinib", "start": 2, "end": 11, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "imatinib", "start": 74, "end": 82, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "[ Nilotinib in patients with chronic myeloid leukemia without response to imatinib ] . Resistance and intolerance to imatinib in patients with chronic myeloid leukemia requires alternative therapies. nilotinib provides a choice as a second-line treatment. The objective of this report was to show the results of a group of patients with chronic myeloid leukemia who received nilotinib as a second-line treatment. ### methods The medical records of 16 patients of both sexes, of any age, diagnosed with chronic myeloid leukemia, who received nilotinib as a second-line treatment, were reviewed. All of them had received imatinib prior as first-line treatment; the causes to switch to nilotinib were intolerance, resistance and clinical progression of leukemia. ### results The sample was of 16 patients, who achieved at least a hematologic response; 10 were males (62.5%). The age range was 24 to 75 years. Two patients received nilotinib due to intolerance to imatinib; seven due to resistance to imatinib and seven due to lack of response. There was response in the two patients who received nilotinib due to intolerance. One patient died five months after starting nilotinib due to progression of leukemia; four patients achieved major molecular response, two patients had reduced expression of BCR-ABL gene. Six patients continued with high expression of BCR-ABL gene; two of them carrying M244V mutation, and one with a complex karyotype with numerical and structural alterations. ### conclusions nilotinib is an option for patients with intolerance or resistance to imatinib.", "source": "https://pubmed.ncbi.nlm.nih.gov/24878095/"}
{"doc_id": "139b9e118c7845a3bd7efe0ae45009ca", "sentence": "At initial treatment with dabrafenib plus trametinib , three patients achieved a partial response and one patient achieved a complete response .", "spans": [{"span_id": 0, "text": "dabrafenib", "start": 26, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "trametinib", "start": 42, "end": 52, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Dabrafenib plus trametinib rechallenge in four melanoma patients who previously progressed on this combination. In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression. At initial treatment with dabrafenib plus trametinib , three patients achieved a partial response and one patient achieved a complete response . Progression-free survival varied from 9.9 to 24.3 (median 19.8) months. The targeted therapy-free interval ranged from 2.3 to 11.7 (median 8.8) months. At rechallenge, all four patients had a partial response, with progression-free survival ranging from 3.6 to 6.8 (median 5.2) months. Clinical benefit and a second radiological response can be obtained upon readministration of dabrafenib plus trametinib after previously acquiring resistance to this combination. A better understanding of the biological underpinnings of genomic and nongenomic mechanisms of resistance to BRAF-inhibitor-based targeted therapy is needed to identify patients who may benefit from this rechallenge approach.", "source": "https://pubmed.ncbi.nlm.nih.gov/28252479/"}
{"doc_id": "464a6b634dbfb4dee12d8d282b9d21f3", "sentence": "We performed this meta-analysis to evaluate the clinical efficacy and safety of gemcitabine plus cisplatin ( GP ) and paclitaxel plus cisplatin ( TP ) combined with thermotherapy in the treatment of NSCLC , as well as to provide reference for clinical practice and future research .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 80, "end": 91, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "cisplatin", "start": 97, "end": 106, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "paclitaxel", "start": 118, "end": 128, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "cisplatin", "start": 134, "end": 143, "token_start": 21, "token_end": 22}, {"span_id": 4, "text": "thermotherapy", "start": 165, "end": 178, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1, 4], "is_context_needed": true}, {"class": "POS", "spans": [2, 3, 4], "is_context_needed": true}], "paragraph": "[Thermo-chemotherapy of GP or TP for advanced non-small cell lung cancer: a systematic review]. Advanced non-small cell lung cancer (NSCLC) is characterized by poor treatment efficacy and short survival time. Clinical trials have shown that the combination of chemotherapy with thermotherapy exhibits strong efficacy. We performed this meta-analysis to evaluate the clinical efficacy and safety of gemcitabine plus cisplatin ( GP ) and paclitaxel plus cisplatin ( TP ) combined with thermotherapy in the treatment of NSCLC , as well as to provide reference for clinical practice and future research . ### methods We searched international (Cochrane Library, PubMed, and EMBASE) and Chinese (CBM, CNKI, VIP and Wanfang) databases for relevant articles and imported other retrievable sources, such as tracing-related references. We also corresponded with other authors to obtain certain inaccessible information. Data from all relevant randomized controlled trials (RCT) were collected to compare GP or TP thermochemotherapy with GP or TP chemotherapy alone. The quality of the included studies was assessed by adequate outcome-based standards and clinical circumstances. The meta-analysis was conducted using RevMan 5.1. ### results Fifteen RCTs involving 952 patients were included in this meta-analysis. The results showed that the thermochemotherapy group had higher rates of improvement in quality of life (OR=3.84, 95%CI: 2.61-5.64), survival at 1 year (HR=1.94, 95%CI: 1.21-3.12), and survival at 2 years (HR=2.05, 95%CI: 1.18-3.58) compared with the chemotherapy group, with the differences between them being significant. However, these groups did not differ in other indicators of treatment effectiveness, such as myelosuppression, alimentary canal reactions, hepatic lesions, and diarrhea. ### conclusions Compared with chemotherapy alone, thermochemotherapy can improve survival rates and curative effects, ameliorate symptoms, and enhance the quality of life of patients with advanced NSCLC, and it has an acceptable safety profile. The results of this meta-analysis warrant further investigation with a larger sample size and using a high-quality RCT design.", "source": "https://pubmed.ncbi.nlm.nih.gov/22901992/"}
{"doc_id": "ae18029f5969f526554b85821e622d76", "sentence": "The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor .", "spans": [{"span_id": 0, "text": "ticagrelor", "start": 31, "end": 41, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "ticagrelor", "start": 62, "end": 72, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "cangrelor", "start": 102, "end": 111, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Pharmacodynamic effects during the transition between cangrelor and ticagrelor. This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor. ### background cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents. ### methods Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 \u03bcmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor. ### results During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity. ### conclusions ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor . Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor.", "source": "https://pubmed.ncbi.nlm.nih.gov/24656538/"}
{"doc_id": "f7d9cb2254b2543d60803eb573a9e7b4", "sentence": "A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin , paclitaxel , and bevacizumab with partial response .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 212, "end": 223, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "paclitaxel", "start": 226, "end": 236, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "bevacizumab", "start": 243, "end": 254, "token_start": 29, "token_end": 30}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report. Homologous recombination deficiency is a marker of response to poly(ADP-ribose) polymerase inhibitors in different cancer types including ovary, prostate, and pancreatic cancer. To date, no report about poly(ADP-ribose) polymerase inhibitors has been published on cervical cancer. ### Case Presentation Here we present the case of a patient with cervical cancer treated in this setting. A 49-year-old woman diagnosed with International Federation of Obstetricians and Gynecologists stage 2018 IIIC2 locally advanced undifferentiated cervical cancer received first-line chemoradiotherapy followed by carboplatin , paclitaxel , and bevacizumab with partial response . Because of a family history of cancers, the patient was tested and found positive for a pathogenic BRCA1 germline and somatic mutation, which motivated bevacizumab plus olaparib maintenance treatment. A simple hysterectomy was performed after 2\u00a0years stable disease; pathological report showed complete pathological response, and 12\u00a0months follow-up showed no recurrence. ### conclusion Poly(ADP-ribose) polymerase inhibitors could be an alternative maintenance treatment for patients with persistent advanced cervical cancer previously treated with platinum, especially when familial history of cancers is reported. Clinical trials using poly(ADP-ribose) polymerase inhibitors for advanced cervical cancer are warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/33888155/"}
{"doc_id": "73f773b02a672dc89e8413a7261f4848", "sentence": "Sipuleucel-T , cabazitaxel , abiraterone , enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years .", "spans": [{"span_id": 0, "text": "Sipuleucel-T", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cabazitaxel", "start": 15, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "abiraterone", "start": 29, "end": 40, "token_start": 4, "token_end": 5}, {"span_id": 3, "text": "enzalutamide", "start": 43, "end": 55, "token_start": 6, "token_end": 7}, {"span_id": 4, "text": "radium-223", "start": 60, "end": 70, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "SEOM clinical guidelines for the treatment of metastatic prostate cancer. Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T , cabazitaxel , abiraterone , enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years . Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required.", "source": "https://pubmed.ncbi.nlm.nih.gov/25319721/"}
{"doc_id": "61f05d751c64820a8d80f60bfc98c237", "sentence": "Therefore , we conducted this phase II study to evaluate the activity and toxicity of the combination paclitaxel and gemcitabine in advanced NSCLC .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 102, "end": 112, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "gemcitabine", "start": 117, "end": 128, "token_start": 19, "token_end": 20}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non-small cell lung cancer. Platinum-based combination chemotherapy has become the standard treatment for good performance patients with stage IIIb and IV non-small cell lung cancer (NSCLC). However, newer agents such as gemcitabine and paclitaxel appear to have superior single agent activity and are more easily tolerated in comparison to the older platinum compounds. Therefore , we conducted this phase II study to evaluate the activity and toxicity of the combination paclitaxel and gemcitabine in advanced NSCLC . gemcitabine was given at 1,000 mg/m(2) intravenously over 30 min followed by paclitaxel at 110 mg/m(2) intravenously over 1 h on days 1, 8 and 15 every 28 days for a maximum of 6 cycles. Between April 1998 and June 1999, 40 of 42 patients entered were eligible and received chemotherapy. Data was available on 39 patients. Toxicities included Grade 3/4 neutropenia in 43% of patients, while thrombocytopenia (13%) and anemia (7%) were less frequent. Five (12.5%) patients developed neutropenic fever. Four (10%) patients developed bilateral interstitial shadows with hypoxia suggestive of a drug-induced pneumonitis. There were 4 treatment-related deaths (1 from pneumonitis, 3 from neutropenic complications). Five patients were not evaluable due to early death. Therefore, 34 patients were evaluable with 12 (35.3%) achieving a partial remission and 1 achieving a complete remission for an overall response rate of 38.2% (32.5% on an intention-to-treat basis). The median progression free survival was 107 days (range, 14-391), median survival was 148 days (range, 12-495) and 1-year survival was 26%. In conclusion, weekly gemcitabine with paclitaxel in patients with advanced NSCLC is an active regimen; however, toxicity and poor survival precludes the use of this regimen as an experimental arm on a future phase III study.", "source": "https://pubmed.ncbi.nlm.nih.gov/12367796/"}
{"doc_id": "bfc82b1e67e91b99aeeb487bebe450c3", "sentence": "Two of these antibodies , cetuximab ( Erbitux ) und bevacizumab ( Avastin ) , directed against the epidermal growth factor receptor ( EGFR ) and the vascular epithelial growth factor ( VEGF ) , respectively , have recently been approved for use in metastatic colorectal cancer .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 26, "end": 35, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "bevacizumab", "start": 52, "end": 63, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "[Antibody treatment in colorectal cancer--what the surgeon needs to know]. Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies , cetuximab ( Erbitux ) und bevacizumab ( Avastin ) , directed against the epidermal growth factor receptor ( EGFR ) and the vascular epithelial growth factor ( VEGF ) , respectively , have recently been approved for use in metastatic colorectal cancer . The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/18415895/"}
{"doc_id": "9f0667d430098de87e37d3fd2f9d7e1b", "sentence": "Physically cross-linked beta-lactoglobulin ( BLG ) protein gels containing theophylline and sulfamethoxazole low molecular weight drugs were prepared in 50 % ethanol solution at pH 8 and two protein concentrations ( 6 and 7 % ( w/v ) ) .", "spans": [{"span_id": 0, "text": "theophylline", "start": 75, "end": 87, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "sulfamethoxazole", "start": 92, "end": 108, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Swelling behavior and controlled release of theophylline and sulfamethoxazole drugs in beta-lactoglobulin protein gels obtained by phase separation in water/ethanol mixture.  Physically cross-linked beta-lactoglobulin ( BLG ) protein gels containing theophylline and sulfamethoxazole low molecular weight drugs were prepared in 50 % ethanol solution at pH 8 and two protein concentrations ( 6 and 7 % ( w/v ) ) . Swelling behavior of cylindrical gels showed that, irrespective of the hydrated or dehydrated state of the gel, the rate of swelling was the highest in water. When the gels were exposed to water, they first showed a swelling phase in which their weight increased 3 and 30 times for hydrated and dehydrated gels, respectively, due to absorption of water, followed by a dissolution phase. The absorption of solvent was however considerably reduced when the gels were exposed to aqueous buffer solutions. The release behavior of both theophylline and sulfamethoxazole drugs from BLG gels was achieved in a time window ranging from 6 to 24 h. The drug release depended mainly on the solubility of the drugs and the physical state of the gel (hydrated or dry form). Analysis of drug release profiles using the model of Peppas showed that diffusion through hydrated gels was governed by a Fickian process whereas diffusion through dehydrated gels was governed partly by the swelling capacities of the gel but also by the structural rearrangements inside the network occurring during dehydration step. By a judicious selection of protein concentration, hydrated or dehydrated gel state, drug release may be modulated to be engineered suitable for pharmaceutical as well as cosmetics and food applications.", "source": "https://pubmed.ncbi.nlm.nih.gov/16398532/"}
{"doc_id": "f4921173486b31b67a10b151e4371b72", "sentence": "Ciprofloxacin , 500 mg orally twice a day plus antifungal prophylaxis , fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets , each 200 mg four times a day , was given .", "spans": [{"span_id": 0, "text": "Ciprofloxacin", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "fluconazole", "start": 72, "end": 83, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "amphotericin", "start": 106, "end": 118, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Infection prevention in autologous bone marrow transplantation and the role of protective isolation. The efficacy of an antimicrobial regimen for prevention of infections was prospectively evaluated in 113 patients undergoing autologous bone marrow transplantation (BMT). Ciprofloxacin , 500 mg orally twice a day plus antifungal prophylaxis , fluconazole 50 mg once daily plus amphotericin B tablets or suspension and tablets , each 200 mg four times a day , was given . In addition all patients received streptococcal prophylaxis for 10 days after BMT. Documented infections occurred in 39% (44 of 113) of patients and unexplained fever in 27% (30 of 113). The efficacy of this regimen was reflected in a low mortality rate (3.5%) from infections and in the low need for intravenous amphotericin B (7%). No benefit of protective isolation was found in 59 patients compared with 54 patients treated without isolation measures.", "source": "https://pubmed.ncbi.nlm.nih.gov/7951125/"}
{"doc_id": "f7706f7238a4a6e6e1f27615c9d55119", "sentence": "In some recently updated clinical guidelines , the fully humanized monoclonal antibody panitumumab , combined with irinotecan , has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer ( mCRC ) .", "spans": [{"span_id": 0, "text": "panitumumab", "start": 87, "end": 98, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "irinotecan", "start": 115, "end": 125, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Prospective, Multicenter Phase II Study of the Efficacy and Feasibility of 15-minute Panitumumab Infusion Plus Irinotecan for Oxaliplatin- and Irinotecan-refractory, KRAS Wild-type Metastatic Colorectal Cancer (Short Infusion of Panitumumab Trial).  In some recently updated clinical guidelines , the fully humanized monoclonal antibody panitumumab , combined with irinotecan , has been recommended as an optional third-line chemotherapy for KRAS wild-type metastatic colorectal cancer ( mCRC ) . The present prospective, multicenter phase II study evaluated the effectiveness and safety of short 15-minute panitumumab infusions. ### Patients And Methods From January 2011 to December 2011, patients with KRAS wild-type mCRC were enrolled at 8 centers. The key eligibility criteria were age\u00a0\u2265 20 years and resistance or intolerance to irinotecan, fluoropyrimidine, and oxaliplatin. All patients received 6 mg/kg of panitumumab and 150 mg/m ### results Of the 43 patients, the median age was 62 years (range, 32-75 years), 58% were male, and the Eastern Cooperative Oncology Group performance status was 0 to 1. The total response rate was 37.2% (95% confidence interval [CI], 23.0-53.3), and the confirmed response rate was 18.6% (95% CI, 8.4-33.4). The median progression-free and overall survival were 5.8 months (95% CI, 3.3-8.4 months) and 13.6 months (95% CI, 10.8-16.5 months), respectively. The most frequent grade 3/4 toxicities were anorexia (12%), leukopenia (9%), and neutropenia (9%). Nine patients did not reach the 15-minute infusion, primarily because of disease progression. No infusion-related reactions were observed. ### conclusion The short 15-minute panitumumab infusion regimen was well tolerated, without compromising safety or efficacy in patients with KRAS wild-type, oxaliplatin- and irinotecan-refractory mCRC.", "source": "https://pubmed.ncbi.nlm.nih.gov/29169974/"}
{"doc_id": "80434a6ceced9fc5c41ba573025ff686", "sentence": "A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon ( VEMUPLINT ) in advanced melanoma patients harboring the V600BRAF mutation .", "spans": [{"span_id": 0, "text": "vemurafenib", "start": 31, "end": 42, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "cobimetinib", "start": 48, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "VEMUPLINT", "start": 82, "end": 91, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon ( VEMUPLINT ) in advanced melanoma patients harboring the V600BRAF mutation . Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-\u03b1 on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-\u03b1 in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. ### Patients And Methods In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib\u2009+\u2009PEG-IFN-\u03b1-2b or vemurafenib\u2009+\u2009cobimetinib\u2009+\u2009PEG-IFN-\u03b1-2b, to assess the safety of the combination and the upregulation of IFN-\u03b1/\u03b2 receptor-1 (IFNAR1). ### results Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on\u2009\u2264\u200935% melanoma cells had a median progression-free survival of 12.0\u00a0months (range: 5.6-18.4\u00a0months) and a median overall survival of 31.0\u00a0months (range: 19.8-42.2\u00a0months), while patients with a pre-treatment IFNAR1 expression on\u2009>\u200935% of melanoma cells had a median progression-free survival of 4.0\u00a0months (range: 0-8.8; p\u2009=\u20090.03), and a median overall survival of 5\u00a0months (p\u2009=\u20090.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. ### conclusion Our study supports the overall safety of the vemurafenib\u2009+\u2009PEG-IFN-\u03b1-2b\u2009+\u2009cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. vemurafenib\u2009+\u2009PEG-IFN-\u03b1-2b\u2009+\u2009cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. ### Trial Registration The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.", "source": "https://pubmed.ncbi.nlm.nih.gov/33407577/"}
{"doc_id": "d89f39f61c1b2844588da47a1cd3c612", "sentence": "Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma .", "spans": [{"span_id": 0, "text": "tremelimumab", "start": 33, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "sunitinib", "start": 51, "end": 60, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma . On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. ### methods Adult patients with mRCC who had received \u2264 1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. ### results Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. ### conclusions In this study of tremelimumab plus sunitinib, rapid-onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/20922784/"}
{"doc_id": "ce24fba138e6c7a35f02adab371a88f2", "sentence": "A working group convened by the Centers for Disease Control recommended three antibiotics for the treatment of recurrent and persistent acute otitis media : ( 1 ) amoxicillin/clavulanate in combination with amoxicillin ( high dose amoxicillin regimen , 80 to 90 mg/kg/day ) ; ( 2 ) cefuroxime axetil ( standard dose , 30 mg/kg/day ) ; and ( 3 ) ceftriaxone ( possibly requiring up to three injections to optimize clinical success ) .", "spans": [{"span_id": 0, "text": "amoxicillin/clavulanate", "start": 163, "end": 186, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "amoxicillin", "start": 207, "end": 218, "token_start": 31, "token_end": 32}, {"span_id": 2, "text": "amoxicillin", "start": 231, "end": 242, "token_start": 35, "token_end": 36}, {"span_id": 3, "text": "cefuroxime", "start": 282, "end": 292, "token_start": 47, "token_end": 48}, {"span_id": 4, "text": "ceftriaxone", "start": 345, "end": 356, "token_start": 61, "token_end": 62}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Recurrent and persistent otitis media. Recurrent acute otitis media occurs during the first several years of life in approximately 20 to 30% of the pediatric population. A clinical challenge closely related to recurrent otitis media is persistent otitis media, manifested by persistence during antimicrobial therapy of symptoms and signs of middle ear infection (treatment failure) and/or relapse of acute otitis media within 1 month of completion of antibiotic therapy. Recurrent and persistent otitis media infections are early childhood problems with identifiable risk factors. Differentiation of these infections from otitis media with effusion is important in avoiding misdiagnosis and overtreatment with antibiotics. The predominant pathogens of recurrent and persistent acute otitis media are antibiotic-resistant Streptococcus pneumoniae and beta-lactamase-producing Haemophilus influenzae. A working group convened by the Centers for Disease Control recommended three antibiotics for the treatment of recurrent and persistent acute otitis media : ( 1 ) amoxicillin/clavulanate in combination with amoxicillin ( high dose amoxicillin regimen , 80 to 90 mg/kg/day ) ; ( 2 ) cefuroxime axetil ( standard dose , 30 mg/kg/day ) ; and ( 3 ) ceftriaxone ( possibly requiring up to three injections to optimize clinical success ) . Other antibiotics were considered suboptimal or had accumulated insufficient data upon which to base a judgment. Conclusions. Optimal management of recurrent and persistent acute otitis media is a clinical challenge. Accurate diagnosis of acute otitis media is the first step in optimal management. Selection of appropriate antibiotic therapy should take into account the major pathogens (S. pneumoniae, H. influenzae and Moraxella catarrhalis) and the occurrence of antibiotic resistance.", "source": "https://pubmed.ncbi.nlm.nih.gov/11001126/"}
{"doc_id": "f0cfa9cab940e4dec4741dc4b6e5231d", "sentence": "On the basis of the estimated costs of infective complications , cefotaxime and ceftriaxone appear equally effective for the prevention of infective complications after abdominal surgery .", "spans": [{"span_id": 0, "text": "cefotaxime", "start": 65, "end": 75, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "ceftriaxone", "start": 80, "end": 91, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "A cost-effectiveness evaluation of 3 antimicrobial regimens for the prevention of infective complications after abdominal surgery. To measure the cost and effectiveness of 3 established antimicrobial regimens for the prevention of infective complications after abdominal surgery. ### design A prospective randomized trial was performed involving a total of 1070 patients undergoing abdominal surgery. ### Setting And Patients All patients having upper gastrointestinal tract, colorectal, appendiceal, or biliary surgery at a major teaching hospital in Melbourne, Australia, were considered for entry into the study. ### interventions Patients were randomized prior to surgery to receive a single dose of cefotaxime sodium (1 g), ticarcillin plus clavulanic acid (3.1 g), or ceftriaxone sodium, (1 g). All drugs were given intravenously at the start of anesthesia. ### Main Outcome Measures Rates of major wound infections, minor wound infections, other wound problems, and other infective complications. The acquisition and administrative costs of the drugs used and the costs of the infective complications were measured. ### results A Total of 1070 patients were entered into the study. Major wound infections occurred in 21 patients (2.0%). Twenty-five patients (2.3%) developed a minor wound infection. Other infective complications developed in 107 patients. There were significantly fewer minor wound infections in the ceftriaxone-treated group as compared with the other 2 groups. There was no differences in the frequency of major wound infections, other wound problems, or other infective complications. The acquisition costs of cefotaxime and ticarcillin plus clavulanic acid were less than those of ceftriaxone. The estimated cost of treating the infective complications in the group of patients who received ticarcillin plus clavulanic acid ($128,039) was greater than the cost associated with the groups being treated with cefotaxime ($91,243) or ceftriaxone ($96,095). ### conclusions The study indicates that each of the 3 regimens was associated with highly satisfactory control of postoperative infective complications after abdominal surgery. On the basis of the estimated costs of infective complications , cefotaxime and ceftriaxone appear equally effective for the prevention of infective complications after abdominal surgery . Acquisition costs for cefotaxime were lower and it is recommended as the preferred agent on this basis.", "source": "https://pubmed.ncbi.nlm.nih.gov/8678775/"}
{"doc_id": "f05493b65f3c5290a97f09afd7ff253b", "sentence": "The epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR TKIs ) like erlotinib and gefitinib have been extensively studied .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 83, "end": 92, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "gefitinib", "start": 97, "end": 106, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer.  The epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR TKIs ) like erlotinib and gefitinib have been extensively studied . Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive results in particular for selected patients with specific clinical characteristic and somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.", "source": "https://pubmed.ncbi.nlm.nih.gov/22263036/"}
{"doc_id": "47520d58ca9f3c5271cd5e1b8f17c8d3", "sentence": "Patients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group ( ECOG ) Performance Status ( PS ) \u22642 were randomised to either : pemetrexed 500 mg/m(2 ) on day 1 plus erlotinib 150 mg daily on days 2 - 14 ; erlotinib 150 mg daily ; or pemetrexed 500 mg/m(2 ) on day 1 of a 21-day cycle until discontinuation criteria were met .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 169, "end": 179, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "erlotinib", "start": 207, "end": 216, "token_start": 37, "token_end": 38}, {"span_id": 2, "text": "erlotinib", "start": 247, "end": 256, "token_start": 47, "token_end": 48}, {"span_id": 3, "text": "pemetrexed", "start": 275, "end": 285, "token_start": 53, "token_end": 54}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer. This randomised controlled phase 2 study compared pemetrexed and erlotinib in combination with either agent alone in terms of efficacy and safety as second-line treatment in a clinically selected population of never-smokers with non-squamous non-small cell lung cancer (NSCLC). ### methods Patients who had failed only one prior chemotherapy regimen and had Eastern Cooperative Oncology Group ( ECOG ) Performance Status ( PS ) \u22642 were randomised to either : pemetrexed 500 mg/m(2 ) on day 1 plus erlotinib 150 mg daily on days 2 - 14 ; erlotinib 150 mg daily ; or pemetrexed 500 mg/m(2 ) on day 1 of a 21-day cycle until discontinuation criteria were met . The primary endpoint, progression-free survival (PFS), was analysed using a multivariate Cox model. Firstly, a global comparison across the three arms was performed. If the global null hypothesis was rejected at a two-sided 0.2 significance level, pairwise comparisons of pemetrexed-erlotinib versus erlotinib or pemetrexed were then conducted using the same model. Statistical significance was claimed only if both global and pairwise null hypotheses were rejected at a two-sided 0.05 significance level. ### findings A total of 240 patients (male, 35%; East Asian, 55%; ECOG PS 0-1, 93%) were included. A statistically significant difference in PFS was found across the three arms (global p=0.003), with pemetrexed-erlotinib significantly better than either single agent: HR=0.57, 95% confidence interval (CI): 0.40-0.81, p=0.002 versus erlotinib; HR=0.58, 95% CI: 0.39-0.85, p=0.005 versus pemetrexed. Median PFS (95% CI) was 7.4 (4.4, 12.9) months in pemetrexed-erlotinib, 3.8 (2.7, 6.3) months in erlotinib and 4.4 (3.0, 6.0) months in pemetrexed. Safety analyses showed a higher incidence of drug-related grade 3/4 toxicity in pemetrexed-erlotinib (60.0%) than in pemetrexed (28.9%) or erlotinib (12.0%); the majority being neutropenia, anaemia, rash and diarrhoea. ### interpretation pemetrexed-erlotinib significantly improved PFS compared to either drug alone in this clinically selected population. The combination had more toxicity, but was clinically manageable.", "source": "https://pubmed.ncbi.nlm.nih.gov/23890768/"}
{"doc_id": "099683c01fbf5f8bc5d641f38273f33e", "sentence": "This study was conducted to test the feasibility of reducing the interval between cycles of doxorubicin , cyclophosphamide , etoposide ( ACE ) chemotherapy to 2 weeks , thereby increasing dose intensity , by adding granulocyte colony-stimulating factor ( G-CSF ) to reduce the duration of neutropenia following a cycle .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 92, "end": 103, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "cyclophosphamide", "start": 106, "end": 122, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "etoposide", "start": 125, "end": 134, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "G-CSF", "start": 255, "end": 260, "token_start": 39, "token_end": 40}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "The feasibility of using glycosylated recombinant human granulocyte colony-stimulating factor (G-CSF) to increase the planned dose intensity of doxorubicin, cyclophosphamide and etoposide (ACE) in the treatment of small cell lung cancer. Medical Research Council Lung Cancer Working Party.  This study was conducted to test the feasibility of reducing the interval between cycles of doxorubicin , cyclophosphamide , etoposide ( ACE ) chemotherapy to 2 weeks , thereby increasing dose intensity , by adding granulocyte colony-stimulating factor ( G-CSF ) to reduce the duration of neutropenia following a cycle . 20 patients with small cell lung cancer (SCLC) were prescribed six cycles of 2-weekly ACE, with G-CSF on the intermediate days. 3 patients died during the treatment period and a further 5 had ACE terminated, 3 for toxicity and 2 for progressive disease. Of the 71 intervals between cycles, 42 (59%) were of the prescribed 14 days, 9 (13%) of 15-20 days, 15 (21%) of 21 days and five (7%) longer, but during the first four cycles, 36 (77%) of 47 intervals were of 14 days. The main reason for delay was haematological toxicity. All 20 patients experienced WHO grade 3 or 4 neutropenia, but at 2 weeks after a cycle only 3 had grade 4 and 1 grade 3. 17 patients required blood transfusion and 12 platelet transfusion. The only potentially serious adverse reaction to G-CSF was an episode of rash with facial oedema. Adding G-CSF allows ACE chemotherapy to be intensified by reducing the interval between cycles.", "source": "https://pubmed.ncbi.nlm.nih.gov/7536433/"}
{"doc_id": "7f838123add04a29b53b03e5253caefe", "sentence": "The rate of down-stage to pT1 or less was 59 % for methotrexate , vinblastine , doxorubicin and cisplatin , and 53 % for gemcitabine and carboplatin ( P = 0.624 ) .", "spans": [{"span_id": 0, "text": "methotrexate", "start": 51, "end": 63, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "vinblastine", "start": 66, "end": 77, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "doxorubicin", "start": 80, "end": 91, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "cisplatin", "start": 96, "end": 105, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "gemcitabine", "start": 121, "end": 132, "token_start": 24, "token_end": 25}, {"span_id": 5, "text": "carboplatin", "start": 137, "end": 148, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [4, 5], "is_context_needed": true}], "paragraph": "Neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer. Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. ### methods We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n = 34) or gemcitabine and carboplatin (n = 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. ### results The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m(2), respectively (P = 0.002). The rate of down-stage to pT1 or less was 59 % for methotrexate , vinblastine , doxorubicin and cisplatin , and 53 % for gemcitabine and carboplatin ( P = 0.624 ) . The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P = 0.85). ### conclusions Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin.", "source": "https://pubmed.ncbi.nlm.nih.gov/23275643/"}
{"doc_id": "ad15c6b2de06399a133cb0989bdd489b", "sentence": "The combined irrigation of bupivacaine and ketorolac showed a clinically significant reduction of pain in the first postoperative hour and on postoperative day 5 .", "spans": [{"span_id": 0, "text": "bupivacaine", "start": 27, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "ketorolac", "start": 43, "end": 52, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "The Role of Local Bupivacaine Irrigation in Postoperative Pain Control After Augmentation Mammoplasty: A Systematic Review and Meta-Analysis. The objective of this study is to analyze the efficacy of local bupivacaine irrigation after augmentation mammoplasty for the control of postoperative pain. ### methods A systematic review and meta-analysis was conducted including all randomized controlled trials (RCTs) that compared the irrigation of bupivacaine (\u00b1ketorolac) versus normal saline or no irrigation for pain control after breast augmentation. The primary outcome was postoperative pain measured by visual analog scale. The study protocol was established a priori according to the recommendations of the Cochrane Collaboration. A bibliographical search was conducted in September 2015 in the following Cochrane Library databases: CENTRAL, MEDLINE, EMBASE, and Scielo. The strategy used for the search was ((augmentation AND (\"mammoplasty\"[MeSH Terms] OR \"mammoplasty\")) OR ((\"breast\"[MeSH Terms] OR \"breast\") AND augmentation)) AND ((\"pain, postoperative\"[MeSH Terms])). ### results Four RCTs with a total of 264 participants were included. Two trials compared bupivacaine alone versus placebo (normal saline or no irrigation) and 3 trials compared bupivacaine plus ketorolac versus placebo. The combined irrigation of bupivacaine and ketorolac showed a clinically significant reduction of pain in the first postoperative hour and on postoperative day 5 . The irrigation with bupivacaine compared with placebo significantly reduced pain assessed on postoperative day 4. ### conclusion The irrigation of bupivacaine with or without ketorolac was associated with a reduction of postoperative pain compared with control groups for the first 5 postoperative days. Due to the few number of trials included, these results should be correlated further clinically.", "source": "https://pubmed.ncbi.nlm.nih.gov/29026810/"}
{"doc_id": "f1d7687091bcc14f1eeb6fad5e6f4ea6", "sentence": "In group I , clinical response was observed in 10 of 19 febrile episodes ( 52.6 % ) treated with carbenicillin plus gentamicin and in 10 of 14 ( 71.4 % ) treated with latamoxef ( p greater than 0.05 ) .", "spans": [{"span_id": 0, "text": "carbenicillin", "start": 97, "end": 110, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "gentamicin", "start": 116, "end": 126, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "latamoxef", "start": 167, "end": 176, "token_start": 34, "token_end": 35}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Latamoxef versus carbenicillin plus gentamicin or carbenicillin plus mecillinam in leukopenic, febrile patients with solid tumors. Sixty-six febrile episodes associated with leukopenia were observed in 56 patients with solid tumors, WBC less than 1.5 X 10(9)/l and temperature greater than or equal to 38.5 degrees C. Stratification to antibiotic treatment regimen was made with regard to prior cis-dichlorodiamineplatinum (cis-platinum) treatment or not. Patients who had received no cis-platinum were randomized between carbenicillin 10 g every 8 h plus gentamicin 80 mg every 8 h or latamoxef 2 g every 8 h (group I). Patients having received cis-platinum were treated with carbenicillin 10 g every 8 h plus mecillinam 800 mg every 8 h or latamoxef 2 g every 8 h (group II). The first dose of latamoxef was preceded by 10 mg of vitamin K i.v. In group I , clinical response was observed in 10 of 19 febrile episodes ( 52.6 % ) treated with carbenicillin plus gentamicin and in 10 of 14 ( 71.4 % ) treated with latamoxef ( p greater than 0.05 ) . In group II, 6 of 14 febrile episodes treated with carbenicillin plus mecillinam responded (42.9%) while 11 of 19 (57.9%) responded to latamoxef (p greater than 0.05). No bleeding due to antibiotic treatment was observed. No statistical difference between standard antibiotic therapy and latamoxef was seen in this subset of patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/3535399/"}
{"doc_id": "a719f348c8f180930525ce7b90846d21", "sentence": "Following lapatinib and trastuzumab , the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest ( 44.5 % , 95 % confidence interval [ CI ] = 35.4 % to 53.9 % vs 11.6 % , 95 % CI = 6.9 % to 18.0 % ; adjusted odds ratio [ OR ] = 6.05 , 95 % CI = 3.10 to 11.80 , P < .001 ) .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 10, "end": 19, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "trastuzumab", "start": 24, "end": 35, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade. Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. ### methods A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24\u2009weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. ### results A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab , the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest ( 44.5 % , 95 % confidence interval [ CI ] = 35.4 % to 53.9 % vs 11.6 % , 95 % CI = 6.9 % to 18.0 % ; adjusted odds ratio [ OR ] = 6.05 , 95 % CI = 3.10 to 11.80 , P < .001 ) . Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI\u2009=\u200922.3% to 95.7% vs 14.7% in others, 95% CI\u2009=\u20094.9% to 31.1%; adjusted OR\u2009=\u200911.60, 95% CI = 1.66 to 81.10, P\u2009=\u2009.01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR]\u2009=\u20090.52, 95% CI = 0.35 to 0.79, P\u2009<\u2009.001); higher ORR (16.3%, 95% CI\u2009=\u20098.9% to 26.2% vs 3.7%, 95% CI\u2009=\u20090.8% to 10.3%, P\u2009=\u2009.02); and longer OS (HR\u2009=\u20090.66, 95% CI\u2009=\u20090.44 to 0.97, P\u2009=\u2009.01). ### conclusions Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/31037288/"}
{"doc_id": "b99eae8266e0ae323ef5089dd410ba9a", "sentence": "A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model .", "spans": [{"span_id": 0, "text": "Troglitazone", "start": 36, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "Lovastatin", "start": 53, "end": 63, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Synergistic Anti-Cancer Effect of Troglitazone and Lovastatin in a Human Anaplastic Thyroid Cancer Cell Line and in a Mouse Xenograft Model . Anaplastic thyroid cancer (ATC) is a malignant subtype of thyroid cancers and its mechanism of development remains inconclusive. Importantly, there is no effective strategy for treatment since ATC is not responsive to conventional therapies, including radioactive iodine therapy and thyroid-stimulating hormone suppression. Here, we report that a combinational approach consisting of drugs designed for targeting lipid metabolism, lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR) and troglitazone (an agonist of peroxisome proliferator-activated receptor gamma, PPAR\u03b3), exhibits anti-proliferation in cell culture systems and leads to tumor regression in a mouse xenograft model. The composition contains a sub-lethal concentration of both drugs and exhibits low toxicity to certain types of normal cells. Our results support a hypothesis that the inhibitory effect of the combination is partly through a cell cycle arrest at G0/G1 phase, as evidenced by the induction of cyclin-dependent kinase inhibitors, p21", "source": "https://pubmed.ncbi.nlm.nih.gov/29932104/"}
{"doc_id": "ba713428f331bd17d48949c1628f5dc4", "sentence": "Fingolimod sensitizes EGFR wild\u2011type non\u2011small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest .", "spans": [{"span_id": 0, "text": "Fingolimod", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "lapatinib", "start": 73, "end": 82, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "sorafenib", "start": 86, "end": 95, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Fingolimod sensitizes EGFR wild\u2011type non\u2011small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest . Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in this gene are major drivers of lung cancer development. EGFR tyrosine kinase inhibitors (TKIs) are standard first\u2011line therapies for patients with advanced non\u2011small cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wild\u2011type EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wild\u2011type NSCLC cells as single treatments or in combination with fingolimod (FTY720), which has been approved for treating multiple sclerosis and has cytotoxic effects against several tumor cell lines. It was found that the combined treatment with TKIs lapatinib (Lap) or sorafenib (Sor) and FTY720 synergistically suppressed the viability of the NSCLC cell lines A549 and H596. Additionally, FTY720 inhibited lysosomal acidification and suppressed autophagy flux. Immunoblotting and reverse transcription\u2011quantitative polymerase chain reaction showed that FTY720 combined with Lap or Sor, enhanced endoplasmic reticulum (ER) stress loading and cell cycle arrest in A549 cells. The enhancement of ER stress loading and cell cycle arrest induced by combined treatment with Lap or Sor and FTY720, which was associated with the cytotoxicity induced by the combination of these drugs. These findings suggested that FTY720 improved TKI therapy in NSCLC patients with wild\u2011type EGFR, by sensitizing NSCLC cells to TKIs.", "source": "https://pubmed.ncbi.nlm.nih.gov/31059070/"}
{"doc_id": "fc993366438427f4d6964fa73e800a2e", "sentence": "To compare levels of apoptosis in granulosa cells from women treated with the gonadotropin-releasing hormone ( GnRH ) agonist triptorelin or the GnRH antagonist cetrorelix .", "spans": [{"span_id": 0, "text": "triptorelin", "start": 126, "end": 137, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "cetrorelix", "start": 161, "end": 171, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Levels of apoptosis in human granulosa cells seem to be comparable after therapy with a gonadotropin-releasing hormone agonist or antagonist.  To compare levels of apoptosis in granulosa cells from women treated with the gonadotropin-releasing hormone ( GnRH ) agonist triptorelin or the GnRH antagonist cetrorelix . ### design Randomized, prospective study. ### setting University hospital. ### Patient S Thirty-two women undergoing assisted reproduction techniques after ovulation induction with recombinant follicle-stimulating hormone (FSH) plus GnRH agonist or antagonist. ### Intervention S Granulosa cells were isolated from follicular aspirates after oocyte removal. ### Main Outcome Measure S Apoptosis was assessed with Annexin V binding assay, terminal deoxynucleotidyl transferase (TdT)-mediated nick-end labeling (TUNEL) assay, flow cytometric analysis of DNA, and ultrastructural analysis of cell morphology in transmission electron microscopy. Serum and follicular hormonal levels were also determined. ### Result S Annexin V binding and TUNEL assays revealed comparable percentages of apoptosis in the two groups under investigation. Analysis of DNA histograms revealed a similar cell cycle distribution in the two groups. Ultrastructural analysis only occasionally displayed patterns of chromatin margination in apoptotic cells. The mean concentrations of all the follicular fluid steroid hormones evaluated (E2, T, and P) were significantly lower in the GnRH antagonist-treated group. ### Conclusion S Therapy with a GnRH agonist or antagonist is associated with comparable levels of apoptosis in granulosa cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/16595220/"}
{"doc_id": "20b68079241cd6dc54411493468becf5", "sentence": "In vitro effects of racemates , separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 78, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "halofantrine", "start": 93, "end": 105, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "metoprolol", "start": 109, "end": 119, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "In vitro effects of racemates , separate enantiomers and major metabolites of mefloquine and halofantrine on metoprolol biotransformation by rat liver microsomes . 1. The effects of the anti-malarial drugs mefloquine and halofantrine and of their major metabolites on metoprolol metabolism by rat liver microsomes have been investigated. 2. The observed Km and Vmax, and the formation kinetics of alpha-hydroxymetoprolol and O-demethylmetoprolol, two major metoprolol metabolites, were in keeping with published data. 3. In vitro, mefloquine competitively inhibited metoprolol biotransformation, whereas halofantrine did so in a mixed fashion. The mefloquine Ki of metoprolol alpha-hydroxylation and O-demethylation were 3.4 and 5.8 microM respectively, whereas those of halofantrine were 0.15 and 0.32 microM respectively. 4. The main metabolites, N-debutylhalofantrine and carboxymefloquine, were 4-10-fold less inhibitory than the parent drugs. The difference in inhibitory potency of parent drugs and metabolites was higher for halofantrine than for mefloquine. The potency order for metoprolol metabolism inhibition was halofantrine >> mefloquine = N-debutylhalofantrine > carboxymefloquine. 5. A preliminary study with anti-malarial enantiomers showed a weak difference, in metoprolol metabolism inhibition between the enantiomers of halofantrine or mefloquine. 6. It is concluded that halofantrine is a potent inhibitor of metoprolol metabolism and that halofantrine metabolites or its enantiomers may have a different inhibitor potency than the parent drug: (1) the inhibition potency of these compounds should be studied in vitro and (2) their in vivo elimination half-life and plasma concentrations should be taken into be account to extrapolate this experimental results to in vivo.", "source": "https://pubmed.ncbi.nlm.nih.gov/10426558/"}
{"doc_id": "5e79090b1a2a1eb6907f90235c5dfb3a", "sentence": "Other studies are evaluating the use of capecitabine , oxaliplatin , and the anti-epidermal growth factor receptor agent cetuximab with RT in this malignancy .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 40, "end": 52, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "oxaliplatin", "start": 55, "end": 66, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "cetuximab", "start": 121, "end": 130, "token_start": 18, "token_end": 19}], "rels": [], "paragraph": "Current management of anal canal cancer. Squamous cell carcinoma of the anal canal historically has been treated with abdominoperineal resection, resulting in high rates of morbidity and local recurrence. Pioneering work led to the finding that radiation therapy (RT) combined with 5-fluorouracil (5-FU) and mitomycin results in high rates of local control and disease-free and colostomy-free survival without surgery. Prospective randomized trials from Europe and the United States have shown the superiority of RT, 5-FU, and mitomycin over 1) RT alone, 2) RT with 5-FU, and 3) neoadjuvant cisplatin/5-FU with concurrent radiation, cisplatin, and 5-FU. At present, RT with 5-FU and mitomycin is the standard of care for anal cancer patients. Recent advances include the integration of positron emission tomography into staging, radiation treatment planning and monitoring, and the use of intensity modulated RT. European randomized trials are further evaluating the role of cisplatin in the neoadjuvant, concurrent, and adjuvant settings, as well as radiation dose escalation. Other studies are evaluating the use of capecitabine , oxaliplatin , and the anti-epidermal growth factor receptor agent cetuximab with RT in this malignancy .", "source": "https://pubmed.ncbi.nlm.nih.gov/19336010/"}
{"doc_id": "c6a3421ac22d4334dd98a5c5dd81e616", "sentence": "Bacteriological , histopathologic , and clinical outcomes after treatment using moxifloxacin , moxifloxacin and dexamethasone combination , and vancomycin were comparable .", "spans": [{"span_id": 0, "text": "moxifloxacin", "start": 80, "end": 92, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "moxifloxacin", "start": 95, "end": 107, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "dexamethasone", "start": 112, "end": 125, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "vancomycin", "start": 144, "end": 154, "token_start": 18, "token_end": 19}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Effects of intravitreal moxifloxacin and dexamethasone in experimental Staphylococcus aureus endophthalmitis. To evaluate the effects of intravitreal moxifloxacin and moxifloxacin and dexamethasone combination in an experimental rabbit model of Staphylococcus aureus endophthalmitis. ### methods The right eyes of 24 rabbits weighing 2 to 3 kg were used. Ten thousand colony-forming units (CFU) of S. aureus in 0.1 ml saline solution were inoculated into the vitreous cavity. The eyes were randomly assigned to one of the four groups equally. Twenty-four hours after the inoculation of S. aureus, group 1 received 50 microg moxifloxacin, group 2 received 50 microg moxifloxacin plus 400 microg dexamethasone, and group 3 received 1 mg vancomycin intravitreally. No treatment was given to group 4. Clinical examination scores were recorded. Vitreous aspirates were obtained for microbiological analysis just before sacrifice, and the eyes were enucleated for histopathologic examination. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests. ### results In all treatment groups, mean number of CFU and histopathologic score were significantly lower compared with control group (p<0.05), and the difference between treatment groups was not statistically significant (p>0.05). The clinical score was not significantly different between groups (p>0.05). ### conclusions Intravitreal injection of 50 microg moxifloxacin was effective in the treatment of S. aureus endophthalmitis. Bacteriological , histopathologic , and clinical outcomes after treatment using moxifloxacin , moxifloxacin and dexamethasone combination , and vancomycin were comparable . Intravitreal moxifloxacin may be an option in the treatment of S. aureus endophthalmitis.", "source": "https://pubmed.ncbi.nlm.nih.gov/17453955/"}
{"doc_id": "d0abfbca5b519e0900c805ecc3a10c4f", "sentence": "Combining erythromycin , clarithromycin , or azithromycin with rifampin resulted in a significant ( P\u22640.005 ) decrease in MPC and MPC/MIC ratio .", "spans": [{"span_id": 0, "text": "erythromycin", "start": 10, "end": 22, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "clarithromycin", "start": 25, "end": 39, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "azithromycin", "start": 45, "end": 57, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "rifampin", "start": 63, "end": 71, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 3], "is_context_needed": false}, {"class": "POS", "spans": [1, 3], "is_context_needed": false}, {"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "Mutant prevention concentration and mutant selection window for 10 antimicrobial agents against Rhodococcus equi. The objectives of this study were to determine the mutant prevention concentration (MPC), time above the MPC and mutant selection window for 10 antimicrobial agents against Rhodococcus equi and to determine if the combination of a macrolide with rifampin would decrease emergence of resistant mutants. Antimicrobial agents investigated (erythromycin, clarithromycin, azithromycin, rifampin, amikacin, gentamicin, enrofloxacin, vancomycin, imipenem, and doxycycline) were selected based on in vitro activity and frequency of use in foals or people infected with R. equi. Each antimicrobial agent or combination of agents was evaluated against four virulent strains of R. equi. MPC were determined using an agar plate assay. Pharmacodynamic parameters were calculated using published plasma and pulmonary pharmacokinetic variables. There was a significant (P<0.001) effect of the type of antimicrobial agent on the MPC. The MPC of clarithromycin (1.0 \u03bcg/ml) was significantly lower and the MPC of rifampin and amikacin (512 and 384 \u03bcg/ml, respectively) were significantly higher than that of all other antimicrobial agents tested. Combining erythromycin , clarithromycin , or azithromycin with rifampin resulted in a significant ( P\u22640.005 ) decrease in MPC and MPC/MIC ratio . When MIC and MPC were combined with pharmacokinetic variables, only gentamicin and vancomycin were predicted to achieve plasma concentrations above the MPC for any given periods of time. Only clarithromycin and the combination clarithromycin-rifampin were predicted to achieve concentrations in bronchoalveolar cells and pulmonary epithelial lining fluid above the MPC for the entire dosing interval. In conclusion, the combination of a macrolide with rifampin considerably decreases the emergence of resistant mutants of R. equi.", "source": "https://pubmed.ncbi.nlm.nih.gov/23915992/"}
{"doc_id": "54964251ce7e6cabed1272f0799d82eb", "sentence": "This was confirmed and show that the dCK levels are retained upon co-treatment , indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 111, "end": 121, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "cytarabine", "start": 152, "end": 162, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-\u03baB activity. The addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line. ### methods Effects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses. ### results Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-\u03baB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment , indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance . The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment. ### conclusion We show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-\u03baB are the main molecular events driving cytarabine resistance development.", "source": "https://pubmed.ncbi.nlm.nih.gov/29695239/"}
{"doc_id": "17ce67b32a1c7321276f9a838007b4ce", "sentence": "Artemether , artesunate , praziquantel and tribendimidine administered singly at different dosages against Clonorchis sinensis : a comparative in vivo study .", "spans": [{"span_id": 0, "text": "Artemether", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "artesunate", "start": 13, "end": 23, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "praziquantel", "start": 26, "end": 38, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Artemether , artesunate , praziquantel and tribendimidine administered singly at different dosages against Clonorchis sinensis : a comparative in vivo study . We comparatively assessed the in vivo efficacy of artemether, artesunate, praziquantel and tribendimidine against different stages of Clonorchis sinensis. Rats were infected with 40-50 C. sinensis metacercariae, and drugs were administered singly by the oral route at different dosages. Rats were dissected 2-4 weeks post-treatment and C. sinensis trematodes were removed from the liver and bile ducts and counted. We used a negative binomial regression model to test the effect of drug and dosage in terms of worm burden reduction. Single 150 mg/kg oral doses of artesunate, artemether, tribendimidine and praziquantel, administered to rats infected with adult C. sinensis, resulted in mean worm burden reductions of 100, 100, 89.5 and 80.7%, respectively (all P<0.001). Halving the dose to 75 mg/kg still resulted in highly significant worm burden reductions for artesunate, artemether and tribendimidine (71.4-100%), but not for praziquantel (20.7%). In the juvenile infection model, a single 150 mg/kg oral dose of tribendimidine and praziquantel resulted in mean worm burden reductions of 99.1 and 90.0%, respectively, whereas considerably lower reductions were observed for artemether (59.2%) and artesunate (57.6%) when used at the same single dose. The in vivo results presented here with the artemisinins and tribendimidine provide further data for clinical investigations to assess the safety and efficacy of these drugs in clonorchiasis patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/18308285/"}
{"doc_id": "9fb1ec9eb7a2348ed2fbd8b3bd74a3a0", "sentence": "The agents studied include : propranolol , timolol , metoprolol , practolol , atenolol and the combined alpha and beta adrenoceptor blocking agent , labetalol .", "spans": [{"span_id": 0, "text": "propranolol", "start": 29, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "timolol", "start": 43, "end": 50, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "metoprolol", "start": 53, "end": 63, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "atenolol", "start": 78, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 4, "text": "labetalol", "start": 149, "end": 158, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Inhibition of purified lysosomal phospholipase A1 by beta-adrenoceptor blockers. Inhibition of rat liver lysosomal phospholipases is one of the main events that leads to accumulation of tissue phospholipids during drug-induced phospholipidosis. Drug inhibition of lysosomal phospholipase A may occur by direct effects of drugs on the enzyme (or substrate) or by drug-induced increases in intralysosomal pH. Although beta-adrenoceptor blockers have not been reported to cause lipid storage, they do inhibit lysosomal phospholipase A. To investigate the structural requirements for drug inhibition, we studied the effects of six beta-adrenoceptor blockers on purified rat liver lysosomal phospholipase A1. The agents studied include : propranolol , timolol , metoprolol , practolol , atenolol and the combined alpha and beta adrenoceptor blocking agent , labetalol . The drugs varied by two logs in their abilities to inhibit phospholipase A1 activity. The relative inhibitory potencies were propranolol greater than labetalol much greater than timolol greater than metoprolol much greater than practolol greater than atenolol. Our studies identify drug hydrophobicity as a key determinant for phospholipase A1 inhibition. A strong negative correlation was noted between the octanol/water partition coefficients and IC50 for phospholipase inhibition (r = -0.91). The ability of propranolol to inhibit phospholipase A1 was identical for the d, l and the d and l stereoisomers.", "source": "https://pubmed.ncbi.nlm.nih.gov/2857566/"}
{"doc_id": "35618f6c493f9bdf1494b7d89163d65b", "sentence": "Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy , including FoxO1 and its targets .", "spans": [{"span_id": 0, "text": "fenofibrate", "start": 11, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "lovastatin", "start": 48, "end": 58, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy , including FoxO1 and its targets . Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPAR\u03b1 knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.", "source": "https://pubmed.ncbi.nlm.nih.gov/33408297/"}
{"doc_id": "e05d747dfa790c1c8bd20db1d9e43d53", "sentence": "Idasanutlin was tolerable alone and in combination with cytarabine .", "spans": [{"span_id": 0, "text": "Idasanutlin", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "cytarabine", "start": 56, "end": 66, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study\u22c6. The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine . The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408.", "source": "https://pubmed.ncbi.nlm.nih.gov/33302031/"}
{"doc_id": "276d55d879d554f558d58f254164d21e", "sentence": "Cell surface proteins induced by fludarabine and cladribine may be targets for therapeutic antibodies .", "spans": [{"span_id": 0, "text": "fludarabine", "start": 33, "end": 44, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "cladribine", "start": 49, "end": 59, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Fludarabine and cladribine induce changes in surface proteins on human B-lymphoid cell lines involved with apoptosis, cell survival, and antitumor immunity. fludarabine and cladribine are purine analogues used to treat hematological malignancies. Alone or in combination with therapeutic antibodies, they are effective in treating patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma. However, the mechanisms of action of these drugs are not well understood. Plasma membrane proteins perform a variety of essential functions that can be affected by malignancy and perturbed by chemotherapy. Analysis of surface proteins may contribute to an understanding of the mechanisms of action of purine analogues and identify biomarkers for targeted therapy. The surface of human cells is rich in N-linked glycoproteins, enabling use of a hydrazide-coupling technique to enrich for glycoproteins, with iTRAQ labeling for quantitative comparison. A number of plasma membrane proteins on human leukemia and lymphoma cells were affected by treatment with a purine analogue, including decreases in CD22 (an adhesion and signaling molecule) and increases in CD205 (a \"damaged cell marker\") and CD80 and CD50 (T-cell interaction molecules). Purine analogues may affect B-cell receptor (BCR) signaling and costimulatory molecules, leading to multiple signals for apoptosis and cell clearance. fludarabine and cladribine induce differential effects, with some cell survival proteins (ECE-1 and CD100) more abundant after fludarabine treatment. Cell surface proteins induced by fludarabine and cladribine may be targets for therapeutic antibodies .", "source": "https://pubmed.ncbi.nlm.nih.gov/22839105/"}
{"doc_id": "642c1582627371fac3aa51763b0b0fcc", "sentence": "After seven days of chemotherapy with 5-fluorouracil , oxaliplatin and bevacizumab , exploratory surgery revealed a perforation at the ileum .", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 38, "end": 52, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "oxaliplatin", "start": 55, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "bevacizumab", "start": 71, "end": 82, "token_start": 10, "token_end": 11}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Intestinal perforation in colorectal cancers treated with bevacizumab (Avastin). bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), and it has shown promise as a clinical agent against metastatic colorectal cancer, and particularly in combination with chemotherapy. Bowel perforation is a known risk that's associated with bevacizumab use, but the etiology is unknown. Here we report on two cases of metastatic colorectal cancer in which the patients suffered from intestinal perforation after chemotherapy with bevacizumab. For the first case, a 47 year-old man had rectal cancer with concurrent liver and lung metastasis. He underwent chemotherapy with 5-fluorouracil, irinotecan and bevacizumab. Fever and abdominal pain developed seven days later, and rectal perforation was identified upon exploration 13 days later. For the second case, a 48 year-old woman had sigmoid colon cancer with peritoneal and ovary metastases. After seven days of chemotherapy with 5-fluorouracil , oxaliplatin and bevacizumab , exploratory surgery revealed a perforation at the ileum .", "source": "https://pubmed.ncbi.nlm.nih.gov/19688063/"}
{"doc_id": "b7a74b8f49372a2cf52016dee22d48bd", "sentence": "Nausea graded none or mild 24 h after the start of cisplatin infusion was reported in 71 and 69 % of patients in the 8- and 32-mg ondansetron groups , respectively , and in 73 % of patients in the granisetron group .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 51, "end": 60, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "ondansetron", "start": 130, "end": 141, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "granisetron", "start": 197, "end": 208, "token_start": 40, "token_end": 41}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. The Ondansetron and Granisetron Emesis Study Group. This is the first international, multi-centre, double-blind, randomised, parallel group study to directly compare the efficacy and safety profile of a single intravenous dose of ondansetron (8 or 32 mg) with granisetron (3 mg) in the control of cisplatin-induced acute emesis. A total of 496 patients were randomised to receive one of three anti-emetic treatments prior to cisplatin chemotherapy (> or = 50 mg/m2). Of these, 165 and 162 patients received 8 and 32 mg of ondansetron, respectively, and 169 patients received 3 mg of granisetron. Complete control of emesis (0 emetic episodes) over 24 h was reported in 59% of patients in the 8-mg ondansetron group, 51% of patients in the 32-mg ondansetron group and 56% of patients in the granisetron group. Complete or major control (< or = 2 emetic episodes) was achieved in 76 and 74% of patients in the 8- and 32-mg ondansetron group, respectively, compared with 78% of patients in the granisetron group. Nausea graded none or mild 24 h after the start of cisplatin infusion was reported in 71 and 69 % of patients in the 8- and 32-mg ondansetron groups , respectively , and in 73 % of patients in the granisetron group . There were no significant differences between the treatment groups when global satisfaction scores were compared. Logistic regression models were fitted to assess any interaction between treatments and prognostic factors (age, gender, alcohol use, cisplatin dose or concomitant chemotherapy) on complete or major response, but there was no evidence of interaction for any factor. All three anti-emetic treatments were well tolerated and no severe or unexpected drug-related adverse events were observed with ondansetron or granisetron. Headache, the most reported drug-related adverse event for all three treatment groups, occurred in 9% of all patients. In summary, no significant difference was observed between any of the treatment groups with respect to emesis, nausea or drug-related adverse events.", "source": "https://pubmed.ncbi.nlm.nih.gov/8265095/"}
{"doc_id": "8797191a6cfcfc6747d63887c0100779", "sentence": "Relatively recent studies have shown that dexmedetomidine is able to decrease circulating plasma norepinephrine and epinephrine concentration in approximately 50 % , decreases brain blood flow by directly acting on post-synaptic alpha 2 receptors , decreases CSF pressure without ischemic suffering and effectively decrease brain metabolism and intracranial pressure and also , able to decrease injury caused by focal ischemia .", "spans": [{"span_id": 0, "text": "dexmedetomidine", "start": 42, "end": 57, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "epinephrine", "start": 116, "end": 127, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Prospective, randomized study to assess the role of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. Preliminary data on the perioperative use of dexmedetomidine in patients undergoing craniotomy for brain tumor under general anaesthesia indicate that the intraoperative administration of dexmedetomidine is opioid-sparing, results in less need for antihypertensive medication, and may offer greater hemodynamic stability at incision and emergence. Dexmedetomidine, alpha 2 adrenoceptor agonist used as adjuvant to anaesthetic agents. Relatively recent studies have shown that dexmedetomidine is able to decrease circulating plasma norepinephrine and epinephrine concentration in approximately 50 % , decreases brain blood flow by directly acting on post-synaptic alpha 2 receptors , decreases CSF pressure without ischemic suffering and effectively decrease brain metabolism and intracranial pressure and also , able to decrease injury caused by focal ischemia . ### purpose This prospective, randomized, double-blind study was designed to assess the perioperative effect of intraoperative infusion of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. ### methods Forty patients with CT- scanning proof of supratentorial tumors. The patients were classified equally into 2 groups (twenty patients in each group). Group A:--The dexmedetomidine was given as a bolus dose of 1 microg/kg in 20 minutes before induction of anaesthesia, followed by a maintenance infusion of 0.4 microg/kg/hr. The infusion was discontinued when surgery ended. Group B:--The patients received similar volumes of saline. ### results The heart rate and mean arterial blood pressure, decreased in patients of group A (dexmedetomidine group) more than group B (placebo group) with significant statistical difference between the two groups (P-value <0.05). No significant statistical difference between the two groups regarding the central venous pressure and arterial partial pressure of Carbon Dioxide (P-value >0.05). The intraoperative end-tidal sevoflurane (%) in patients of group A less than in patients of group B (P-value <0.05).The intracranial pressure decreased in patients of Group A more than group B (P-value <0.05). The Glasgow coma scale (GCS) improved in patients of group A and deteriorated in patients of Group B with significant statistical difference between the two groups (P-value <0.05). The total fentanyl requirements from induction to extubation of patients increased in patients of group B more than in patients of group A (P-value <0.05). The total postoperative patients' requirements for antiemetic drugs within the 2 hours after extubation decreased in patients of group A more than group B (P-value <0.05). The postoperative duration from the end of surgery to extubation decreased significantly in patients of group A more than group B (P-value <0.05). The total urine output during the duration from drug administration to extubation of patients increased in patients of group A more than group B (P-value <0.05). ### conclusions Continuous intraoperative infusion of dexmedetomidine during craniotomy for supratentorial tumors under general anaesthesia maintained the haemodynamic stability, reduced sevoflurane and fentanyl requirements, decreased intracranial pressure, and improved significantly the outcomes.", "source": "https://pubmed.ncbi.nlm.nih.gov/22428485/"}