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+{"doc_id": "4a5a8940cfaed4c9cfd066173390b1dc", "sentence": "A randomized Phase III trial demonstrated noninferiority of APF530 500 mg SC ( granisetron 10 mg ) to intravenous palonosetron 0.25 mg in preventing CINV in patients receiving MEC or HEC in acute ( 0 - 24 hours ) and delayed ( 24 - 120 hours ) settings , with activity over 120 hours .", "spans": [{"span_id": 0, "text": "granisetron", "start": 79, "end": 90, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "palonosetron", "start": 114, "end": 126, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Biochronomer\u2122 technology and the development of APF530, a sustained release formulation of granisetron. granisetron and other 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are first-line agents for preventing chemotherapy-induced nausea and vomiting (CINV). Current treatment guidelines prefer the longer-acting agent, palonosetron, for CINV prevention in some chemotherapy regimens. A new granisetron formulation, APF530, has been developed as an alternative long-acting agent. APF530 utilizes Biochronomer(\u2122) technology to formulate a viscous tri(ethylene glycol) poly(orthoester)-based formulation that delivers - by single subcutaneous (SC) injection - therapeutic granisetron concentrations over 5 days. The poly(orthoester) polymer family contain an orthoester linkage; these bioerodible polymer systems are specifically designed for controlled, sustained drug delivery. Pharmacokinetics and pharmacodynamics of APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively) administered 30-60 minutes before chemotherapy were evaluated in two Phase II trials in cancer patients receiving moderately (MEC) or highly (HEC) emetogenic chemotherapy. Pharmacokinetics were dose proportional, with slow granisetron absorption and elimination. Both trials demonstrated similar results for median half-life, time to maximum concentration, and exposure for APF530 250 and 500 mg, with no differences between patients receiving MEC or HEC. A randomized Phase III trial demonstrated noninferiority of APF530 500 mg SC ( granisetron 10 mg ) to intravenous palonosetron 0.25 mg in preventing CINV in patients receiving MEC or HEC in acute ( 0 - 24 hours ) and delayed ( 24 - 120 hours ) settings , with activity over 120 hours . Mean maximum granisetron plasma concentrations were 10.8 and 17.8 ng/mL, and mean half-lives were 30.8 and 35.9 hours after SC administration of APF530 250 and 500 mg, respectively. Therapeutic granisetron concentrations were maintained for greater than 120 hours (5 days) in both APF530 dose groups. These data suggest that APF530 - an SC-administered formulation of granisetron delivered via Biochronomer technology - represents an effective treatment option for the prevention of both acute and delayed CINV in patients receiving either MEC or HEC.", "source": "https://pubmed.ncbi.nlm.nih.gov/27186139/"}
+{"doc_id": "ef4fb4cd54c88e22cd1b882061876c8d", "sentence": "Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen , celecoxib and rofecoxib in AD clinical trials .", "spans": [{"span_id": 0, "text": "naproxen", "start": 175, "end": 183, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "celecoxib", "start": 186, "end": 195, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "rofecoxib", "start": 200, "end": 209, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen , celecoxib and rofecoxib in AD clinical trials . Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.", "source": "https://pubmed.ncbi.nlm.nih.gov/15974901/"}
+{"doc_id": "f3c31f04fdf5a6a559c0fd215a4ebe4c", "sentence": "Between 1987 and 2003 , patients 18 years old were given adjuvant chemotherapy consisting of one of two ' paediatric ' regimens ( depending on the time of presentation ) and craniospinal local-boost radiotherapy : regimen A ( n = 12 ) , vincristine ( VCR ) , intrathecal and/or intravenous methotrexate and conventional radiotherapy ; or regimen B ( n = 11 ) sequencing intensive doses of multiple agents followed by hyperfractionated accelerated radiotherapy ( HART ) .", "spans": [{"span_id": 0, "text": "vincristine", "start": 237, "end": 248, "token_start": 43, "token_end": 44}, {"span_id": 1, "text": "methotrexate", "start": 290, "end": 302, "token_start": 51, "token_end": 52}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Survival of adults treated for medulloblastoma using paediatric protocols. We retrospectively studied 26 consecutive adults treated for medulloblastoma using paediatric protocols. Between 1987 and 2003 , patients 18 years old were given adjuvant chemotherapy consisting of one of two ' paediatric ' regimens ( depending on the time of presentation ) and craniospinal local-boost radiotherapy : regimen A ( n = 12 ) , vincristine ( VCR ) , intrathecal and/or intravenous methotrexate and conventional radiotherapy ; or regimen B ( n = 11 ) sequencing intensive doses of multiple agents followed by hyperfractionated accelerated radiotherapy ( HART ) . A VCR-lomustine-based maintenance followed both regimens. Three additional patients received a tailored treatment due to their impaired neurological status after surgery. The median age at diagnosis was 26 years (range 18-41 years). With a median follow-up of 46 months, 5-year disease-free and overall survival rates were 65+/-11% and 73+/-10%, respectively, for the series as a whole. All patients who received regimen B (5 of whom had metastatic Chang M2-M3 disease) are alive with no evidence of disease at 39 months. Although the number of patients is limited, our data suggest that the sandwich sequential, moderately intensive chemotherapy in combination with HART is an effective treatment for medulloblastoma in adults, and this approach seems to overcome previously-recognised risk factors.", "source": "https://pubmed.ncbi.nlm.nih.gov/15869875/"}
+{"doc_id": "7c1b48c4fded5536004f52b2f9c14572", "sentence": "The US Food and Drug Administration ( FDA ) recommends that \" concomitant use of drugs that inhibit CYP2C19 ( e.g. , omeprazole ) should be discouraged . \" As the presence of PPIs and clopidogrel in plasma is short lived , separation by 12 - 20 h should in theory prevent competitive inhibition of CYP metabolism and minimize any potential , though unproven , clinical interaction .", "spans": [{"span_id": 0, "text": "omeprazole", "start": 117, "end": 127, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "clopidogrel", "start": 184, "end": 195, "token_start": 35, "token_end": 36}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Proton pump inhibitor and clopidogrel interaction: fact or fiction? Current consensus recommendations state that patients prescribed clopidogrel plus aspirin should receive a proton pump inhibitor (PPI) to reduce gastrointestinal bleeding. clopidogrel is converted to its active metabolite by cytochrome P450 (CYP) enzymes. clopidogrel users with decreased CYP2C19 function have less inhibition of platelet aggregation and increased cardiovascular (CV) events. As PPI metabolism also involves CYP2C19, it was hypothesized that competition by PPIs might interfere with clopidogrel's action. omeprazole, but not other PPIs, worsens surrogate markers of clopidogrel efficacy. Some (but not all) observational studies show that clopidogrel users prescribed PPIs have increased risks of CV events (hazard/odds ratios=1.25-1.5). When effect sizes are small to moderate (relative risks<1.5-2.0), however, it is only possible to conclude whether statistical associations are valid in randomized trials. A randomized trial of omeprazole vs. placebo in clopidogrel users showed no difference in CV events (hazard ratio=1.02,0.70-1.51). Thus, current evidence does not justify a conclusion that PPIs are associated with CV events among clopidogrel users, let alone a judgment of causality. Nonetheless, positive results from some observational studies and biological plausibility have led some health-care providers to accept that PPIs reduce clopidogrel's efficacy. The US Food and Drug Administration ( FDA ) recommends that \" concomitant use of drugs that inhibit CYP2C19 ( e.g. , omeprazole ) should be discouraged . \" As the presence of PPIs and clopidogrel in plasma is short lived , separation by 12 - 20 h should in theory prevent competitive inhibition of CYP metabolism and minimize any potential , though unproven , clinical interaction . PPI may be given before breakfast and clopidogrel at bedtime, or PPI may be taken before dinner and clopidogrel at lunchtime.", "source": "https://pubmed.ncbi.nlm.nih.gov/19904241/"}
+{"doc_id": "7639b3ca6251f63f76d161da9c24f217", "sentence": "Long-term overall- and progression-free survival after pentostatin , cyclophosphamide and rituximab therapy for indolent non-Hodgkin lymphoma .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 69, "end": 85, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "rituximab", "start": 90, "end": 99, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "pentostatin", "start": 55, "end": 66, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Long-term overall- and progression-free survival after pentostatin , cyclophosphamide and rituximab therapy for indolent non-Hodgkin lymphoma . In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108\u00a0months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108\u00a0months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2\u00b72 and \u22652\u00b72\u00a0mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10\u00a0years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21\u00b77%) patients with second malignancies and 2 (2\u00b74%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL.", "source": "https://pubmed.ncbi.nlm.nih.gov/30820940/"}
+{"doc_id": "70e681adca9791cf2e10d9bd14f4c430", "sentence": "Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection .", "spans": [{"span_id": 0, "text": "isoniazid", "start": 12, "end": 21, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "rifapentine", "start": 26, "end": 37, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine.  Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection . This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. ### methods This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. ### results The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-\u03b3, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. ### conclusions The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. ### Clinical Trials Registration NCT02771249.", "source": "https://pubmed.ncbi.nlm.nih.gov/29415190/"}
+{"doc_id": "5e01b68299caff14016a31896c325af2", "sentence": "We investigated the effects of these inhibitors on other anticancer drugs including docetaxel , vinblastine , doxorubicin , 10-Hydroxycamptothecin ( 10-HCPT ) and cisplatin and find that both inhibitors induces DU145-TxR cells to be more sensitive only to the microtubule-targeting drugs ( paclitaxel , docetaxel and vinblastine ) .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 84, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "vinblastine", "start": 96, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "doxorubicin", "start": 110, "end": 121, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "cisplatin", "start": 163, "end": 172, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "paclitaxel", "start": 290, "end": 300, "token_start": 42, "token_end": 43}, {"span_id": 5, "text": "docetaxel", "start": 303, "end": 312, "token_start": 44, "token_end": 45}, {"span_id": 6, "text": "vinblastine", "start": 317, "end": 328, "token_start": 46, "token_end": 47}], "rels": [], "paragraph": "The Upregulation of PI3K/Akt and MAP Kinase Pathways is Associated with Resistance of Microtubule-Targeting Drugs in Prostate Cancer. Resistance is a significant limitation to the effectiveness of cancer therapies. The PI3K/Akt and MAP kinase pathways play important roles in a variety of normal cellular processes and tumorigenesis. This study is designed to explore the relationship of these signaling pathways with multidrug resistance in prostate cancer (PCa). The PI3K/Akt and MAP kinase pathways were investigated utilizing paclitaxel resistant DU145-TxR PCa cells and their parental non-resistant DU145 cells to determine their relationship with resistance to paclitaxel and other anticancer drugs. Our results demonstrate that the PI3K/Akt and MAP kinase pathways are upregulated in DU145-TxR cells compared to the DU145 cells. Inactivating these pathways using the PI3K/Akt pathway inhibitor LY294002 or the MAP kinase pathway inhibitor PD98059 renders the DU145-TxR cells more sensitive to paclitaxel. We investigated the effects of these inhibitors on other anticancer drugs including docetaxel , vinblastine , doxorubicin , 10-Hydroxycamptothecin ( 10-HCPT ) and cisplatin and find that both inhibitors induces DU145-TxR cells to be more sensitive only to the microtubule-targeting drugs ( paclitaxel , docetaxel and vinblastine ) . Furthermore, the treatment with these inhibitors induces cleaved-PARP production in DU145-TxR cells, suggesting that apoptosis induction might be one of the mechanisms for the reversal of drug resistance. In conclusion, the PI3K/Akt and MAP kinase pathways are associated with resistance to multiple chemotherapeutic drugs. Inactivating these pathways renders these PCa cells more sensitive to microtubule-targeting drugs such as paclitaxel, docetaxel and vinblastine. Combination therapies with novel inhibitors of these two signaling pathways potentially represents a more effective treatment for drug resistant PCa.", "source": "https://pubmed.ncbi.nlm.nih.gov/25640606/"}
+{"doc_id": "960105c5f66a50001d208fdbe4f96ccb", "sentence": "Group B : From January , 1976 to December , 1980 , 55 evaluable patients participated in a consecutive study that added Adriamycin ( doxorubicin ) and cyclophosphamide to the former induction regimen .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 133, "end": 144, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "cyclophosphamide", "start": 151, "end": 167, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Comparison of two consecutive trials for treatment of childhood non-Hodgkin's lymphoma. Two consecutive trials for the treatment of childhood non-Hodgkin's lymphoma were evaluated, carried out by the same cooperative groups. Group A: From June, 1973 to December, 1975, 50 evaluable patients under 16 years of age participated in a study that included vincristine and prednisone plus surgery and/or radiotherapy as induction. This was followed by 2400 rad of cranial radiotherapy plus 5 doses of intrathecal methotrexate-dexamethasone and anti-leukemia (6-mercaptopurine, methotrexate, cyclophosphamide) or anti-lymphoma (cyclophosphamide, vincristine, procarbazine, and prednisone) maintenance treatment. Group B : From January , 1976 to December , 1980 , 55 evaluable patients participated in a consecutive study that added Adriamycin ( doxorubicin ) and cyclophosphamide to the former induction regimen . Central nervous system (CNS) prevention was performed with 5 doses of intrathecal methotrexate-dexamethasone. Maintenance treatment was the same. Prognostic factors as stage and primary site were comparable in both groups. A total of 33 (66%) of 50 children of Group A and 48 (87%) of 55 children of Group B achieved complete remission (P less than 0.005). Disease-free survival at 60 months was 27% in Group A and 49% in Group B; for Stage I-II, 30% in Group A and 85% in Group B (P less than 0.025); for Stage III-IV 28% in Group A and 36% in Group B (not significant). In Group A, 9.1% and in Group B, 8.3% had primary CNS relapse. Both maintenance schedules had the same relapse rate. It was concluded that: (1) the addition of Adriamycin and cyclophosphamide to vincristine-prednisone in Group B produces a higher rate of complete remission in Stage III-IV, a higher rate of disease-free survival in Stage I-II, and a higher survival rate in all stages; (2) CNS prevention with intrathecal methotrexate-dexamethasone is equally effective as cranial radiation plus intrathecal methotrexate-dexamethasone; and (3) anti-leukemia and anti-lymphoma maintenance are equally effective in the context of this study.", "source": "https://pubmed.ncbi.nlm.nih.gov/6388820/"}
+{"doc_id": "db3dec1a94dc53bf5435039c482e060c", "sentence": "When given in repeated doses from 6 h on , 50 g followed by 12.5 g at 6-h intervals , charcoal shortened the serum half-life of amitriptyline by 20 % and that of nortriptyline by 35 % ( p less than 0.05 ) .", "spans": [{"span_id": 0, "text": "amitriptyline", "start": 128, "end": 141, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "nortriptyline", "start": 162, "end": 175, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Pharmacokinetics of amitriptyline influenced by oral charcoal and urine pH. The effects of orally given activated charcoal, sodium bicarbonate and ammonium chloride on the pharmacokinetics of amitriptyline were studied in 6 volunteers in a randomized, cross-over study. The serum and urine concentrations of amitriptyline and nortriptyline were determined by HPLC for up to 72 h. activated charcoal (50 g), given within 5 min of the amitriptyline hydrochloride dose (75 mg), reduced its absorption by 99%. When given in repeated doses from 6 h on , 50 g followed by 12.5 g at 6-h intervals , charcoal shortened the serum half-life of amitriptyline by 20 % and that of nortriptyline by 35 % ( p less than 0.05 ) . The renal excretions of amitriptyline and nortriptyline increased 1000-fold by the acidification of urine pH to 4. However, the cumulative excretion of amitriptyline and nortriptyline even into acidic urine only accounted for up to 5% of the dose during 72 h. Since urinary pH has a great influence on the ratio of urinary versus serum amitriptyline and nortriptyline concentrations, pH should be taken into consideration, when the clinical significance of their concentrations in urine is evaluated. activated charcoal in adequate doses very effectively prevents the absorption of that fraction of amitriptyline which is in the stomach at the time of charcoal administration. Furthermore, given in repeated oral doses, charcoal increases, to some extent, the rate of elimination of amitriptyline and nortriptyline, probably by interrupting their enterohepatic or enteroenteric circulation.", "source": "https://pubmed.ncbi.nlm.nih.gov/3015809/"}
+{"doc_id": "db0e74273491043a8d918e7ddae08e7d", "sentence": "The median overall survival time was 22.7 months in the docetaxel arm and 22.4 months in the paclitaxel arm .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 56, "end": 65, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "paclitaxel", "start": 93, "end": 103, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "A phase II randomized study of two taxanes and cisplatin for metastatic breast cancer after anthracycline: a final analysis. The purpose of the study is to compare two taxanes/cisplatin combinations for metastatic breast cancer in terms of time to disease progression, response rates and toxicity. ### methods Between April 2000 and December 2002, 101 patients with advanced breast carcinoma, previously treated with an anthracycline but not with a taxane, were enrolled. Fifty patients were treated with docetaxel 60 mg/m2 and cisplatin 50 mg/m2, and 51 patients were treated with paclitaxel 175 mg/m2 and cisplatin 50 mg/m2. Each cycle repeated every 3 weeks. ### results The overall response rate was 62.5 and 42.6% in the docetaxel and palcitaxel groups respectively (P = 0.06). Median time to disease progression was 9.8 and 6.5 months in docetaxel and paclitaxel groups respectively (P = 0.15). The median overall survival time was 22.7 months in the docetaxel arm and 22.4 months in the paclitaxel arm . Grade 3/4 arthralgia/myalgia, sensory neuropathy and anemia occurred more frequently in the paclitaxel arm, while more mucositis, fatigue and neutropenia occurred in the docetaxel arm. ### conclusion Taxane/cisplatin combinations were active for advanced breast cancer, while there appeared to be evidence in favor of a docetaxel/cisplatin combination. The toxicity in favor of docetaxel/cisplatin warrants future first-line clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/17172351/"}
+{"doc_id": "faf0c9f77be3f3da48e14be921b759f0", "sentence": "We hypothesized that Aurora A kinase ( AK ) contributes to castrate resistance in prostate cancer ( PCa ) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor ( AR ) inhibitor abiraterone .", "spans": [{"span_id": 0, "text": "alisertib", "start": 134, "end": 143, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "abiraterone", "start": 208, "end": 219, "token_start": 36, "token_end": 37}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A Phase I/II Study of the Investigational Drug Alisertib in Combination With Abiraterone and Prednisone for Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Abiraterone. Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone. ### background We hypothesized that Aurora A kinase ( AK ) contributes to castrate resistance in prostate cancer ( PCa ) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor ( AR ) inhibitor abiraterone . ### methods This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3+3 design. ### results Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early. ### conclusion A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.", "source": "https://pubmed.ncbi.nlm.nih.gov/28178640/"}
+{"doc_id": "64be1cf1b7842c1f1e561a1885ffcb34", "sentence": "Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2 + breast cancer whose tumors have progressed during treatment with trastuzumab .", "spans": [{"span_id": 0, "text": "Tanespimycin", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "trastuzumab", "start": 18, "end": 29, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "trastuzumab", "start": 165, "end": 176, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. ### Patients And Methods Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels. ### results Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. ### conclusion Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2 + breast cancer whose tumors have progressed during treatment with trastuzumab . These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.", "source": "https://pubmed.ncbi.nlm.nih.gov/18048823/"}
+{"doc_id": "259fcb11e8020d04ee63f8e43cb90c7a", "sentence": "It contains data on prophylaxis with mefloquine ( n = 48,264 ) , with chloroquine ( 6,752 ) , with chloroquine plus proguanil ( 19,727 ) , and with no prophylaxis ( 3,871 ) .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 37, "end": 47, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "chloroquine", "start": 70, "end": 81, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "chloroquine", "start": 99, "end": 110, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "proguanil", "start": 116, "end": 125, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Tolerability and Effectiveness of Malaria Chemoprophylaxis with Mefloquine or Chloroquine with or without Co-medication. Background: To determine the relevance of drug interactions with co-medication for effectiveness and tolerability of antimalarial chemoprophylaxis. Method: A database (MALPRO2) on travelers on their flight home from Africa to Europe between July 1988 and December 1991 was reanalyzed. It contains data on prophylaxis with mefloquine ( n = 48,264 ) , with chloroquine ( 6,752 ) , with chloroquine plus proguanil ( 19,727 ) , and with no prophylaxis ( 3,871 ) . The comparison of rates of malaria incidence and adverse events (AEs) between users and nonusers of co-medication was expressed by relative risk (RR). Results: Fifty-three percent of travelers (63% of females, 43% of males) used co-medication in all prophylaxis groups, with an average of 1.35 additional drugs per person and about two AEs reported per person. With the exception of antidiarrheals plus mefloquine, malaria incidence with co-medication was lower (RR = 0.8) than without co-medication. In all regimens, the proportion of travelers reporting AEs was about 1.5-fold with co-medication (p<.01); that reporting severe AEs was twice as high as compared to with no co-medication. mefloquine AE rates for various classes of co-medication were similar to that of chloroquine, with highest AE and severity rates with neuropsychiatric drugs (excluding antiepileptics, RR = 1.9 and 2.9), and lowest rates with cardiovasculars (RR = 1.1 and 1.0). Various co-medications were used with different frequencies in males and females, and the latter reported more AEs. Conclusion: These data suggest that co-medications commonly used by travelers have no significant clinical impact on safety and effectiveness of prophylaxis with mefloquine or chloroquine. Increased frequency and severity of AEs when using co-medication rather is explained by underlying illness.", "source": "https://pubmed.ncbi.nlm.nih.gov/9815496/"}
+{"doc_id": "dd0068d9fba06a8e7c381728dd8e1029", "sentence": "We hypothesized that the brain damage mitigating effect of mild hypothermia after cardiac arrest can be enhanced with thiopental loading , and even more so with the further addition of phenytoin and methylprednisolone .", "spans": [{"span_id": 0, "text": "phenytoin", "start": 185, "end": 194, "token_start": 30, "token_end": 31}, {"span_id": 1, "text": "methylprednisolone", "start": 199, "end": 217, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Thiopental combination treatments for cerebral resuscitation after prolonged cardiac arrest in dogs. Exploratory outcome study. We postulate that mitigating the multifactorial pathogenesis of postischemic encephalopathy requires multifaceted treatments. In preparation for expensive definitive studies, we are reporting here the results of small exploratory series, compared with historic controls with the same model. We hypothesized that the brain damage mitigating effect of mild hypothermia after cardiac arrest can be enhanced with thiopental loading , and even more so with the further addition of phenytoin and methylprednisolone . Twenty-four dogs (four groups of six dogs each) received VF 12.5 min no-flow, reversed with brief cardiopulmonary bypass (CPB), controlled ventilation to 20 h, and intensive care to 96 h. Group 1 with normothermia throughout and randomized group 2 with mild hypothermia (from reperfusion to 2 h) were controls. Then, group 3 received in addition, thiopental 90 mg/kg i.v. over the first 6 h. Then, group 4 received, in addition to group 2 treatment, thiopental 30 mg/kg i.v. over the first 90 min (because the larger dose had produced cardiopulmonary complications), plus phenytoin 15 mg/kg i.v. at 15 min after reperfusion, and methylprednisolone 130 mg/kg i.v. over 20 h. All dogs survived. Best overall performance categories (OPC) achieved (OPC 1 = normal, OPC 5 = brain death) were better in group 2 than group 1 (< 0.05) and numerically better in groups 3 or 4 than in groups 1 or 2. Good cerebral outcome (OPC 1 or 2) was achieved by all six dogs only in group 4 (P < 0.05 group 4 vs. 2). Best NDS were 44 +/- 3% in group 1; 20 +/- 14% in group 2 (P = 0.002); 21 +/- 15% in group 3 (NS vs. group 2); and 7 +/- 8% in group 4 (P = 0.08 vs. group 2). Total brain histologic damage scores (HDS) at 96 h were 156 +/- 38 in group 1; 81 +/- 12 in group 2 (P < 0.001 vs. group 1); 53 +/- 25 in group 3 (P = 0.02 vs. group 2); and 48 +/- 5 in group 4 (P = 0.02 vs. group 2). We conclude that after prolonged cardiac arrest, the already established brain damage mitigating effect of mild immediate postarrest hypothermia might be enhanced by thiopental, and perhaps then further enhanced by adding phenytoin and methylprednisolone.", "source": "https://pubmed.ncbi.nlm.nih.gov/10950320/"}
+{"doc_id": "138ed4d659b783b0815a4433b59d0cff", "sentence": "Caspase-independent mechanisms , mainly based on increased oxidative stress , result from 2-methoxyestradiol , Artesunate , ascorbic acid , Dihydroartemisinin , Evodiamine , b-AP15 , VLX1570 , Erw-ASNase , and TAK-242 .", "spans": [{"span_id": 0, "text": "Artesunate", "start": 111, "end": 121, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "Dihydroartemisinin", "start": 140, "end": 158, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma. Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms , mainly based on increased oxidative stress , result from 2-methoxyestradiol , Artesunate , ascorbic acid , Dihydroartemisinin , Evodiamine , b-AP15 , VLX1570 , Erw-ASNase , and TAK-242 . Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/33669515/"}
+{"doc_id": "b0d5192b7353b914214db1d91f189d3a", "sentence": "In the xenograft model , more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone .", "spans": [{"span_id": 0, "text": "bortezomib", "start": 67, "end": 77, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "gemcitabine", "start": 96, "end": 107, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "gemcitabine", "start": 113, "end": 124, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer. Earlier studies that dealt with the combination therapy of gemcitabine and histone deacetylation inhibitors for pancreatic cancer revealed unsatisfactory results. The activation of nuclear factor \u03baB (NF-\u03baB) was referred as one of the attributable causes, and we attempted to overcome this resistance by the addition of a proteasome inhibitor. ### methods The influences of suberoylanilide hydroxamic acid (vorinostat, SAHA), a histone deacetylase inhibitor, and bortezomib, a novel selective antagonist of 26S proteasome, with or without gemcitabine on cell growth and apoptosis and the expressions of related proteins were observed in pancreatic cancer cell lines (MiaPaCa-2 and ASPC-1). The xenograft model of pancreatic cancer was used to notice effects in vivo. ### results vorinostat and bortezomib had independent inhibitory effects and potentiated the antitumor property of gemcitabine in vitro. In the xenograft model , more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone . The down-regulation of pAkt and suppression of NF-\u03baB activity was induced by the triple combination. ### conclusions The triple combination of vorinostat, bortezomib, and gemcitabine resulted in the strongest antitumor effects both in vitro and in vivo and pAkt and NF-\u03baB seems to be involved in this process.", "source": "https://pubmed.ncbi.nlm.nih.gov/21487323/"}
+{"doc_id": "00d0330eaf9fcbfda83b9dcc6dde58ce", "sentence": "The effectiveness of combination therapy with afatinib and bevacizumab may provide a new therapeutic option for these patients .", "spans": [{"span_id": 0, "text": "afatinib", "start": 46, "end": 54, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "bevacizumab", "start": 59, "end": 70, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Combination therapy with afatinib and bevacizumab in an EGFR-mutated non-small cell lung cancer patient with acquired ERBB2 amplification: A case report. Acquired resistance to reversible EGFR tyrosine kinase inhibitors remains a significant obstacle, and acquired ERBB2 amplification is the most common \"bypass\" mechanism. For patients with sensitizing EGFR mutation who experience resistance via ERBB2 amplification, no targeted drug has been demonstrated to be effective. ### Patient Concerns A 56-year-old female nonsmoker suffered from left leg paralysis and low back pain. Imaging examination revealed a mass in the anterior segment of the right upper lobe lung and possible multiple metastases in the right hilar, mediastinal lymph nodes, bone metastases, and soft tissue invasion. ### diagnosis Transbronchial lung biopsy revealed a moderately differentiated adenocarcinoma (cT4N2M1c, stage IV). An EGFR exon 19 deletion was identified using amplification refractory mutation system. ### interventions After the patient was treated with gefitinib initiation (250\u200amg/d) for 15\u200amonths, the tumor progressed with ERBB2 amplification revealed by next-generation sequencing test. Then, the patient was started on afatinib (40\u200amg/d) plus bevacizumab (7.5\u200amg/kg every 3\u200aweeks). ### outcomes The combination therapy of afatinib and bevacizumab in this patient was effective with some slight side effects. Computed tomography scans showed the tumor shrinkage and the pleural effusion disappeared in the right lung. The overall survival was 23.5\u200amonths. ### conclusion To date, there is no targeted therapy approved and demonstrated to be effective for non-small cell lung cancer patients with EGFR sensitizing mutations, and ERBB2 amplification. The effectiveness of combination therapy with afatinib and bevacizumab may provide a new therapeutic option for these patients .", "source": "https://pubmed.ncbi.nlm.nih.gov/33663050/"}
+{"doc_id": "af2a75784262b4e7c5c2ad00bb39becb", "sentence": "Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone .", "spans": [{"span_id": 0, "text": "enzalutamide", "start": 21, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "docetaxel", "start": 41, "end": 50, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "abiraterone", "start": 118, "end": 129, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone . The optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone. ### methods We performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n=30) or docetaxel (n=31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups. ### results Compared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53-3.66, P=0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77-2.71, P=0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups. ### conclusions Treatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.", "source": "https://pubmed.ncbi.nlm.nih.gov/25053178/"}
+{"doc_id": "864521b20a79cd641bf02b5c5c24716a", "sentence": "The use of cyclophosphamide in patients with NSVN is controversial , but recent retrospective data suggest that those treated with prednisone and cyclophosphamide from the outset fare better than those initially treated only with prednisone .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 11, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "prednisone", "start": 131, "end": 141, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "cyclophosphamide", "start": 146, "end": 162, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "prednisone", "start": 230, "end": 240, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Therapy for vasculitic neuropathies. The term vasculitis refers to a pathologic condition defined by inflammatory cell infiltration and destruction of blood vessels. Systemic vasculitis is classified as primary (eg, polyarteritis nodosa, Churg-Strauss syndrome) or secondary, the latter associated with connective tissue disorders, infections, medications, and rarely, as a paraneoplastic phenomenon. Neuropathy is a common complication of systemic vasculitis and is related to ischemic nerve fiber damage with axon loss. Peripheral neuropathy may be the sole manifestation of vasculitis, a condition termed nonsystemic vasculitic neuropathy (NSVN). Treatment of vasculitic neuropathy requires long-term immunosuppressive therapies with potential side effects. The diagnosis of vasculitis should be established by tissue (preferably nerve) biopsy. High-dose prednisone is the standard platform therapy for patients with systemic and NSVN; for those with systemic vasculitis, at least 3 to 12 months of treatment with cyclophosphamide (monthly intravenous pulse or daily oral therapy) is also necessary to sustain remission and allow successful prednisone tapering. The use of cyclophosphamide in patients with NSVN is controversial , but recent retrospective data suggest that those treated with prednisone and cyclophosphamide from the outset fare better than those initially treated only with prednisone . If prednisone is administered as monotherapy, cyclophosphamide should be added after several months if there is no improvement or relapse occurs with tapering of prednisone. Intravenous pulse and daily oral cyclophosphamide probably offer similar efficacy, although the risk of complications is greater with oral therapy. azathioprine can be safely substituted for cyclophosphamide after 3 months without an increased relapse rate. azathioprine, methotrexate, intravenous immune globulin, mycophenolate mofetil, plasma exchange, and rituximab can be offered to patients who are intolerant or have a contraindication to cyclophosphamide. However, efficacy is unproven for any of these therapies. Interferon-alpha, sometimes combined with plasma exchange, is used to treat vasculitis associated with hepatitis B infection. Some patients also may improve with corticosteroids. The classification of diabetic lumbosacral radiculoplexus neuropathy as a vasculitic disorder remains controversial. However, there is compelling pathological evidence that this condition represents a T-cell-mediated microvasculitis. Some patients treated with intravenous corticosteroids may have greater recovery and improved pain control.", "source": "https://pubmed.ncbi.nlm.nih.gov/16464407/"}
+{"doc_id": "5edd6b7bf1ec8e231328a5a83f5b82ae", "sentence": "This was a multi-center randomized , two-armed , double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy .", "spans": [{"span_id": 0, "text": "cediranib", "start": 89, "end": 98, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "gefitinib", "start": 104, "end": 113, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "cediranib", "start": 121, "end": 130, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. ### Methods And Findings This was a multi-center randomized , two-armed , double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy . The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. ### conclusions cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. ### Trial Registration ClinicalTrials.gov NCT01310855.", "source": "https://pubmed.ncbi.nlm.nih.gov/27232884/"}
+{"doc_id": "aef35abee464e3a0075caeb3d70926f6", "sentence": "This study aims to compare the biological , molecular , pharmacological , and clinical characteristics of these three treatment modalities for SARS-COV-2 infections , Chloroquine and Hydroxychloroquine , Convalescent Plasma , and Remdesivir .", "spans": [{"span_id": 0, "text": "Chloroquine", "start": 167, "end": 178, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "Hydroxychloroquine", "start": 183, "end": 201, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "Remdesivir", "start": 230, "end": 240, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Biological, molecular and pharmacological characteristics of chloroquine, hydroxychloroquine, convalescent plasma, and remdesivir for COVID-19 pandemic: A comparative analysis. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, also known as COVID-19 pandemic has caused an alarming situation worldwide. Since the first detection, in December 2019, there have been no effective drug therapy options for treating the SARS-CoV-2 pandemic. However, healthcare professionals are using chloroquine, hydroxychloroquine, remdesivir, convalescent plasma and some other options of treatments. This study aims to compare the biological , molecular , pharmacological , and clinical characteristics of these three treatment modalities for SARS-COV-2 infections , Chloroquine and Hydroxychloroquine , Convalescent Plasma , and Remdesivir . ### methods A search was conducted in the \"Institute of Science Information (ISI)-Web of Science, PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library databases, Scopus, and Google Scholar\" for peer reviewed, published studies and clinical trials through July 30, 2020. The search was based on keywords \"COVID-19\" SARS-COV-2, chloroquine, hydroxychloroquine, convalescent plasma, remdesivir and treatment modalities. ### results As of July 30, 2020, a total of 36,640 relevant documents were published. From them 672 peer reviewed, published articles, and clinical trials were screened. We selected 17 relevant published original articles and clinical trials: 05 for chloroquine and/or hydroxychloroquine with total sample size (n\u202f=\u202f220), 05 for remdesivir (n\u202f=\u202f1,781), and 07 for Convalescent Plasma therapy (n\u202f=\u202f398), with a combined total sample size (n\u202f=\u202f2,399). Based on the available data, convalescent plasma therapy showed clinical advantages in SARS-COV-2 patients. ### conclusions All three treatment modalities have both favorable and unfavorable characteristics, but none showed clear evidence of benefit for early outpatient disease or prophylaxis. Based on the current available data, convalescent plasma therapy appears to show clinical advantages for inpatient use. In the future, ongoing large sample size randomized controlled clinical trials may further clarify the comparative efficacy and safety of these three treatment classes, to conclusively determine whom to treat with which drug and when to treat them.", "source": "https://pubmed.ncbi.nlm.nih.gov/32921965/"}
+{"doc_id": "be6dfc402b0da5cb965fc0a6da145866", "sentence": "Patients received a mean ( \u00b1standard deviation ) of 8.8 \u00b1 4.9 intravitreal bevacizumab injections prior to the switch to intravitreal ranibizumab .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 75, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "ranibizumab", "start": 134, "end": 145, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel (DERBI study). To evaluate the outcome of second-line intravitreal ranibizumab treatment in eyes with diabetic macular edema having persistent edema following initial therapy with intravitreal bevacizumab. ### Methods Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel was a retrospective, multi-center study. Consecutive eyes with persistent diabetic macular edema following at least three previous intravitreal bevacizumab injections prior to intravitreal ranibizumab, at least three-monthly intravitreal ranibizumab injections and at least 12\u2009months of follow-up were included. Data collected included demographics, ocular findings, diabetes control, details of intravitreal bevacizumab and ranibizumab injections, and visual and anatomical measurements before and after intravitreal ranibizumab treatment. ### Results In total, 202 eyes of 162 patients treated at 11 medical centers across Israel were included. Patients received a mean ( \u00b1standard deviation ) of 8.8 \u00b1 4.9 intravitreal bevacizumab injections prior to the switch to intravitreal ranibizumab . A mean of 7.0\u2009\u00b1\u20092.7 intravitreal ranibizumab injections were given during the 12\u2009months following the switch to intravitreal ranibizumab. The median central subfield retinal thickness (\u00b1interquartile range) by spectral-domain optical coherence tomography decreased from 436\u2009\u00b1\u2009162\u2009\u00b5m at baseline to 319\u2009\u00b1\u2009113\u2009\u00b5m at month 12 (p\u2009<\u20090.001). Median logMAR visual acuity (\u00b1interquartile range) improved from 0.40\u2009\u00b1\u20090.48 at baseline to 0.38\u2009\u00b1\u20090.40 at month 12 (p\u2009=\u20090.001). Linear regression suggested that higher number of intravitreal ranibizumab injections and higher pre-switch central subfield retinal thickness were associated with favorable visual outcome. Higher number of intravitreal bevacizumab injections and the presence of intraretinal fluid before the switch lessened the odds of favorable outcome. ### Conclusion Switching from bevacizumab to ranibizumab in persistent diabetic macular edema was associated with anatomical improvement in the majority of eyes and \u2a7e2 lines of vision improvement in 22% of eyes.", "source": "https://pubmed.ncbi.nlm.nih.gov/29916263/"}
+{"doc_id": "0a53b483acefa9c81b17bd994c27ddfd", "sentence": "Combinations of penicillin and streptomycin and penicillin and amikacin were synergistic only against those strains that were not highly resistant to streptomycin and kanamycin , respectively .", "spans": [{"span_id": 0, "text": "streptomycin", "start": 31, "end": 43, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "amikacin", "start": 63, "end": 71, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "streptomycin", "start": 150, "end": 162, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "kanamycin", "start": 167, "end": 176, "token_start": 23, "token_end": 24}, {"span_id": 4, "text": "penicillin", "start": 16, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 5, "text": "penicillin", "start": 48, "end": 58, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 4], "is_context_needed": false}, {"class": "POS", "spans": [1, 5], "is_context_needed": false}], "paragraph": "Species-specific resistance to antimocrobial synergism in Streptococcus faecium and Streptococcus faecalis. Combinations of penicillin with various aminoglycosidic aminocyclitols were tested against a collection of clinical isolates of Streptococcus faecium in vitro and were used to treat endocarditis caused by S. faecium in the rabbit model. S. faecium proved more resistant to penicillin than Streptococcus faecalis. Even more striking, however, was the resistance to in vitro synergism by combinations of penicillin and various aminoglycosides. At clinically achievable concentrations, penicillin-gentamicin was the only combination that was synergistic against all strains that were tested. Combinations of penicillin and streptomycin and penicillin and amikacin were synergistic only against those strains that were not highly resistant to streptomycin and kanamycin , respectively . Combinations of penicillin with kanamycin, tobramycin, sisomicin, or netilmicin failed to produce synergism against any of these strains. The possible clinical significance of these findings was verified by use of the rabbit model of endocarditis. Combinations of penicillin with gentamicin or streptomycin were synergistic in the therapy of endocarditis that was produced by a strain of S. faecium that did not have a high level of resistance to aminoglycosides. However, the combination of penicillin and netilmicin was no more effective than penicillin alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/113469/"}
+{"doc_id": "7d64d6b1c7e8c6d3edc29168ad6c4477", "sentence": "Treatment with a combination chemotherapeutic regimen consisting of cyclophosphamide , vincristine , and dacarbazine for malignant paraganglioma with hepatic metastasis is reported .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 68, "end": 84, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "vincristine", "start": 87, "end": 98, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "dacarbazine", "start": 105, "end": 116, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Combination chemotherapy for malignant paraganglioma.  Treatment with a combination chemotherapeutic regimen consisting of cyclophosphamide , vincristine , and dacarbazine for malignant paraganglioma with hepatic metastasis is reported . A 51-year-old male presented with tumors in the retroperitoneal space and liver. The patient was diagnosed as having paraganglioma based on elevated levels of serum neuron-specific enolase, urinary catecholamine and vanillylmandelic acid, and on histological findings of the liver specimen. The patient was treated with this combination chemotherapy in repeated 21-day cycles. Temporary improvement in laboratory findings and a 20% reduction in the size of the hepatic masses were observed without severe adverse effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/9058098/"}
+{"doc_id": "498f31d903df63cf2f948946a8ee5018", "sentence": "The aim of this study was to evaluate the in vitro effect of single antibiotic ( ciprofloxacin , ceftazidime , or ampicillin ) treatment on adherence of Escherichia coli and Enterococcus to plastic stents .", "spans": [{"span_id": 0, "text": "ciprofloxacin", "start": 81, "end": 94, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "ceftazidime", "start": 97, "end": 108, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "ampicillin", "start": 114, "end": 124, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "In vitro evaluation of antibiotic prophylaxis in the prevention of biliary stent blockage. Bacterial adherence and biofilm formation are important factors in the blockage of biliary stents. Clinical studies with oral antibiotic prophylaxis to prevent stent blockage have produced conflicting results. The aim of this study was to evaluate the in vitro effect of single antibiotic ( ciprofloxacin , ceftazidime , or ampicillin ) treatment on adherence of Escherichia coli and Enterococcus to plastic stents . ### methods Selected clinical isolates of E coli and Enterococcus were perfused through a modified Robbins device containing segments of polyethylene stents. The stents were removed daily and the number of bacteria attached was measured. The effect of antibiotic treatment on bacterial adherence was tested by the perfusion of individual antibiotics into separate modified Robbins devices using a side-arm adaptor and the results were compared with saline controls. ### results Compared with the saline controls, ciprofloxacin and ceftazidime caused a 10- to 100-fold reduction in the number of E coli attached to the stents, whereas ampicillin had no effect on adherence of E coli. ampicillin caused a 5- to 10-fold reduction in Enterococcus adherence but there was no change with ceftazidime. Sustained reduction in E coli adherence was observed with prolonged ciprofloxacin perfusion. ### conclusion Timely treatment with appropriate antibiotics reduced bacterial adherence in vitro and may be potentially beneficial in the prevention of stent blockage.", "source": "https://pubmed.ncbi.nlm.nih.gov/10699774/"}
+{"doc_id": "717f8a8c20069d19d917002e078901ef", "sentence": "Paclitaxel and docetaxel as single agents have yielded overall response rates of 7 % to 56 % , depending on whether the patients have received prior chemotherapy for metastatic disease .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "docetaxel", "start": 15, "end": 24, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Current and future perspectives in advanced bladder cancer: is there a new standard? The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been the standard treatment in patients with locally advanced and metastatic urothelial cancer for the past 15 years. The minimal or moderate survival benefit-depending on prognostic features-and the severe toxicity associated with the MVAC regimen have made the search for new drugs and drug combinations of utmost importance to increase efficacy and/or decrease toxicity. In this respect, the taxanes and gemcitabine are promising new drugs. Paclitaxel and docetaxel as single agents have yielded overall response rates of 7 % to 56 % , depending on whether the patients have received prior chemotherapy for metastatic disease . The combination of paclitaxel and cisplatin has been explored in three studies with a total of 104 evaluable patients, a pooled overall response (OR) rate of 61%, and a complete response (CR) rate of 20%. There are two studies of docetaxel and cisplatin with a total of 91 evaluable patients, an OR rate of 54%, and a CR rate of 16%. The OR rate for paclitaxel and carboplatin in six studies was 43%, with a CR rate of 13%; however, the reported median survival was only 8.5 to 9.5 months. The OR rate for single-agent gemcitabine based on five studies was 26%, with a CR rate of 9%, which was apparently independent of whether the patients had received prior chemotherapy. The OR rate for gemcitabine and cisplatin in four phase II studies ranged from 41% to 57%, with a CR rate of 15% to 22% and a median survival of 12.5 to 14.3 months. Based on the encouraging results for the combination of gemcitabine and cisplatin (GC), a randomized phase III trial comparing GC and MVAC was begun in late 1996. This study of 405 randomized patients showed that the two regimens were associated with similar response rates, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC. On the basis of this superior risk-benefit ratio, the GC regimen should be favored as a new standard treatment in patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine and paclitaxel, with or without cisplatin, and the combination of ifosfamide, paclitaxel, and cisplatin. The triple combination of gemcitabine, paclitaxel, and cisplatin has yielded an OR rate of 78%, a CR rate of 28%, and a median survival of 24 months. An international phase III trial comparing this triple combination with GC in patients with locally advanced and metastatic urothelial cancer has now been initiated.", "source": "https://pubmed.ncbi.nlm.nih.gov/11894002/"}
+{"doc_id": "a963d46b799a8ea638850359444188f9", "sentence": "The most effective treatment regimens for advanced nonseminomatous testicular tumors employ vinblastine , CDDP and bleomycin and adjunctive surgery .", "spans": [{"span_id": 0, "text": "vinblastine", "start": 92, "end": 103, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "bleomycin", "start": 115, "end": 124, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[Preoperative chemotherapy of testicular cancer and Wilm's tumor]. Of the various urogenital malignancies, preoperative chemotherapy is most effective for testicular cancer and Wilms' tumor. The most effective treatment regimens for advanced nonseminomatous testicular tumors employ vinblastine , CDDP and bleomycin and adjunctive surgery . Another effective chemotherapy regimen is combination of vinblastine, actinomycin D, bleomycin, cyclophosphamide and CDDP presented by MSKCC. Available pretreatment with 4 courses of platinum, vinblastine and bleomycin before any surgical treatment in those with massive bulk metastatic disease seems to provide the most effective cytoreduction and best survival. Donohue has shown that in a primary chemotherapy group, there is only 20% active carcinoma after primary chemotherapy, whereas in a salvage chemotherapy group there is approximately 50% active carcinoma at surgery. It must therefore be emphasized that complete remission should be obtained by primary chemotherapy and adjunctive surgery. In Wilms' tumor preoperative chemotherapy with vincristine and actinomycin D should be given.", "source": "https://pubmed.ncbi.nlm.nih.gov/2581512/"}
+{"doc_id": "773651170795da523779ad0a4d8fdd24", "sentence": "27 patients suffering from disseminated carcinoma of the breast with at least two visceral metastases , and two had become resistant to conventional chemotherpy and hormones , received a combination of , in the present trial , vincristine followed by cyclophosphamide with 5-fluoro-uracil .", "spans": [{"span_id": 0, "text": "vincristine", "start": 227, "end": 238, "token_start": 37, "token_end": 38}, {"span_id": 1, "text": "cyclophosphamide", "start": 251, "end": 267, "token_start": 40, "token_end": 41}, {"span_id": 2, "text": "5-fluoro-uracil", "start": 273, "end": 288, "token_start": 42, "token_end": 43}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "[Chemotherapeutic combinations of mutually potentializing drugs. 1-Application to the treatment of breast cancers].  27 patients suffering from disseminated carcinoma of the breast with at least two visceral metastases , and two had become resistant to conventional chemotherpy and hormones , received a combination of , in the present trial , vincristine followed by cyclophosphamide with 5-fluoro-uracil . Chemotherapy was administered intermittently: each cycle of treatment lasted 6 days and was followed by a period without treatment of 25 days. Haematological tolerance was satisfactory. No serious incidents occurred during two years use of the combination. 20 out of 27 patients showed objective tumour regression of more than 50 p.cent lasting for more than 6 months, whilst 9 showed apparent complete regression of the malignant lesions. There was one complete failure. Chemotherapy was continued in all cases after regression of the neoplastic process was obtained.", "source": "https://pubmed.ncbi.nlm.nih.gov/1129034/"}
+{"doc_id": "8a164fc8cdf186bd07aed353d735c00b", "sentence": "We previously demonstrated that the combination of oral estramustine ( 15 mg/kg/day ) and oral etoposide ( 50 mg/m2/day ) is effective first-line therapy for the treatment of hormone refractory prostate cancer .", "spans": [{"span_id": 0, "text": "estramustine", "start": 56, "end": 68, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 95, "end": 104, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A phase II trial of oral estramustine and oral etoposide in hormone refractory prostate cancer.  We previously demonstrated that the combination of oral estramustine ( 15 mg/kg/day ) and oral etoposide ( 50 mg/m2/day ) is effective first-line therapy for the treatment of hormone refractory prostate cancer . We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment. ### methods estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up. ### results Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival. ### conclusions We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/9301705/"}
+{"doc_id": "3065e65032c8537a0d4a53be07e8519a", "sentence": "Therapy consisted of bendamustine ( 70 mg/m(2 ) ) for 2 consecutive days every 28 days , and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle , and 1000 mg on day 1 subsequently .", "spans": [{"span_id": 0, "text": "bendamustine", "start": 21, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "ofatumumab", "start": 93, "end": 103, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial. We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine ( 70 mg/m(2 ) ) for 2 consecutive days every 28 days , and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle , and 1000 mg on day 1 subsequently . Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade \u22653 neutropenia was observed in 61.7% of patients; however, grade \u22653 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.", "source": "https://pubmed.ncbi.nlm.nih.gov/24220274/"}
+{"doc_id": "304fb876f9dfa960295aef5a6099c04b", "sentence": "All consecutive patients with advanced BTC received the GEMOX regimen in a setting outside a study : gemcitabine 1,000 mg/m(2 ) on day 1 , and oxaliplatin 100 mg/m(2 ) on day 2 , treatment repeated every 2 weeks until progression or unacceptable toxicity .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 101, "end": 112, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "oxaliplatin", "start": 143, "end": 154, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Experience of gemcitabine plus oxaliplatin chemotherapy in patients with advanced biliary tract carcinoma. The combination gemcitabine-oxaliplatin (GEMOX) is frequently used in patients with advanced biliary tract carcinoma (BTC). However, this is only based on phase II studies performed in selected patients.We assessed the efficacy and safety of the GEMOX regimen in non-selected patients with advanced BTC. ### methods All consecutive patients with advanced BTC received the GEMOX regimen in a setting outside a study : gemcitabine 1,000 mg/m(2 ) on day 1 , and oxaliplatin 100 mg/m(2 ) on day 2 , treatment repeated every 2 weeks until progression or unacceptable toxicity . ### results Forty-four patients were enrolled. ### efficacy 1 complete and 6 partial responses (objective response rate = 16.3%), 18 tumour stabilizations (41.9%, disease control rate = 58.1%), median progression-free survival was 5.0 months and median overall survival was 11.0 months. ### toxicity grade 3 neuropathy in 4 patients, grade 3 asthenia in 5 patients. ### conclusion The GEMOX combination was well tolerated, with a modest activity in non-selected patients with advanced BTC. This regimen should be compared to the new standard gemcitabine-cisplatin combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/20551640/"}
+{"doc_id": "70bd47165d708bee82beff55a73c29fc", "sentence": "Recent randomized controlled trials ( RCT ) have failed to demonstrate the efficacy of widely used therapies , such as rituximab plus intravenous immunoglobulin or proteasome inhibition ( bortezomib ) , reinforcing a great need for new therapeutic concepts .", "spans": [{"span_id": 0, "text": "rituximab", "start": 119, "end": 128, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "intravenous immunoglobulin", "start": 134, "end": 160, "token_start": 22, "token_end": 24}, {"span_id": 2, "text": "bortezomib", "start": 188, "end": 198, "token_start": 28, "token_end": 29}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}, {"class": "NEG", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial. Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials ( RCT ) have failed to demonstrate the efficacy of widely used therapies , such as rituximab plus intravenous immunoglobulin or proteasome inhibition ( bortezomib ) , reinforcing a great need for new therapeutic concepts . One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. ### methods This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR \u2265\u2009365\u2009days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charit\u00e9 University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25\u2009mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4-12), all patients will receive clazakizumab at 25\u2009mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. ### discussion Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. ### Trial Registration ClinicalTrials.gov, NCT03444103 . Registered on 23 February 2018 (retrospective registration).", "source": "https://pubmed.ncbi.nlm.nih.gov/30635033/"}
+{"doc_id": "42c1681f652cf35adf1ced53b97516f8", "sentence": "The aim of this study was to find an experimental model of a donor-recipient rat strain combination that , under triple drug immunosuppressive treatment ( methylprednisolone , cyclosporine , and azathioprine ) , would develop chronic rejection within a few weeks .", "spans": [{"span_id": 0, "text": "methylprednisolone", "start": 155, "end": 173, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "cyclosporine", "start": 176, "end": 188, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "azathioprine", "start": 195, "end": 207, "token_start": 30, "token_end": 31}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "An experimental model of chronic renal allograft rejection in the rat using triple drug immunosuppression. Chronic rejection is a major problem in renal transplantation. Various experimental models have been developed to study vasculopathy of chronic rejection. However, animal models resembling the clinical situation of renal transplantation with combination therapy of basic immunosuppression are not available. The aim of this study was to find an experimental model of a donor-recipient rat strain combination that , under triple drug immunosuppressive treatment ( methylprednisolone , cyclosporine , and azathioprine ) , would develop chronic rejection within a few weeks . ### methods Renal transplantations were performed in strain combinations of DA-->AO, PVG-->BN, and DA-->BN. In each group, 5-8 animals received triple drug treatment of methylprednisolone (2 mg/kg), azathioprine (2 mg/kg), and cyclosporine (5 mg/kg) daily, 5-10 animals were left without treatment, and 6 syngenic transplantations were performed. The grafts were monitored with ultrasound-guided fine needle aspiration biopsies to quantify the inflammation in the graft. Graft histology was performed in parallel and quantified by using the chronic allograft damage index (CADI). ### results In nonimmunosuppressed animals, irreversible acute rejection with a high peak of inflammation appeared in every strain combination within 5-8 days. In triple drug-treated rats, the DA-->AO combination demonstrated a prolonged acute rejection but no characteristic chronic changes, and the PVG-->BN combination showed practically no inflammation and did not develop any signs of chronic rejection within 60 days (CADI: 2.7+/-2.1), but the DA-->BN combination showed an early, mild inflammatory response 5-7 days after transplantation and developed chronic rejection within 40-60 days after transplantation (CADI: 7.9+/-3.1). Syngenic animals showed no inflammation or histological alterations (CADI: 1.7+/-2.0). ### conclusions In conclusion, in the DA-->BN combination with triple drug treatment, early mild inflammation was followed by the development of chronic rejection and can be used as an experimental model that resembles the clinical situation in renal transplantation.", "source": "https://pubmed.ncbi.nlm.nih.gov/9448142/"}
+{"doc_id": "373bedaa15b826ea4c469e0ce2643608", "sentence": "In FOLL05 trial , R-CHOP was compared with R-CVP ( cyclophosphamide , vincristine , prednisone ) and R-FM ( fludarabine , mitoxantrone ) .", "spans": [{"span_id": 0, "text": "R-CHOP", "start": 18, "end": 24, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "cyclophosphamide", "start": 51, "end": 67, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "vincristine", "start": 70, "end": 81, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "prednisone", "start": 84, "end": 94, "token_start": 14, "token_end": 15}, {"span_id": 4, "text": "fludarabine", "start": 108, "end": 119, "token_start": 19, "token_end": 20}, {"span_id": 5, "text": "mitoxantrone", "start": 122, "end": 134, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [1, 2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [4, 5], "is_context_needed": true}], "paragraph": "Rituximab and new regimens for indolent lymphoma: a brief update from 2012 ASCO Annual Meeting. Indolent lymphoma (IL), the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains the standard frontline regimen for diffuse Large B -cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab) has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial , R-CHOP was compared with R-CVP ( cyclophosphamide , vincristine , prednisone ) and R-FM ( fludarabine , mitoxantrone ) . The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab) has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/22913602/"}
+{"doc_id": "a4a83ba48665f39aac03658bbacb486b", "sentence": "All patients underwent 3 cycles of neoadjuvant gemcitabine , paclitaxel , and capecitabine .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 47, "end": 58, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "paclitaxel", "start": 61, "end": 71, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "capecitabine", "start": 78, "end": 90, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Direct percutaneous transhepatic portomesenteric venous stenting in management of locally advanced pancreatic cancer. Pancreatectomy with portal and/or superior mesenteric vein resection remains a controversial procedure because of high complexity and morbidity. Neoadjuvant chemotherapy has been shown to increase resectability of these locally advanced lesions. We aimed to assess the utility and efficacy of direct percutaneous transhepatic portomesenteric venous stenting (THVS) with neoadjuvant chemotherapy in increasing surgical resectability of locally advanced pancreatic carcinoma. ### methods Forty pancreatic carcinoma patients with tumor thrombus involving the portal vein and superior mesenteric vein were identified. Patients underwent THVS followed by neoadjuvant chemotherapy. Whipple procedure was offered to responders. ### results THVS was attempted in all. The tumor thrombus could not be crossed in 2 patients (95% technical success rate). All patients underwent 3 cycles of neoadjuvant gemcitabine , paclitaxel , and capecitabine . Disease progression was noted in 16 patients and surgery was not offered. Twenty-two patients were explored with intent-to-perform a Whipple procedure. In 7 of these (32%), extensive disease precluding surgical resection was identified and the procedure was abandoned. Whipple procedure without vascular resection was performed successfully in 15 patients (68%). There were no perioperative deaths. Negative vascular margins were noted in 3 patients and negative peripancreatic lymph nodes in 5 patients. Median survival was 17 months (range, 5 to 70 mo). In the stented nonoperative group, median survival was 9 months (range, 3 to 19 mo). The stented and resected group achieved a statistically significant (P=0.0422) survival advantage. ### conclusions THVS in combination with neoadjuvant chemotherapy can increase tumor resectability and survival in a select group of locally advanced pancreatic cancer patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/23608832/"}
+{"doc_id": "509f0b830dc248843856cc659af95634", "sentence": "The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B.", "spans": [{"span_id": 0, "text": "voriconazole", "start": 81, "end": 93, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "amphotericin", "start": 124, "end": 136, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "B.", "start": 137, "end": 139, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model.  The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B. ### methods Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole. ### results voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure. ### conclusions voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/18408237/"}
+{"doc_id": "f9f7d99cac5550bbc464785cf3e3db64", "sentence": "Dual Therapy with Aspirin and Cilostazol May Improve Platelet Aggregation in Noncardioembolic Stroke Patients : A Pilot Study .", "spans": [{"span_id": 0, "text": "Aspirin", "start": 18, "end": 25, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "Cilostazol", "start": 30, "end": 40, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Dual Therapy with Aspirin and Cilostazol May Improve Platelet Aggregation in Noncardioembolic Stroke Patients : A Pilot Study . Objective Some previous studies have found clinical benefit of dual antiplatelet therapy with aspirin and cilostazol for prevention of secondary stroke, but the physiological mechanism involved remains unknown. We aimed to clarify the effects of aspirin/cilostazol therapy on the platelet and endothelial functions of patients with acute noncardioembolic ischemic stroke, in comparison to patients who were treated with aspirin alone. Methods The present randomized prospective pilot study enrolled 24 patients within a week after the onset of noncardioembolic ischemic stroke. The patients were randomly allocated to receive aspirin (100 mg/day) (A group; 11 patients) or cilostazol (200 mg/day) plus aspirin (100 mg/day) (CA group; 13 patients). We measured platelet aggregation, platelet activation, and the thrombomodulin (TM), highly sensitive C-reactive protein (hs-CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand (vWF) antigen levels and vWF activity over a 4-week period after enrollment. Results There was no significant difference in the platelet functions of the A and CA groups. However, the platelet aggregation induced by adenosine diphosphate (ADP) was decreased at 2 and 4 weeks (p<0.05) after treatment in comparison to the pre-treatment values in the CA group, but not in the A group. Platelet activation, and the hs-CRP, TM, ICAM-1, VCAM-1 and vWF values did not significantly decrease after treatment in either group. Conclusion Although there were no significant differences in platelet aggregation, platelet activation or the endothelial biomarker levels of the A and CA groups, dual therapy with aspirin and cilostazol inhibited platelet aggregation in comparison to the pre-treatment values, similarly to patients who received aspirin alone. This may suggest the clinical usefulness of dual therapy with aspirin and cilostazol in the treatment of patients with noncardioembolic ischemic stroke.", "source": "https://pubmed.ncbi.nlm.nih.gov/28566591/"}
+{"doc_id": "d9bc9e760dfd975a2703bfd8e7ef700e", "sentence": "Gemcitabine and vinorelbine have shown activity in the first-line setting .", "spans": [{"span_id": 0, "text": "Gemcitabine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "vinorelbine", "start": 16, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting . The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM. ### methods From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. gemcitabine 1000 mg/m(2) and vinorelbine 25 mg/m(2) were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity. ### results A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild. ### conclusions The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.", "source": "https://pubmed.ncbi.nlm.nih.gov/18286536/"}
+{"doc_id": "4dfb347a107d0cb265cbec52dc05280d", "sentence": "The combination of tenofovir disoproxil fumarate ( TDF ) plus emtricitabine ( FTC ) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus ( HBV ) infection .", "spans": [{"span_id": 0, "text": "tenofovir disoproxil fumarate", "start": 19, "end": 48, "token_start": 3, "token_end": 6}, {"span_id": 1, "text": "emtricitabine", "start": 62, "end": 75, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Efficacy and tolerance of a combination of tenofovir disoproxil fumarate plus emtricitabine in patients with chronic hepatitis B: a European multicenter study.  The combination of tenofovir disoproxil fumarate ( TDF ) plus emtricitabine ( FTC ) is used extensively to treat HIV infection and also has potent activity against hepatitis B virus ( HBV ) infection . The aim of this study was to assess the efficacy and tolerance of TDF + FTC in patients with chronic hepatitis B (CHB). ### methods Seventy eight consecutive CHB patients from five European centers were included. All started a TDF + FTC combination between October 2005 and March 2010. Virological, biochemical, and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified into either treatment simplification (TS), where efficacy of the previous treatment was obtained at TDF + FTC initiation, and treatment intensification (TI), where the previous line of therapy had failed. ### results TDF + FTC was given as a TI to 54 patients (69%) and as a TS to 24 (31%). Among patients with TI, 83% were males. The median baseline HBV-DNA was 4.4 log10 IU/mL, and median alanine-transaminase (ALT) was 1.10 \u00d7 ULN. Sixty percent were HBeAg positive, 47% had significant fibrosis (\u2265 F3 Metavir equivalent), and 29% had confirmed cirrhosis. Median treatment duration was 76 weeks (interquartile range 60-116). Kaplan-Meier analysis showed that, 48 weeks after TI, the probability of being HBV-DNA becoming undetectable was 76%, and reached 94% at week 96. No viral breakthrough occurred. Patients with TS (87% males, median baseline HBV-DNA 1.1 log10 IU/mL, median ALT 0.79 \u00d7 ULN, 33% HBeAg positive, 61% with significant fibrosis) were treated for a median duration of 76 weeks. In this subgroup, all patients but one remained HBV-DNA undetectable and no ALT flare-up occurred during follow-up. Creatinine levels did not show kidney-function deterioration in either group of patients. ### conclusions After a median follow-up of > 76 weeks, the TDF + FTC combination showed encouraging antiviral efficacy and a good safety profile in all patients with CHB. TDF + FTC may represent an interesting clinical option to simplify therapy and increase the barrier to resistance, which should be assessed in the long term.", "source": "https://pubmed.ncbi.nlm.nih.gov/21767570/"}
+{"doc_id": "c9947a148118a7c7c0374ef9e7f3a915", "sentence": "HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 63, "end": 72, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "exemestane", "start": 97, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "anastrozole", "start": 111, "end": 122, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04). Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the tamoxifen exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P\u00a0=\u00a00.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole . HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.", "source": "https://pubmed.ncbi.nlm.nih.gov/22234519/"}
+{"doc_id": "250ab0e4ff2d5694d10eb236713fe562", "sentence": "This was driven by the relative advantage of weight loss compared with rosiglitazone , glimepiride , and insulin glargine , and administration frequency compared with exenatide .", "spans": [{"span_id": 0, "text": "rosiglitazone", "start": 71, "end": 84, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "glimepiride", "start": 87, "end": 98, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Willingness to pay for diabetes drug therapy in type 2 diabetes patients: based on LEAD clinical programme results. The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials. ### methods Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments. ### results People with type 2 diabetes were prepared to pay an extra \u20ac2.64/day for liraglutide compared with rosiglitazone, an extra \u20ac1.94/day compared with glimepiride, an extra \u20ac3.36/day compared with insulin glargine, and an extra \u20ac0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators. ### conclusions WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone , glimepiride , and insulin glargine , and administration frequency compared with exenatide .", "source": "https://pubmed.ncbi.nlm.nih.gov/22853443/"}
+{"doc_id": "8cc636e27faf0c1e91489ed1d054c255", "sentence": "Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer : results of the phase II CAPRICE study .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 20, "end": 31, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "cyclophosphamide", "start": 37, "end": 53, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "paclitaxel", "start": 66, "end": 76, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer : results of the phase II CAPRICE study . Anthracycline and taxane-based primary chemotherapy (PCT) is the standard treatment for high-risk breast cancer (HRBC). However, conventional anthracyclines are not commonly used in elderly patients or those prone to cardiotoxicity. Pegylated liposomal doxorubicin, (PLD) has comparable efficacy, but less cardiotoxicity than conventional anthracyclines. We conducted a phase II single-arm trial to assess the efficacy and safety of PCT based on PLD followed by paclitaxel (PTX) in a HRBC population usually undertreated. Fifty patients with stage II-IIIB breast cancer and at least one risk factor for developing cardiotoxicity initiated PLD 35\u00a0mg/m(2) plus cyclophosphamide 600\u00a0mg/m(2) every 4\u00a0weeks for four cycles, followed by 80\u00a0mg/m(2) weekly PTX for 12. Close cardiac monitoring was performed. Primary endpoint was the pathological complete response rate (pCR) in the breast. Treatment delivery and toxicities were assessed. Eighty-four per cent of patients were older than 65\u00a0years, 64\u00a0% suffered from hypertension, and 10\u00a0% had prior cardiac disease. In an intention-to-treat analysis, breast pCR was 32\u00a0% (95\u00a0% CI 19.5-46.7\u00a0%) and pCR in breast and axilla was 24\u00a0% (95\u00a0% CI 12.1-35.8\u00a0%). At diagnosis only, 26\u00a0% of patients were candidates for breast conservative surgery, which increased to 58.7\u00a0% after PCT. No significant decrease in left ventricular ejection fraction was seen. PLD followed by PTX was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. Moreover, it achieved a pCR similar to standard therapy and could therefore be an option for elderly patients or cardiotoxicity-prone who present HRBC.", "source": "https://pubmed.ncbi.nlm.nih.gov/25981896/"}
+{"doc_id": "e062362953dea1901bad45908e5e5566", "sentence": "We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin ( 75 mg per square meter of body-surface area ) with either cyclophosphamide ( 750 mg per square meter ) or paclitaxel ( 135 mg per square meter over 24 hours ) .", "spans": [{"span_id": 0, "text": "cisplatin", "start": 130, "end": 139, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "cyclophosphamide", "start": 200, "end": 216, "token_start": 34, "token_end": 35}, {"span_id": 2, "text": "paclitaxel", "start": 248, "end": 258, "token_start": 43, "token_end": 44}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. ### methods We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin ( 75 mg per square meter of body-surface area ) with either cyclophosphamide ( 750 mg per square meter ) or paclitaxel ( 135 mg per square meter over 24 hours ) . ### results Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). ### conclusions Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/7494563/"}
+{"doc_id": "fa7f8a42646dfc70fb18482ae0847d68", "sentence": "Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men .", "spans": [{"span_id": 0, "text": "ezetimibe", "start": 70, "end": 79, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "simvastatin", "start": 87, "end": 98, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men . This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). simvastatin did not significantly affect cholesterol absorption. ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.", "source": "https://pubmed.ncbi.nlm.nih.gov/19380898/"}
+{"doc_id": "7f084f3d889b6776bd35615a619ad87c", "sentence": "The US government regulated precursor chemicals , ephedrine and pseudoephedrine , multiple times to limit methamphetamine production/availability and thus methamphetamine problems .", "spans": [{"span_id": 0, "text": "pseudoephedrine", "start": 64, "end": 79, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "methamphetamine", "start": 106, "end": 121, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "methamphetamine", "start": 155, "end": 170, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Impacts of federal precursor chemical regulations on methamphetamine arrests.  The US government regulated precursor chemicals , ephedrine and pseudoephedrine , multiple times to limit methamphetamine production/availability and thus methamphetamine problems . Research has found that the regulations reduced methamphetamine hospital admissions, but authors have argued that other problems were unaffected. This study examines whether the regulations impacted methamphetamine arrests. ### design ARIMA-intervention time-series analysis with control series. ### setting California (1982-2001). ### measurements Dependent variable series: monthly methamphetamine arrests. Control series: monthly marijuana arrests and cocaine/heroin arrests. ### interventions Bulk powder ephedrine and pseudoephedrine: regulated November 1989. Products containing ephedrine as the single active medicinal ingredient: regulated August 1995. pseudoephedrine products: regulated October 1997. Large-scale producers used ephedrine and pseudoephedrine in these forms. Ephedrine combined with other active medicinal ingredients (e.g. various cold medicines)-used mainly by small-scale producers: regulated October 1996. ### findings The regulation targeting small-scale producers (1996) had no significant impact. In contrast, methamphetamine arrests stopped rising and dropped 31% to 45% each of the three times precursor chemicals used by large-scale producers were regulated. Within 3 years of the bulk powder regulation (1989) and again within 2 years of the ephedrine single ingredient regulation (1995), arrests fully rebounded. During the 4 years following the last regulation (pseudoephedrine products, 1997) arrests only partially rebounded. These effects parallel those reported on hospital admissions. The control series were generally unaffected. ### conclusions Precursor regulations targeting large-scale producers impacted methamphetamine arrests, a criminal justice problem, much as they impacted the public health problem of methamphetamine hospital admissions. Ongoing research is needed to determine whether these problems eventually fully rebound from the last regulation.", "source": "https://pubmed.ncbi.nlm.nih.gov/15784062/"}
+{"doc_id": "967ea702edc061a8a1b8b17a2d779d8c", "sentence": "We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine , lomustine , and vincristine ( PCV ) chemotherapy to radiotherapy ( RT ) .", "spans": [{"span_id": 0, "text": "procarbazine", "start": 113, "end": 125, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "lomustine", "start": 128, "end": 137, "token_start": 22, "token_end": 23}, {"span_id": 2, "text": "vincristine", "start": 144, "end": 155, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "radiotherapy", "start": 180, "end": 192, "token_start": 31, "token_end": 32}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine , lomustine , and vincristine ( PCV ) chemotherapy to radiotherapy ( RT ) . ### Patients And Methods Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. ### results A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. ### conclusion The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.", "source": "https://pubmed.ncbi.nlm.nih.gov/23071237/"}
+{"doc_id": "8c229f9bee992965dc0cac147088ce6d", "sentence": "A phase II clinical trial was conducted to evaluate the efficacy and toxicity of vinorelbine plus gemcitabine in very old patients with inoperable ( stage IIIb or IV ) NSCLC .", "spans": [{"span_id": 0, "text": "vinorelbine", "start": 81, "end": 92, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "gemcitabine", "start": 98, "end": 109, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase II trial of vinorelbine plus gemcitabine in previously untreated inoperable (stage IIIb/IV) non-small-cell lung cancer patients aged 80 or older. vinorelbine and gemcitabine are two active single agents with mild toxicity profiles that are used in the treatment of non-small-cell lung cancer (NSCLC). Whether or not very old NSCLC patients, such as those aged 80 years or older, should still be considered for chemotherapy is unknown, since their response to the treatment is also unknown. A phase II clinical trial was conducted to evaluate the efficacy and toxicity of vinorelbine plus gemcitabine in very old patients with inoperable ( stage IIIb or IV ) NSCLC . vinorelbine 20 mg/m(2) was given as a 10-min intravenous infusion, followed by a 30-min intravenous infusion of gemcitabine 800 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. From March 1998 to December 2001, 20 patients (16 males, four females) were enrolled in the study. The median age was 83 years, within the range 80-88 years. The median number of treatment cycles per patient was four. With the exception of one, all patients received at least two cycles of treatment. Thirteen patients achieved a partial response, with an overall response rate of 65% (95% confidence interval, 44.1-85.9%). Median survival was 10 months. The significant (WHO grade 3/4) toxicities were myelosuppression, including leukopenia in five (25%) patients, neutropenia in eight (40%), anaemia in six (30%), and thrombocytopenia in three (15%) patients. Febrile neutropenia occurred in two patients and accounted for one treatment-related death. Non-haematological toxicity was generally mild, except one patient who suffered from grade 3 interstitial pneumonitis. Another patient suffered from a cerebral infarction after three cycles of treatment. In conclusion, the combination of vinorelbine and gemcitabine in very old patients with advanced NSCLC is a highly active regimen with an acceptable toxicity profile.", "source": "https://pubmed.ncbi.nlm.nih.gov/12711125/"}
+{"doc_id": "e49b2723397411ce15b49761296e1576", "sentence": "Tobramycin was probably less effective than gentamicin in combination with the penicillinase-resistant penicillins against enterococci .", "spans": [{"span_id": 0, "text": "Tobramycin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "gentamicin", "start": 44, "end": 54, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "penicillins", "start": 103, "end": 114, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": false}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Comparative in vitro activity of nafcillin, oxacillin, and methicillin in combination with gentamicin and tobramycin against enterococci. The in vitro activity of nafcillin, oxacillin, and methicillin alone and in combination with gentamicin and tobramycin against 30 strains of enterococci was investigated. The penicillinase-resistant penicillins were less active than penicillin and ampicillin against the enterococci. nafcillin was more active than oxacillin and methicillin. Sixty-six percent of strains were inhibited by nafcillin at 6.25 mug/ml, but none was inhibited by oxacillin and methicillin at the same concentration. At 12.5 mug/ml, 83, 16, and 0% were inhibited by nafcillin, oxacillin, and methicillin, respectively. By using a variety of criteria and analyses, it was shown that none of the antibiotic combinations studied demonstrated enhanced killing of all strains of enterococci. nafcillin-gentamicin was the best combination, and enhanced killing was demonstrated against most strains. oxacillin was more effective than methicillin when combined with gentamicin. Tobramycin was probably less effective than gentamicin in combination with the penicillinase-resistant penicillins against enterococci .", "source": "https://pubmed.ncbi.nlm.nih.gov/836017/"}
+{"doc_id": "aca79bc0aba0854bf6e69d6468578862", "sentence": "Despite the absence of strong data , entecavir and telbivudine seem to be the preferred options for nucleoside analogue-naive CHB patients with chronic kidney disease , depending on viraemia and severity of renal dysfunction .", "spans": [{"span_id": 0, "text": "entecavir", "start": 37, "end": 46, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "telbivudine", "start": 51, "end": 62, "token_start": 9, "token_end": 10}], "rels": [], "paragraph": "Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. The treatment of chronic hepatitis B (CHB) in patients with chronic kidney disease (CKD) is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs), but it may be complex and the information is scarce. entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides. ### aim To review the efficacy and safety of NAs in adult CHB patients with CKD and to provide reasonable recommendations for their optimal management. ### methods Literature search in PubMed/Medline and manual search of relevant articles, reviews and book chapters. ### results NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance <50\u00a0mL/min. There are concerns about nephrotoxic potential of the nucleotides, particularly adefovir, while improvements of creatinine clearance have been reported under telbivudine. Most existing data in CHB patients with CKD are for lamivudine and, less frequently, for other NAs, mostly entecavir. Besides CHB, NA should be used in case of immunosuppressive therapy in any HBsAg-positive patient with CKD including renal transplant (RT) recipients and in anti-HBs-positive recipients of kidney grafts from HBsAg-positive donors. ### conclusions Chronic hepatitis B patients with chronic kidney disease receiving nucleoside analogues should be followed carefully for treatment efficacy and renal safety. Despite the absence of strong data , entecavir and telbivudine seem to be the preferred options for nucleoside analogue-naive CHB patients with chronic kidney disease , depending on viraemia and severity of renal dysfunction . More studies are certainly needed in this setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/24299322/"}
+{"doc_id": "bddb579070955f889fea255e42d919f5", "sentence": "Results from clinical trials evaluating agents such as ixabepilone , albumin-bound paclitaxel , capecitabine , vinorelbine , pemetrexed , and irinotecan are presented .", "spans": [{"span_id": 0, "text": "ixabepilone", "start": 55, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "paclitaxel", "start": 83, "end": 93, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "capecitabine", "start": 96, "end": 108, "token_start": 13, "token_end": 14}, {"span_id": 3, "text": "vinorelbine", "start": 111, "end": 122, "token_start": 15, "token_end": 16}, {"span_id": 4, "text": "pemetrexed", "start": 125, "end": 135, "token_start": 17, "token_end": 18}, {"span_id": 5, "text": "irinotecan", "start": 142, "end": 152, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Management of metastatic breast cancer: monotherapy options for patients resistant to anthracyclines and taxanes. Resistance to chemotherapeutic agents is a significant obstacle to the effective treatment of metastatic breast cancer (MBC). Anthracycline- and taxane-based regimens are active as first-line treatment for MBC; however, MBC often progresses because of primary or acquired resistance to anthracyclines and taxanes. There are few options for the treatment of patients with anthracycline- and taxane-resistant or taxane-refractory MBC. This article reviews several single agents that have demonstrated activity as treatment for patients with MBC who progress during, or rapidly following, treatment with anthracyclines and taxanes. Results from clinical trials evaluating agents such as ixabepilone , albumin-bound paclitaxel , capecitabine , vinorelbine , pemetrexed , and irinotecan are presented . Single-agent capecitabine is approved for the treatment of patients after failure of anthracyclines and taxanes. ixabepilone has demonstrated efficacy in patients with MBC resistant to multiple chemotherapeutic agents and is the only agent approved by the Food and Drug Administration as monotherapy for anthracycline-, taxane-, and capecitabine-resistant MBC. Improved treatment strategies and further evaluation of newer agents may reduce the current burden of treatment-resistant or treatment-refractory MBC.", "source": "https://pubmed.ncbi.nlm.nih.gov/19675449/"}
+{"doc_id": "1a4b7002c34da6a84d3592bc7bc47325", "sentence": "The clinical studies provide evidence that combined fluticasone/formoterol is more efficacious than fluticasone or formoterol given alone , and provides similar improvements in lung function to fluticasone ( Flixotide ( \u00ae ) ) and formoterol ( Foradil ( \u00ae ) ) administered concurrently .", "spans": [{"span_id": 0, "text": "fluticasone", "start": 100, "end": 111, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "formoterol", "start": 115, "end": 125, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "fluticasone", "start": 194, "end": 205, "token_start": 26, "token_end": 27}, {"span_id": 3, "text": "formoterol", "start": 230, "end": 240, "token_start": 34, "token_end": 35}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": false}], "paragraph": "[A new fixed dose combination of fluticasone and formoterol in a pressurised metered-dose inhaler for the treatment of asthma]. The combination of an inhaled corticosteroid and a long acting beta-2 agonist is indicated for the regular treatment of persistent moderate-to-severe asthmatics whose asthma is not controlled by inhaled corticosteroids and the occasional use of a short acting beta-2 agonist. The aim of this review is to give an overview of the rationale of combining formoterol and fluticasone and to analyze the clinical data concerning a new fixed combination of fluticasone and formoterol in a pressurised metered-dose inhaler with a dose counter (Flutiform(\u00ae)) that was approved for the treatment of asthma in France in 2013. The clinical studies provide evidence that combined fluticasone/formoterol is more efficacious than fluticasone or formoterol given alone , and provides similar improvements in lung function to fluticasone ( Flixotide ( \u00ae ) ) and formoterol ( Foradil ( \u00ae ) ) administered concurrently . The combination of fluticasone/formoterol gave a more rapid bronchodilatation than the combination fluticasone/salmeterol. As a whole, the combination of fluticasone/formoterol had similar efficacy and tolerability profiles to the combinations of either budesonide/formoterol or fluticasone/salmeterol.", "source": "https://pubmed.ncbi.nlm.nih.gov/25391505/"}
+{"doc_id": "b34f763241f46b224f71b6494c6b2fb8", "sentence": "Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen : a TransATAC study .", "spans": [{"span_id": 0, "text": "anastrozole", "start": 167, "end": 178, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "tamoxifen", "start": 182, "end": 191, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen : a TransATAC study . PURPOSE To determine whether the Recurrence Score (RS) provided independent information on risk of distant recurrence (DR) in the tamoxifen and anastrozole arms of the Arimidex, tamoxifen, Alone or in Combination (ATAC) Trial. PATIENTS AND METHODS RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor-positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessed by quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox proportional hazards models assessed the value of adding RS to a model with clinical variables (age, tumor size, grade, and treatment) in node-negative (N0) and node-positive (N+) women. RESULTS Reportable scores were available from 1,231 evaluable patients (N0, n = 872; N+, n = 306; and node status unknown, n = 53); 72, 74, and six DRs occurred in N0, N+, and node status unknown patients, respectively. For both N0 and N+ patients, RS was significantly associated with time to DR in multivariate analyses (P < .001 for N0 and P = .002 for N+). RS also showed significant prognostic value beyond that provided by Adjuvant! Online (P < .001). Nine-year DR rates in low (RS < 18), intermediate (RS = 18 to 30), and high RS (RS > or = 31) groups were 4%, 12%, and 25%, respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N+ patients. The prognostic value of RS was similar in anastrozole- and tamoxifen-treated patients. CONCLUSION This study confirmed the performance of RS in postmenopausal HR+ patients treated with tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DR in N0 and N+ hormone receptor-positive patients treated with anastrozole, adding value to estimates with standard clinicopathologic features.", "source": "https://pubmed.ncbi.nlm.nih.gov/20212256/"}
+{"doc_id": "a8312c2cee1d08090d323d2c0b611d9e", "sentence": "When novel DMARDs were used as monotherapies , greater ACR20/50/70 responses were observed with tocilizumab than with anti-tumor necrosis factor agents ( aTNF ) or tofacitinib .", "spans": [{"span_id": 0, "text": "tocilizumab", "start": 96, "end": 107, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "tofacitinib", "start": 164, "end": 175, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "Comparative Efficacy of Novel DMARDs as Monotherapy and in Combination with Methotrexate in Rheumatoid Arthritis Patients with Inadequate Response to Conventional DMARDs: A Network Meta-Analysis. Given the availability of a number of alternative biologic treatment options and other novel disease-modifying antirheumatic drugs (DMARDs) for the treatment of patients with rheumatoid arthritis (RA), clinicians are faced with an increasingly challenging choice regarding optimal treatment. Biologics are usually combined with traditional DMARDs, primarily methotrexate (MTX), but some biologics and tofacitinib (together referred to in this article as novel DMARDs) have been shown to be efficacious as monotherapy as well. In real-world practice, approximately one-third of RA patients receiving biologics are on monotherapy, primarily because of intolerance of, or noncompliance with, MTX. Limited data, however, are available analyzing the effectiveness of monotherapy compared with combination therapy across novel DMARDs. ### objective To compare American College of Rheumatology (ACR) responses to approved novel DMARDs used as monotherapy or as combination therapy with methotrexate (MTX) at 24 weeks in RA patients who have shown inadequate response to conventional DMARDs (DMARD-IR). ### methods Through a systematic review of the literature, we identified randomized controlled trials that assessed approved novel DMARDs used as monotherapy or as combination therapy with MTX in DMARD-IR RA patients. Twenty-eight RCTs were identified that evaluated abatacept, anakinra, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib. ACR responses at 24 weeks were extracted and combined by means of Bayesian network meta-analyses. ### results With the exception of anakinra plus MTX, which was less efficacious, most novel DMARDs, when used in combination with MTX, demonstrated comparable ACR responses. When novel DMARDs were used as monotherapies , greater ACR20/50/70 responses were observed with tocilizumab than with anti-tumor necrosis factor agents ( aTNF ) or tofacitinib . Furthermore, ACR20/50/70 responses with tocilizumab plus MTX were similar to those with tocilizumab monotherapy (odds ratio [OR] for the indirect comparison\u2009=\u20091.08, 95% credible interval [CrI]\u2009=\u20090.40-2.84; OR\u2009=\u20091.24, CrI\u2009=\u20090.44-3.61; OR\u2009=\u20090.95, CrI\u2009=\u20090.33-2.72, respectively), whereas greater responses were observed with aTNF plus MTX than with aTNF monotherapy (OR\u2009=\u20092.41, CrI\u2009=\u20090.51-11.61; OR\u2009=\u20092.85, CrI\u2009=\u20090.51-17.67; OR\u2009=\u20091.28, CrI\u2009=\u20090.21-8.42, respectively). Relative efficacy estimates for the indirect comparison of tofacitinib plus MTX with tofacitinib monotherapy were very uncertain. ### conclusions Results suggest that in combination with MTX most of the available novel DMARDs have similar levels of efficacy in DMARD-IR patients. As monotherapy, however, tocilizumab displayed higher ACR responses than aTNF or tofacitinib. ACR responses with tocilizumab plus MTX were similar to those with tocilizumab as monotherapy, whereas aTNF in combination with MTX demonstrated greater ACR responses than aTNF as monotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/25943002/"}
+{"doc_id": "f084f9073c5c11b6bcc521f746c7f0f8", "sentence": "Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "fulvestrant", "start": 62, "end": 73, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer. To investigate the prognostic role of the estrogen receptor (ER) in gastric cancer (GC) patients, tumor tissues from 932 patients with advanced GC were assessed for ER expression using immunohistochemistry, and their clinicopathologic features were evaluated. Forty patients (4.3%) had ER expression and they were more frequently associated with diffuse type gastric cancer and shorter disease free survival. Furthermore, we carried out in vitro analysis to evaluate the effect of ER modulation on the proliferation of GC cell lines. Estradiol enhanced proliferation of ER positive GC cells while it did not show any effect on ER negative GC cells. When ER was inhibited by fulvestrant and ER siRNA, estradiol-induced proliferation of ER positive GC cell was suppressed. Paclitaxel showed synergistic anti-proliferative impacts with fulvestrant . Suppressing ER by fulvestrant, paclitaxel and ER siRNA showed increased expression of E-cadherin, which is a crucial factor in diffuse-type carcinogenesis.", "source": "https://pubmed.ncbi.nlm.nih.gov/25534230/"}
+{"doc_id": "0702354a47fff4da19d07a1467671915", "sentence": "The experimental protocol was as follows : ( 1 ) at time zero , intravenous infusion of ritodrine was begun ; ( 2 ) at 120 min , 2 % lidocaine was given epidurally to achieve a sensory level of at least T6 ; and ( 3 ) at 135 min , an intravenous bolus of either ephedrine , phenylephrine , or normal saline-control was given , followed by a continuous intravenous infusion of the same agent for 30 min .", "spans": [{"span_id": 0, "text": "ritodrine", "start": 88, "end": 97, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "lidocaine", "start": 133, "end": 142, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "phenylephrine", "start": 274, "end": 287, "token_start": 59, "token_end": 60}, {"span_id": 3, "text": "ephedrine", "start": 262, "end": 271, "token_start": 57, "token_end": 58}], "rels": [{"class": "POS", "spans": [0, 1, 3], "is_context_needed": true}, {"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Ephedrine remains the vasopressor of choice for treatment of hypotension during ritodrine infusion and epidural anesthesia. Historically, ephedrine has been the vasopressor of choice for treatment of most cases of hypotension in obstetric patients. However, the choice of vasopressor in the parturient receiving a beta-adrenergic agent for tocolysis has not been evaluated extensively. The current study evaluated whether ephedrine or phenylephrine better restores uterine blood flow and fetal oxygenation during ritodrine infusion and epidural anesthesia-induced hypotension in gravid ewes. ### methods Fourteen chronically instrumented gravid ewes between 0.8 and 0.9 timed gestational age were used. On separate days, each animal underwent the experimental protocol with one of three agents: ephedrine, phenylephrine, and normal saline-control. The experimental protocol was as follows : ( 1 ) at time zero , intravenous infusion of ritodrine was begun ; ( 2 ) at 120 min , 2 % lidocaine was given epidurally to achieve a sensory level of at least T6 ; and ( 3 ) at 135 min , an intravenous bolus of either ephedrine , phenylephrine , or normal saline-control was given , followed by a continuous intravenous infusion of the same agent for 30 min . In the ephedrine and phenylephrine experiments, the rate of infusion was adjusted to maintain maternal mean arterial pressure close to baseline. ### results ritodrine infusion alone significantly increased maternal heart rate and cardiac output in all three groups. Epidural anesthesia during ritodrine infusion significantly decreased maternal mean arterial pressure, heart rate, cardiac output, uterine blood flow, and fetal arterial oxygen tension for each of the three groups. Both ephedrine and phenylephrine restored maternal mean arterial pressure to baseline, as designed. Ephedrine significantly increased uterine blood flow and fetal arterial oxygen tension when compared with normal saline--control, but phenylephrine did not. phenylephrine significantly increased uterine vascular resistance when compared with normal saline--control, but ephedrine did not. ### conclusions Although ephedrine and phenylephrine provided similar restoration of maternal mean arterial pressure, ephedrine was superior to phenylephrine in restoring uterine blood flow during ritodrine infusion and epidural anesthesia-induced hypotension in gravid ewes. Also, ephedrine, but not phenylephrine, significantly improved fetal oxygenation, when compared to normal saline--control.", "source": "https://pubmed.ncbi.nlm.nih.gov/8017645/"}
+{"doc_id": "f9b1f1a93c415dc0e29c0a8bed13dc1c", "sentence": "compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia .", "spans": [{"span_id": 0, "text": "busulfan", "start": 12, "end": 20, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "cyclophosphamide", "start": 25, "end": 41, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia . busulfan plus cyclophosphamide (BuCy) is the traditional conditioning regimen for allogeneic stem cell transplant (allo-SCT) for young, fit patients with acute myeloid leukemia (AML). The thiotepa-busulfan-fludarabine (TBF) protocol has recently demonstrated promising outcome in cord blood and haploidentical SCT; however, there is limited evidence about this regimen in transplant from matched siblings (MSD) and unrelated donors (UD). We retrospectively compared outcomes of 2523 patients aged 18-50 with AML in remission, undergoing transplant from MSD or UD prepared with either TBF or BuCy conditioning. A 1:3 pair-matched analysis was performed: 146 patients receiving TBF were compared with 438 patients receiving BuCy. Relapse risk was significantly lower in the TBF when compared with BuCy group (HR 0.6, P\u2009=\u2009.02), while NRM did not differ. No significant difference was observed in LFS and OS between the two regimens. TBF was associated with a trend towards higher risk of grades III-IV aGVHD (HR 1.8, P\u2009=\u2009.06) and inferior cGVHD (HR 0.7, P\u2009=\u2009.04) when compared with BuCy. In patients undergoing transplant in first remission, the advantage for TBF in terms of relapse was more evident (HR 0.4, P\u2009=\u2009.02), leading to a trend for better LFS in favor of TBF (HR 0.7, P\u2009=\u2009.10), while OS did not differ between the two cohorts. In conclusion, TBF represents a valid myeloablative conditioning regimen providing significantly lower relapse and similar survival when compared with BuCy. Patients in first remission appear to gain the most from this protocol, as in this subgroup a tendency for better LFS was observed when compared with BuCy.", "source": "https://pubmed.ncbi.nlm.nih.gov/30033639/"}
+{"doc_id": "dc747d23089de0920b9129198f64388e", "sentence": "Posttransplant immunosuppression to prevent graft-versus-host disease ( GVHD ) consisted of cyclosporine and prednisone ( CSA/PSE ) .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 92, "end": 104, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "prednisone", "start": 109, "end": 119, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study. Two novel preparatory regimens for conditioning of patients with leukemia for allogeneic bone marrow transplantation (BMT) from histocompatible sibling donors have been tested in a phase III trial under the auspices of the Southwest Oncology Group (SWOG 8612). These two regimens consisted either of fractionated total body irradiation and etoposide (FTBI/VP-16) or high-dose busulfan with cyclophosphamide (BU/CY). Only patients who had failed prior conventional management at least once were study eligible, ie, no patients with acute leukemia in first remission (CR) or in first chronic phase (CP) of chronic myelogenous leukemia (CML) participated. Patients were stratified according to the following risk criteria: \"good-risk\" patients were those who were in second CR of their acute leukemia or in accelerated phase (AP) of CML; \"poor-risk\" patients had further advanced stages of leukemia. During a 52-month period, 131 patients were registered of whom 122 (93%) were study eligible. Sixty-one eligible patients were randomized to the FTBI/VP-16 arm and 61 to the BU/CY regimen. Of these 122 patients, 114 (93%) proceeded to BMT according to protocol. Posttransplant immunosuppression to prevent graft-versus-host disease ( GVHD ) consisted of cyclosporine and prednisone ( CSA/PSE ) . Neither overall survival nor disease-free survival (DFS) differed significantly between the two treatment groups (P = .89 and .69, respectively). Estimated DFS for \"good-risk\" patients who had been prepared with the FTBI/VP-16 regimen was 55% +/- 11%, as compared with patients treated with BU/CY whose DFS figure was 34% +/- 10% (P = .30). For \"poor-risk\" candidates, the DFS rates at 24 months were 17% +/- 6% (for FTBI/VP-16) and 24% +/- 8% (for BU/CY), respectively (P = .81). These figures do not differ significantly, especially in view of the fact that the \"good-risk\" patients prepared with the FTBI/VP-16 regimen were younger than those treated with BU/CY. Both regimens were well tolerated with no regimen-related deaths encountered during the 6-week period after BMT. This study also confirmed the efficacy of the CSA/PSE combination in the prevention of GVHD with 23 of 113 (20%) of BMT recipients developing moderate to severe acute GVHD. The leading cause for treatment failure was leukemic relapse (45 of the 114 BMT recipients suffered a recurrence of their leukemia), whereas 38 patients died without evidence of relapse. Thirty-one patients are alive and in continued CR after marrow transplantation; four are alive in relapse.(ABSTRACT TRUNCATED AT 400 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/8471778/"}
+{"doc_id": "f76446fad47e58f6c8cbe3add6b8bde7", "sentence": "Tadalafil 20 mg was preferred to sildenafil 50 mg for the initiation of ED therapy in this study population .", "spans": [{"span_id": 0, "text": "Tadalafil", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "sildenafil", "start": 33, "end": 43, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. tadalafil is a phosphodiesterase 5 (PDE5) inhibitor approved in >30 countries for the treatment of erectile dysfunction (ED). It has been shown to improve erectile function compared with placebo in Phase III studies, but clinical experience comparing tadalafil with the PDE5 inhibitor sildenafil citrate is lacking. ### objective This study compared patient preference for tadalafil 20 mg or sildenafil 50 mg during initial treatment for ED. It also compared the tolerability of the 2 agents at these doses. ### methods This randomized, double-blind, fixed-dose, 2-period crossover trial took place at 13 sites in the United States and Germany. Patients were randomized 1:1 to receive 4 weeks of treatment with tadalafil 20 mg or sildenafil 50 mg, followed by the alternative treatment, to be taken as needed up to once daily before sexual activity. ### results The study enrolled 215 men with ED, 109 randomized to the tadalafil-sildenafil sequence and 106 to the sildenafil-tadalafil sequence. Their mean age was 49.8 years; 84.7% were sildenafil naive and 15.3% had undergone a previous inadequate trial of sildenafil. Most patients had moderate ED (60.5%) of >or=1 year's duration (74.9%). Of 190 evaluable patients, 126 (66.3%) preferred to initiate treatment with tadalafil, compared with 64 (33.7%) with sildenafil (P < 0.001). Patients' preference did not differ by age, duration of ED, treatment sequence, or previous sildenafil exposure. Both medications were well tolerated, with no significant differences in the incidence of treatment-emergent adverse events. Headache (11.2% tadalafil, 8.8% sildenafil), dyspepsia (6.0% and 4.2%, respectively), nasopharyngitis (4.7% and 2.8%), and flushing (2.8% and 4.7%) were the most common adverse events. The rate of ocular disturbances was low: 1 patient experienced intermittent bilateral reduction in visual acuity with tadalafil, and 2 exhibited conjunctival hyperemia or eyelid edema with sildenafil. ### conclusions Tadalafil 20 mg was preferred to sildenafil 50 mg for the initiation of ED therapy in this study population . Both medications were well tolerated.", "source": "https://pubmed.ncbi.nlm.nih.gov/14693299/"}
+{"doc_id": "f445aee54445b061d12d9c0396914f89", "sentence": "Reactivity of factor IXa with basic pancreatic trypsin inhibitor is enhanced by low molecular weight heparin ( enoxaparin ) .", "spans": [{"span_id": 0, "text": "heparin", "start": 101, "end": 108, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "enoxaparin", "start": 111, "end": 121, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Heparin modulates the 99-loop of factor IXa: effects on reactivity with isolated Kunitz-type inhibitor domains.  Reactivity of factor IXa with basic pancreatic trypsin inhibitor is enhanced by low molecular weight heparin ( enoxaparin ) . Previous studies by us have suggested that this effect involves allosteric modulation of factor IXa. We examined the reactivity of factor IXa with several isolated Kunitz-type inhibitor domains: basic pancreatic trypsin inhibitor, the Kunitz inhibitor domain of protease Nexin-2, and the first two inhibitor domains of tissue factor pathway inhibitor. We find that enhancement of factor IXa reactivity by enoxaparin is greatest for basic pancreatic trypsin inhibitor (>10-fold), followed by the second tissue factor pathway inhibitor domain (1.7-fold) and the Kunitz inhibitor domain of protease Nexin-2 (1.4-fold). Modeling studies of factor IXa with basic pancreatic trypsin inhibitor suggest that binding of this inhibitor is sterically hindered by the 99-loop of factor IXa, specifically residue Lys(98). Slow-binding kinetic studies support the formation of a weak initial enzyme-inhibitor complex between factor IXa and basic pancreatic trypsin inhibitor that is facilitated by enoxaparin binding. Mutation of Lys(98) to Ala in factor IXa results in enhanced reactivity with all inhibitors examined, whereas almost completely abrogating the enhancing effects of enoxaparin. The results implicate Lys(98) and the 99-loop of factor IXa in defining enzyme inhibitor specificity. More importantly, these results demonstrate the ability of factor IXa to be allosterically modulated by occupation of the heparin-binding exosite.", "source": "https://pubmed.ncbi.nlm.nih.gov/16766524/"}
+{"doc_id": "9f6a5691861df15334acb4b555ed7ee0", "sentence": "Either 5-fluorouracil ( 5-FU ) and leucovorin for 6 months or 5-FU and levamisole for 12 months are currently considered standard adjuvant treatment for stage III colorectal cancer .", "spans": [{"span_id": 0, "text": "leucovorin", "start": 35, "end": 45, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "levamisole", "start": 71, "end": 81, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "5-FU", "start": 24, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 3, "text": "5-FU", "start": 62, "end": 66, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 2], "is_context_needed": false}, {"class": "POS", "spans": [1, 3], "is_context_needed": false}], "paragraph": "National Cancer Institute Clinical Trials Program in Colorectal Cancer. Colorectal cancer will be diagnosed in approximately 150,000 patients in the USA this year. Chemotherapy has recently been shown to improve survival when given as adjuvant therapy to surgery in patients with stage III colorectal cancer. Demonstration of this benefit required large, randomized controlled trials. Either 5-fluorouracil ( 5-FU ) and leucovorin for 6 months or 5-FU and levamisole for 12 months are currently considered standard adjuvant treatment for stage III colorectal cancer . However, current adjuvant trials are comparing continuous infusion and intravenous bolus 5-FU regimens and oral uracil/Ftorafur with intravenous 5-FU and leucovorin, as well as studying the timing of chemotherapy in the adjuvant setting. Subsequent adjuvant trials will examine newer regimens with activity in advanced colorectal cancer, as well as the efficacy of monoclonal antibodies. Other trials will study which type of surgery is optimal and whether adjuvant therapy is helpful in stage II colon cancer. Trials in metastatic disease will focus on combinations of newer agents which may improve survival in this patient group. Studies in rectal cancer will focus on determining which agents are optimal in combination with radiation therapy in the adjuvant setting. Molecular characteristics of tumor cells are being defined, which may guide therapy in the future. Careful, logically designed clinical trials will hopefully provide more efficacious therapy for this common cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/9750034/"}
+{"doc_id": "9303b9f861ab1f3f663f6a8f02a12cf4", "sentence": "Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer , who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor , were randomly assigned ( 1:1 ) to receive 5 years of letrozole ( 2\u00b75 mg orally per day ) or placebo .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 167, "end": 176, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "letrozole", "start": 267, "end": 276, "token_start": 42, "token_end": 43}], "rels": [], "paragraph": "Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. ### methods This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer , who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor , were randomly assigned ( 1:1 ) to receive 5 years of letrozole ( 2\u00b75 mg orally per day ) or placebo . Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0\u00b70418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. ### findings Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6\u00b79 years (IQR 6\u00b71-7\u00b75). letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0\u00b785, 95% CI 0\u00b773-0\u00b7999; p=0\u00b7048). 7-year disease-free survival estimate was 81\u00b73% (95% CI 79\u00b73-83\u00b71) in the placebo group and 84\u00b77% (82\u00b79-86\u00b74) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). ### interpretation After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. ### funding National Cancer Institute, Korea Health Technology R&D Project, Novartis.", "source": "https://pubmed.ncbi.nlm.nih.gov/30509771/"}
+{"doc_id": "df88c83dd24ae56c97d4410a9555cf7c", "sentence": "Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 12, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "flavopiridol", "start": 58, "end": 70, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression. To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclin-dependent kinase (CDK) inhibition in therapy. ### Experimental Design The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenib-sensitive (Huh-7 and HepG2, IC50 5-6 \u03bcmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 \u03bcmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosis-related proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments . The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments. ### results Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect. ### conclusions The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. Clin Cancer Res; 22(10); 2555-64. \u00a92015 AACR.", "source": "https://pubmed.ncbi.nlm.nih.gov/26603262/"}
+{"doc_id": "7ac7f5459159308e28b92b4bf1bdf281", "sentence": "Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 14, "end": 23, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "curcumin", "start": 28, "end": 36, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma . Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Herein, we first reported the codelivery of sorafenib and curcumin by directed self-assembled nanoparticles (SCN) to enhance the therapeutic effect on HCC. SCN was formed by employing the hydrophobic interactions among the lipophilic structure in sorafenib, curcumin, and similar hydrophobic segments of polyethylene glycol derivative of vitamin E succinate (PEG-VES), which comprised uniform spherical particles with particle size of 84.97 \u00b1 6.03 nm. SCN presented superior effects over sorafenib, curcumin, and their physical mixture (Sora + Cur) on enhancing in vitro cytotoxicity and cell apoptosis in BEL-7402 cells and Hep G2 cells, and antiangiogenesis activities in tube formation and microvessel formation from aortic rings. Moreover, the tissue concentration of sorafenib and curcumin in gastrointestinal tract and major organs were significantly improved after their coassembly into SCN. In particular, in BEL-7402 cells induced tumor xenograft, SCN treatment displayed the obviously enhanced inhibitory effect on tumor progression over free drug monotherapy or their physical mixture, with significantly increased antiproliferation and antiangiogenesis capability. Thereby, the codelivered nanoassemblies of sorafenib and curcumin provided a promising strategy to enhance the combinational therapy of HCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/25622075/"}
+{"doc_id": "975254697195819e20dfd94a71918e9a", "sentence": "Single treatment of closantel plus albendazole mixture reduced egg counts in camels by 100 % , 100 % , 98 % and 77 % for Haemonchus longistipes , Ascaris spp . , Monezia expansa and Fasciola hepatica , respectively .", "spans": [{"span_id": 0, "text": "closantel", "start": 20, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "albendazole", "start": 35, "end": 46, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Efficacy of closantel plus albendazole liquid suspension against natural infection of gastrointestinal parasites in camels. Oral administration of closantel in a dose of 10 mg/kg plus albendazole in a dose of 5 mg/kg liquid suspension was studied in 75 camels naturally infected with various types of gastrointestinal parasites. The camels involved were 15 pregnant she-camels, 20 non-pregnant she-camels and 40 male camels of various ages. Each camel received a single oral dose of closantel (10 mg/kg) plus albendazole (5 mg/kg) orally. Two weeks later, 20 camels of this group were re-dosed again with the same dose of the anthelmintic. Fecal samples were collected per rectum from all camels at the time of treatment and again 14 and 42 days post treatment. Fecal egg counts and generic determination of third stage larvae was performed. Results indicated that six different species of gastrointestinal tract parasites were identified in camels. Single treatment of closantel plus albendazole mixture reduced egg counts in camels by 100 % , 100 % , 98 % and 77 % for Haemonchus longistipes , Ascaris spp . , Monezia expansa and Fasciola hepatica , respectively . However, administration of the drug twice on the base of 2 weeks apart significantly raised the efficacy of the drug for clearance of the parasites from 92.5% to 100% in camels infected with various parasites. Camels were not adversely affected by treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/10321589/"}
+{"doc_id": "a810b68cf7ccc6138320048a4167e583", "sentence": "In contrast to patients receiving lidocaine , older patients receiving tetracaine experienced significantly less overall pain and discomfort , unpleasant taste , and dyspnea .", "spans": [{"span_id": 0, "text": "lidocaine", "start": 34, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "tetracaine", "start": 71, "end": 81, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "A prospective, randomized, double-blind study comparing the efficacy of topical anesthetics in nasal endoscopy. Transnasal endoscopy is commonly performed in an outpatient otolaryngology setting. Patients are typically administered a topical anesthetic and decongestant prior to this procedure to alleviate discomfort and improve visualization. There is no consensus on which topical anesthetic is most effective in optimizing patient experience during the procedure. ### objective To determine whether there is a difference in the efficacy between atomized 2% tetracaine and 4% lidocaine as a topical anesthetic prior to transnasal endoscopy. ### Study Design Prospective, randomized, double-blind study. ### methods A total of 99 patients received oxymetazoline and were randomized to receive either 2% tetracaine or 4% lidocaine prior to transnasal endoscopy. Immediately following the procedure, participants completed a survey assessing level of discomfort and other adverse symptoms pertaining to the procedure using a 10-point visual analog scale (VAS). ### results There were no significant differences in VAS scores between the lidocaine and tetracaine groups. There were also no significant differences between genders in overall VAS scores and in the lidocaine and tetracaine subgroups. Older patients demonstrated significantly less discomfort or a sensation of bad taste overall. In contrast to patients receiving lidocaine , older patients receiving tetracaine experienced significantly less overall pain and discomfort , unpleasant taste , and dyspnea . ### conclusion In patients undergoing transnasal endoscopy, use of either 2% tetracaine or 4% lidocaine has similar effect. tetracaine may be a better choice in older patients, however.", "source": "https://pubmed.ncbi.nlm.nih.gov/23404424/"}
+{"doc_id": "8426f8e8f60a6c637801b577610e05d9", "sentence": "Second-line chemotherapy was also ineffective ; therefore , the bevacizumab and irinotecan were given after a third gross-total resection of the tumor .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 64, "end": 75, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "irinotecan", "start": 80, "end": 90, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Long-term efficacy of bevacizumab and irinotecan in recurrent pediatric glioblastoma. A 5-year-old boy with glioblastoma relapsed soon after postoperative irradiation in combination with temozolomide. Second-line chemotherapy was also ineffective ; therefore , the bevacizumab and irinotecan were given after a third gross-total resection of the tumor . Treatment was interrupted for 1 month due to development of posterior reversible encephalopathy syndrome, but was re-initiated at a lower dose of bevacizumab with prolonged intervals between treatments. The patient was alive and disease free 2 years after initial diagnosis. bevacizumab and irinotecan are a promising regimen for pediatric cases of recurrent glioblastoma after gross-total resection, although the optimal treatment schedule must be determined on a patient-by-patient basis.", "source": "https://pubmed.ncbi.nlm.nih.gov/25711258/"}
+{"doc_id": "532c3c76c61f8d9eb020f295bd8cbfc8", "sentence": "In unselected patients with advanced HCC immunotherapeutics , namely the programmed cell death-1 ( PD-1 ) antibodies , nivolumab and pembrolizumab have shown promising efficacy in therapy-na\u00efve , as well as pre-treated patients with advanced HCC .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 119, "end": 128, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "pembrolizumab", "start": 133, "end": 146, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Recent developments with immunotherapy for hepatocellular carcinoma. Immunotherapy is on the way to become the new standard of care for advanced hepatocellular carcinoma (HCC) worldwide. With higher rates of objective responses, and overall less side effects compared to tyrosine-kinase inhibitors (TKIs) immunotherapeutics will probably replace sorafenib from standard first-line treatment. ### Areas Covered This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC focusing on immunotherapy. ### Expert Opinion In unselected patients with advanced HCC immunotherapeutics , namely the programmed cell death-1 ( PD-1 ) antibodies , nivolumab and pembrolizumab have shown promising efficacy in therapy-na\u00efve , as well as pre-treated patients with advanced HCC . However, only 10-20 percent of treated patients show an objective and durable response to the indicated therapeutics. Therefore, combination therapies including different immunotherapeutics, e.g. PD-1/programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, or combinations of immunotherapeutics and small molecules, or bifunctional antibodies will be needed to improve response rates. ### abbreviations HCC: hepatocellular carcinoma; TKI: tyrosine-kinase inhibitors; PD-1: programmed death receptor-1; PD-L1: programmed cell death 1 ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated Protein 4; CAR-T: chimeric T cell receptors; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; SBRT: stereotactic body radiation therapy; VEGF: vascular endothelial growth factor; MEK: mitogen-activated protein kinase kinase; NK cell: natural killer cell; TGF\u03b2: transforming growth factor-\u03b2; OV: Oncolytic viruses; PFU: plaque-forming unit.", "source": "https://pubmed.ncbi.nlm.nih.gov/29995439/"}
+{"doc_id": "fa1e8b298a512fc856c1e81df55911b0", "sentence": "Treatment with rapamycin and paclitaxel resulted in decreased phosphorylation of S6 and 4E-BP1 , two critical downstream targets of the mTOR pathway .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "paclitaxel", "start": 29, "end": 39, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Mammalian target of rapamycin (mTOR) inhibitors modulate signaling pathways involved in cell cycle progression, and recent phase II trials demonstrate activity in patients with endometrial cancer. Our objective was to examine the effects of combination therapy with rapamycin and paclitaxel in endometrial cancer cell lines. paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC(50) values of 0.1-0.5 nM and 1-5 nM for Ishikawa and ECC-1 cells, respectively. To assess synergy of paclitaxel and rapamycin, the combination index (CI) was calculated by the method of Chou and Talalay. Simultaneous exposure of cells to various doses of paclitaxel in combination with rapamycin (1 nM) resulted in a significant synergistic anti-proliferative effect (CI <1, range 0.131-0.920). rapamycin alone did not induce apoptosis, but combined treatment with paclitaxel increased apoptosis over that of paclitaxel alone. Treatment with rapamycin and paclitaxel resulted in decreased phosphorylation of S6 and 4E-BP1 , two critical downstream targets of the mTOR pathway . rapamycin decreased hTERT mRNA expression by real-time RT-PCR while paclitaxel alone had no effect on telomerase activity. paclitaxel increased polymerization and acetylation of tubulin, and rapamycin appeared to enhance this effect. Thus, in conclusion, we demonstrate that rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation, induction of apoptosis and potentially increased polymerization and acetylation of tubulin. This suggests that the combination of rapamycin and paclitaxel may be a promising effective targeted therapy for endometrial cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/19688827/"}
+{"doc_id": "d49e128f648e789ddc390d1f87e75031", "sentence": "Conversely , the IMbrave150 trial recently showed that , among patients with previously untreated unresectable HCC , treatment with atezolizumab plus bevacizumab resulted in significantly longer overall survival and progression-free survival compared to sorafenib monotherapy .", "spans": [{"span_id": 0, "text": "atezolizumab", "start": 132, "end": 144, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "bevacizumab", "start": 150, "end": 161, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "sorafenib", "start": 254, "end": 263, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma. Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver cancer worldwide, and the overall survival of patients with unresectable disease is poor. In the last five years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment scenario of several hematological and solid tumors, and these agents have been actively explored in unresectable HCC. Firstly, promising findings of phase I and II clinical studies reporting durable responses and a tolerable safety profile have led to the assessment of ICIs as single agents in phase III clinical studies; however, the latter have provided controversial results, and the activity of ICI monotherapy seems limited to a small subgroup of patients. Conversely , the IMbrave150 trial recently showed that , among patients with previously untreated unresectable HCC , treatment with atezolizumab plus bevacizumab resulted in significantly longer overall survival and progression-free survival compared to sorafenib monotherapy . In addition, the activity of several other ICIs is under investigation, as combination immunotherapy as well as combinations of immunotherapy with antiangiogenic agents. Nonetheless, there are currently no validated predictive biomarkers able to guide treatment choice in this setting, where the identification of specific predictors of response to ICIs represents a major challenge. In this review, we aim to provide a critical overview of recent evidence on biochemical predictors of response to ICIs in patients with unresectable HCC, especially focusing on PD-L1, TMB, MSI, and other emerging biomarkers.", "source": "https://pubmed.ncbi.nlm.nih.gov/33549983/"}
+{"doc_id": "400a1eae25bec51f7399dce5efbc4014", "sentence": "Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 14, "end": 23, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "letrozole", "start": 29, "end": 38, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer . The goals of this clinical trial involving postmenopausal women with metastatic breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM) pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and time to progression for the combination. Postmenopausal women with measurable or evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM], serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase inhibition, serum samples were obtained before treatment and at 6, 12, 18, and 24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding globulin. A total of 34 patients were entered on this trial, and 23 patients were still on study at week 24, 18 of whom had blood samples available at both week 6 and week 24. The 95% confidence interval for the mean difference between levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45 ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6 weeks of letrozole, which was maintained for an additional 12 weeks. Similar significant reductions were identified for E1. E1 sulfate levels increased after 6 weeks of TAM alone but then decreased significantly after the addition of letrozole. Sex hormone-binding globulin levels were significantly elevated after 6 weeks of TAM alone and remained elevated after the addition of letrozole. Six of the 34 patients (17.6%) achieved an objective response (95% confidence interval, 6.8-34.5%), with a median time to disease progression of 7.6 months. There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or 4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by letrozole was substantial despite the concomitant administration of TAM. The antitumor effect of TAM plus letrozole was less than expected.", "source": "https://pubmed.ncbi.nlm.nih.gov/10430063/"}
+{"doc_id": "0a4bbd89b0116fe38b5aa37d3710db43", "sentence": "Moreover , the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs .", "spans": [{"span_id": 0, "text": "nilotinib", "start": 35, "end": 44, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "ponatinib", "start": 49, "end": 58, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML. In chronic myelogenous leukemia (CML), leukemic stem cells (LSC) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel relevant markers of CML LSCs. ### Experimental Design CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25(+)CML cell line KU812. ### results In contrast to normal hematopoietic stem cells, CD34(+)/CD38(-)CML LSCs expressed the IL-2 receptor alpha chain, IL-2RA (CD25). STAT5 was found to induce expression of CD25 in Lin(-)/Sca-1(+)/Kit(+)stem cells in C57Bl/6 mice. Correspondingly, shRNA-induced STAT5 depletion resulted in decreased CD25 expression in KU812 cells. Moreover , the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs . A CD25-targeting shRNA was found to augment proliferation of KU812 cellsin vitroand their engraftmentin vivoin NOD/SCID-IL-2R\u03b3(-/-)mice. In drug-screening experiments, the PI3K/mTOR blocker BEZ235 promoted the expression of STAT5 and CD25 in CML cells. Finally, we found that BEZ235 produces synergistic antineoplastic effects on CML cells when applied in combination with nilotinib or ponatinib. ### conclusions CD25 is a novel STAT5-dependent marker of CML LSCs and may be useful for LSC detection and LSC isolation in clinical practice and basic science. Moreover, CD25 serves as a growth regulator of CML LSCs, which may have biologic and clinical implications and may pave the way for the development of new more effective LSC-eradicating treatment strategies in CML.", "source": "https://pubmed.ncbi.nlm.nih.gov/26607600/"}
+{"doc_id": "4f3b59fab506326763dc670b527a345f", "sentence": "The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting .", "spans": [{"span_id": 0, "text": "somatostatin", "start": 46, "end": 58, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "everolimus", "start": 88, "end": 98, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study. Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials. ### Materials And Methods This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression). ### results Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS. ### conclusion The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting. ### Implications For Practice The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting .", "source": "https://pubmed.ncbi.nlm.nih.gov/29794066/"}
+{"doc_id": "90bfe4266085a7725c0b30a40fca9cc6", "sentence": "Synergism between anti-HER2 monoclonal antibody ( trastuzumab ) and paclitaxel has been shown in vitro and in vivo .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 50, "end": 61, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "paclitaxel", "start": 68, "end": 78, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer.  Synergism between anti-HER2 monoclonal antibody ( trastuzumab ) and paclitaxel has been shown in vitro and in vivo . In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/14710203/"}
+{"doc_id": "71f038d703d77df97e666dc522f17849", "sentence": "Between September 1998 and December 1999 , we treated 25 patients at risk for post-operative renal dysfunction ( high-risk basiliximab group ) with the new induction regimen and another 33 patients not at risk ( low-risk CsA group ) for renal dysfunction with our standard cyclosporine protocol .", "spans": [{"span_id": 0, "text": "basiliximab", "start": 123, "end": 134, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "cyclosporine", "start": 273, "end": 285, "token_start": 45, "token_end": 46}], "rels": [], "paragraph": "Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. cyclosporine (CsA) is frequently initiated as induction therapy in patients undergoing orthotopic heart transplantation, but our experience has identified a significant rate of post-operative renal dysfunction. We therefore devised a renal-sparing cyclosporine-free induction regimen consisting of the early administration basiliximab, an interleukin-2 receptor monoclonal antibody, followed by the late initiation of cyclosporine on post-operative Day 4. ### methods Between September 1998 and December 1999 , we treated 25 patients at risk for post-operative renal dysfunction ( high-risk basiliximab group ) with the new induction regimen and another 33 patients not at risk ( low-risk CsA group ) for renal dysfunction with our standard cyclosporine protocol . We identified a historical control group (1996 through 1998) of 32 patients at risk for renal dysfunction (high-risk CsA group) who had received our standard cyclosporine protocol. ### results The increase in serum creatinine levels after transplantation was less in the high-risk basiliximab group (-0.1 +/- 0.7) than in the high-risk CsA group (0.5 +/- 1.0, p < 0.02) and comparable to the low-risk CsA group (0.03 +/- 0.6). The basiliximab protocol did not increase rejection; the percentage of rejection episodes was high-risk basiliximab, 0; high-risk CsA, 13; and low-risk CsA, 3 (p = .13). ### conclusion basiliximab induction therapy allows delayed initiation of cyclosporine after cardiac transplantation without an increase in rejection and reduces the risk of post-operative renal dysfunction.", "source": "https://pubmed.ncbi.nlm.nih.gov/16143252/"}
+{"doc_id": "afb487e5f3a9ba9b35526d05826560e6", "sentence": "Cardiac events occurred after posaconazole administration , incriminating posaconazole use , alone or in combination with voriconazole , as the culpable agent .", "spans": [{"span_id": 0, "text": "posaconazole", "start": 30, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "posaconazole", "start": 74, "end": 86, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "voriconazole", "start": 122, "end": 134, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": false}], "paragraph": "Long QT Syndrome Leading to Multiple Cardiac Arrests After Posaconazole Administration in an Immune-Compromised Patient with Sepsis: An Unusual Case Report. We present the case of a septic patient with severe immunodeficiency, who developed QT interval prolongation followed by episodes of lethal cardiac arrhythmia. Cardiac events occurred after posaconazole administration , incriminating posaconazole use , alone or in combination with voriconazole , as the culpable agent . ### Case Report A 26-year-old female patient underwent orthopedic surgery to remove ectopic calcifications in her left hip joint. On the first post-operative day she became septic due to a surgical wound infection. Despite being treated according to the therapeutic protocols for sepsis, no clinical improvement was noticed and further assessment revealed an underlying immunodeficiency. Considering the underlying immunodeficiency and to that point poor clinical response, an antifungal agent was added to the antibiotic regiment. Following discontinuation of multiple antifungal agents due to adverse effects, posaconazole was administered. posaconazole oral intake was followed by episodes of bradycardia and QT interval prolongation. The patient suffered continuous incidents of cardiac arrest due to polymorphic ventricular tachycardia (torsades des pointes) that degenerated to lethal ventricular fibrillation. posaconazole was immediately discontinued and a temporary pacemaker was installed. The patient finally recovered without any neurological deficit, and was discharged in a good clinical status. ### conclusions Close cardiac monitoring is recommended in cases where posaconazole administration is combined with coexisting risk factors, as they may lead to severe ECG abnormalities and cardiac arrhythmias such as long QT interval syndrome and torsades de pointes. posaconazole interactions with medications metabolized via the CYP3A4 pathway should be considered an additional risk factor for lethal cardiac incidents.", "source": "https://pubmed.ncbi.nlm.nih.gov/27125217/"}
+{"doc_id": "d27c12a579e30cabf1743a89badedece", "sentence": "Prognostic value of expression of Kit67 , p53 , TopoIIa and GSTP1 for curatively resected advanced gastric cancer patients receiving adjuvant paclitaxel plus capecitabine chemotherapy .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 142, "end": 152, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "capecitabine", "start": 158, "end": 170, "token_start": 23, "token_end": 24}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Prognostic value of expression of Kit67 , p53 , TopoIIa and GSTP1 for curatively resected advanced gastric cancer patients receiving adjuvant paclitaxel plus capecitabine chemotherapy . To investigate the role of Kit67, p53, topoisomerase II (TopoII) and glutathione S-transferase P1 (GSTP1) in predicting clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel chemotherapy. ### methodology The clinical data and tissue samples from 136 curatively resected advanced gastric cancer patients receiving capecitabine plus paclitaxel in the third affiliated hospital of Kunming medical university from January 2005 to December 2007 were retrospectively collected and analyzed for Kit67, p53, TopoIIa and GSTP1 expressions by immunohistochemistry. The relationships between expressions of the biomarkers and survival were analyzed. ### results p53 expression were associated with the significantly shorter disease-free survival (DFS) (p<0.001) and overall survival (OS) (p=0.012) in the curatively resected advanced gastric cancer patients receiving capecitabine plus paclitaxel. Kit67, TopoIIa and GSTP1 expressions were not related to DFS and OS. ### conclusions p53 expression positive might predict prognosis in gastric cancer patients who underwent curative surgery followed by adjuvant capecitabine plus paclitaxel chemotherapy. A favorable effect of capecitabine plus paclitaxel might therefore be expected in patients that do not express p53.", "source": "https://pubmed.ncbi.nlm.nih.gov/22534478/"}
+{"doc_id": "8d395c0462d3164578455a4339b29ea1", "sentence": "The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin ( FL ) .", "spans": [{"span_id": 0, "text": "fluorouracil", "start": 51, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "leucovorin", "start": 69, "end": 79, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.  The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin ( FL ) . oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. ### methods We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. ### results A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). ### conclusions Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/15175436/"}
+{"doc_id": "dbe218b8b09950b9c28f7a92e7b5f29d", "sentence": "Effects of ultrasound were similar at baseline and after propranolol but increased after phenylephrine .", "spans": [{"span_id": 0, "text": "propranolol", "start": 57, "end": 68, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "phenylephrine", "start": 89, "end": 102, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Alteration of left ventricular endocardial function by intracavitary high-power ultrasound interacts with volume, inotropic state, and alpha 1-adrenergic stimulation. High-power intracavitary ultrasound abbreviates left ventricular (LV) ejection duration, thereby decreasing mechanical LV performance, presumably by selective impairment of endocardial endothelial function. ### Methods And Results Effects of ultrasound were evaluated in the ejecting LV of anesthetized, open-chest dogs under different conditions of LV volume and contractile state and after mild selective alpha 1-adrenergic stimulation. LV pressures, left atrial pressures, and regional segment lengths were measured in anterior and posterior midwall. A cylindrical ultrasound probe (0.9 MHz, 25 W) mounted on a catheter was inserted into the LV cavity through the apex and was activated for 4 minutes in each condition. In protocol A (n = 7), LV volume was altered with caval vein occlusion and intravenous dextran infusion. The ultrasound probe was activated at low (4.1 +/- 0.9 mm Hg), mid (10.6 +/- 1.5 mm Hg), and high (17.9 +/- 1.8 mm Hg) LV end-diastolic pressure (EDP). Effects of ultrasound were less pronounced at higher EDP. For example, the time interval from end-diastole to peak (-)dP/dt decreased by 7.5 +/- 2.3% at low, 4.4 +/- 2.2% at mid, and 1.9 +/- 1.6% at high LVEDP (p < 0.001). In protocol B (n = 7), LV inotropic state was altered by slow intravenous infusion of low-dose calcium. The ultrasound probe was activated before and after calcium. Effects of ultrasound were less pronounced after calcium. Time from end-diastole to peak (-)dP/dt decreased by 8.4 +/- 3.1% at baseline and by 3.5 +/- 2.1% after calcium (p < 0.001). In protocol C (n = 7), activation of the ultrasound probe was performed at baseline and after mild selective alpha 1-adrenergic stimulation (propranolol plus phenylephrine). Effects of ultrasound were similar at baseline and after propranolol but increased after phenylephrine . Time from end-diastole to peak (-)dP/dt decreased by 5.2 +/- 2.4% at baseline, by 5.3 +/- 1.9% after propranolol, and by 8.9 +/- 3.2% after phenylephrine (p < 0.05). ### conclusions Effects of intracavitary ultrasound, which are presumably mediated through modulation of endocardial endothelial function, were more important at low volume, lower calcium, and under mild selective alpha 1-adrenergic stimulation.", "source": "https://pubmed.ncbi.nlm.nih.gov/7681734/"}
+{"doc_id": "e164b14965950212d9af8afd0dc70c96", "sentence": "Thirty-four patients ( 4 patients with stage IIIb , 30 patients in stage IV ) , with median age 66 and performance status 0 - 1 , were administered paclitaxel , 175 mg/m(2 ) in a 3-h infusion rate on day 1 and vinorelbine , 25 mg/m(2 ) in a 10-min infusion rate on days 1 , and 8 with G-CSF and EPO support .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 148, "end": 158, "token_start": 29, "token_end": 30}, {"span_id": 1, "text": "vinorelbine", "start": 210, "end": 221, "token_start": 43, "token_end": 44}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase II study of non-platinum based chemotherapy with paclitaxel and vinorelbine in non-small cell lung cancer. paclitaxel and vinorelbine combination in previous untreated patients with stage IIIb-IV non-small cell lung cancer (NSCLC) as a phase II study. ### Patients And Methods Thirty-four patients ( 4 patients with stage IIIb , 30 patients in stage IV ) , with median age 66 and performance status 0 - 1 , were administered paclitaxel , 175 mg/m(2 ) in a 3-h infusion rate on day 1 and vinorelbine , 25 mg/m(2 ) in a 10-min infusion rate on days 1 , and 8 with G-CSF and EPO support . ### results Among our 33 evaluable patients for toxicity 16 patients (48.4%) presented leukopenia and 15 patients (45.4%) presented anemia despite G-CSF and EPO administration. Two patients (6%) presented Grade III-IV peripheral neuropathy. The overall response rate was 67.7%; 5 patients (16.1%) showed complete response (2 patients stage IIIb) and 16 patients (51.6%) showed partial response (1 patient stage IIIb). The overall median survival time was 10 months (range 3-18 months) and the median disease-free survival was 9 months (range 3-15 months) with an 1-year survival time of 45.1% (14 patients). ### conclusion The results of the combination as 1st line treatment for patients with non-operable NSCLC are promising and should be further investigated.", "source": "https://pubmed.ncbi.nlm.nih.gov/12399133/"}
+{"doc_id": "f34bb0d6ddd6e05d3a7d9a2cac06618f", "sentence": "Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia .", "spans": [{"span_id": 0, "text": "decitabine", "start": 17, "end": 27, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "valproic", "start": 57, "end": 65, "token_start": 10, "token_end": 11}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia . To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML). ### Patients And Methods Twenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21). ### results The OBD of decitabine was 20 mg/m(2)/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P < or = .05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% (11 of 25). Of 21 assessable patients, 11 (52%) responded: four with morphologic and cytogenetic complete remission (CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA. ### conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m(2)/d for 10 days) alone or with an alternative deacetylating agent are warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/17679729/"}
+{"doc_id": "324a822968415251d1110100374543de", "sentence": "Early discontinuation of clopidogrel results in a transient rebound increase in risk of recurrence in acute coronary syndromes , but there are no published data on any similar rebound effect in patients with TIA or stroke that might inform the design of clinical trials of aspirin and clopidogrel in the acute phase .", "spans": [{"span_id": 0, "text": "clopidogrel", "start": 25, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "aspirin", "start": 273, "end": 280, "token_start": 45, "token_end": 46}, {"span_id": 2, "text": "clopidogrel", "start": 285, "end": 296, "token_start": 47, "token_end": 48}], "rels": [], "paragraph": "Low risk of rebound events after a short course of clopidogrel in acute TIA or minor stroke. The combination of aspirin and clopidogrel is indicated after acute coronary events and possibly for a short period after TIA or minor ischemic stroke. Early discontinuation of clopidogrel results in a transient rebound increase in risk of recurrence in acute coronary syndromes , but there are no published data on any similar rebound effect in patients with TIA or stroke that might inform the design of clinical trials of aspirin and clopidogrel in the acute phase . ### methods A 30-day course of aspirin and clopidogrel (both 75 mg daily) was given to high-risk patients with TIA or minor ischemic stroke seen acutely in the EXPRESS study clinic from April 1, 2002, to March 31, 2009. clopidogrel was stopped after 30 days and aspirin continued. Recurrent events were ascertained at face-to-face follow-up. ### results A total of 320 patients were prescribed a 30-day course of aspirin and clopidogrel acutely after TIA or minor stroke. There were 5 recurrent ischemic strokes and 7 TIAs during the aspirin and clopidogrel treatment period, but no strokes and 4 TIAs during the 30 days after stopping clopidogrel. A similar temporal trend in stroke risk was seen in the 487 patients prescribed aspirin alone in the acute phase, with 12 and 5 strokes in the equivalent time periods. The upper 95% confidence intervals of the observed 0% risk of stroke during the 30 days after stopping clopidogrel was 1.15% overall. ### conclusion Although larger studies are required, our findings suggest there is unlikely to be a large rebound effect after discontinuation of a 30-day course of clopidogrel in acute TIA and minor ischemic stroke. However, planned trials of aspirin and clopidogrel in the acute phase after TIA or stroke should still follow-up beyond the cessation of clopidogrel treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/20530325/"}
+{"doc_id": "e168784c0e299ecd1e3b2e48bfe61993", "sentence": "Patients received docetaxel 35 mg/m(2 ) and irinotecan 60 mg/m(2 ) , intravenously , on Days 1 and 8 , every 21 days , until disease progression .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 18, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "irinotecan", "start": 44, "end": 54, "token_start": 7, "token_end": 8}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Docetaxel and irinotecan in recurrent or metastatic head and neck cancer: a phase 2 trial of the Eastern Cooperative Oncology Group. docetaxel and irinotecan have single-agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN. ### methods Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m(2 ) and irinotecan 60 mg/m(2 ) , intravenously , on Days 1 and 8 , every 21 days , until disease progression . The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase-2 and VEGF in baseline tumor tissue. ### results Fifty-two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel-exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression-free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085). ### conclusions docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum-based regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/19634157/"}
+{"doc_id": "c00ca372934cc418ceb8a2e859b60fbe", "sentence": "Most patients with advanced ovarian cancer achieve a clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel plus carboplatin .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 135, "end": 145, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "carboplatin", "start": 151, "end": 162, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Gemcitabine and carboplatin in second-line ovarian cancer.  Most patients with advanced ovarian cancer achieve a clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel plus carboplatin . However, a majority of these patients will ultimately recur, and second-line treatment for this group of patients is an important aspect of management of this disease as well as an area of active clinical investigation. Until recently, for patients with platinum-sensitive ovarian cancer (more than 6-month disease-free interval), chemotherapy with single-agent carboplatin was frequently recommended. However, two recent prospective randomized trials have shown that combination chemotherapy produces higher response rates and improvement in progression-free survival compared with treatment with single-agent carboplatin. One trial compared treatment with paclitaxel plus a platinum compound with re-treatment with platinum, and a second trial compared carboplatin plus gemcitabine re-treatment against carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Both trials showed a 3-month improvement in progression-free survival in patients treated with the combination, as well as acceptable toxicity. In the absence of a prospective randomized trial comparing these two regimens in patients with platinum-sensitive recurrent ovarian cancer, the choice of which combination to use may depend on toxicity considerations.", "source": "https://pubmed.ncbi.nlm.nih.gov/16143161/"}
+{"doc_id": "457f957cafaf7d707f008bebb67491e7", "sentence": "Patients were assigned to receive either oxaliplatin ( 100 mg/m(2 ) ) in the SOX arm or docetaxel ( 40 mg/m(2 ) ) in the mDS arm on day 1 of every 3-week cycle .", "spans": [{"span_id": 0, "text": "oxaliplatin", "start": 41, "end": 52, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "docetaxel", "start": 88, "end": 97, "token_start": 17, "token_end": 18}], "rels": [], "paragraph": "Low-dosed docetaxel showed equivalent efficacy but improved tolerability compared with oxaliplatin in the S-1-based first-line chemotherapy regimen for metastatic or recurrent gastric adenocarcinoma. Platinum-fluoropyrimidine combinations are the preferred first-line options for advanced gastric cancer (AGC) in East Asia. On the other hand, docetaxel-containing regimens without platinum have demonstrated promising activity in AGC. However, dose-related toxicity of docetaxel has limited its clinical adoption. This study compared the efficacy and safety of a modified low-dosed docetaxel plus S-1 (mDS) with oxaliplatin plus S-1 (SOX) in Chinese patients with AGC. Patients were assigned to receive either oxaliplatin ( 100 mg/m(2 ) ) in the SOX arm or docetaxel ( 40 mg/m(2 ) ) in the mDS arm on day 1 of every 3-week cycle . S-1 80-120 mg/day was administered orally on days 1-14 in the 3-week cycle in both groups. One hundred and eighty-eight patients (mDS regimen 101; SOX 87) showed similar overall survival (OS; 13.1 vs 12.8 months, P = 0.878), progression-free survival (PFS; 5.8 vs 5.5 months, P = 0.924), and overall response rate (39.7 vs 44.2%, P = 0.569) in the mDS and SOX arms, respectively. mDS was associated with significantly less grade 3/4 toxicities in thrombocytopenia (5.9 vs 16.1%) and gastrointestinal disturbances (1.0 vs 8.0%). Furthermore, in patients who had ever received oxaliplatin-based adjuvant chemotherapy (N = 40), mDS resulted in significantly superior OS (17.8 vs 9.5 months, P = 0.015) and PFS (7.0 vs 4.2 months, P = 0.008) compared with SOX. In conclusion, mDS was as effective as SOX in Chinese patients with AGC, but it resulted in a significantly improved tolerability. In patients who received oxaliplatin-based adjuvant chemotherapy before, mDS was associated with improved efficacy in the first-line setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/26268397/"}
+{"doc_id": "21f9362aa253d6a8783dfec4552cd563", "sentence": "Agents in clinical trials for subsets of MDS include luspatercept , antibodies targeting CD33 , isocitrate dehydrogenase inhibitors , deacetylase inhibitors , venetoclax , and immunotherapies designed to overcome immune checkpoint inhibition .", "spans": [{"span_id": 0, "text": "luspatercept", "start": 53, "end": 65, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "venetoclax", "start": 159, "end": 169, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Recent advances in the cellular and molecular understanding of myelodysplastic syndromes: implications for new therapeutic approaches. It has been more than 10 years since any new disease-modifying therapies have received regulatory approval for indications related to myelodysplastic syndromes (MDS). Advances in our collective biological understanding of MDS in the last decade, however, have made it possible to hope that effective therapeutics can be designed to improve MDS-associated cytopenias and patients' quality of life, and perhaps even delay clonal progression and extend survival. Classes of MDS-associated mutations and disordered biological pathways targeted by developmental therapeutics include the following: aberrant messenger RNA splicing, neomorphic enzymes in the citric acid cycle with oncogenic activity, overactivated tyrosine and serine-threonine kinases, epigenetic and chromatin remodeling alterations, abnormal telomere dynamics, and failed protection of DNA integrity. At present, treatments for MDS are usually administered as sequential monotherapy, but there is a trend toward clinical trials of combination therapies-in which new agents are added to a DNA hypomethylating agent backbone-for both upfront treatment and the treatment of relapsed/refractory disease. Agents in clinical trials for subsets of MDS include luspatercept , antibodies targeting CD33 , isocitrate dehydrogenase inhibitors , deacetylase inhibitors , venetoclax , and immunotherapies designed to overcome immune checkpoint inhibition . These biologically based therapeutics, as well as the encouraging precedent of 7 new approvals by the US Food and Drug Administration in 2017 for the treatment of acute leukemia, offer the prospect that 10 more years will not elapse before another new therapy is approved for MDS.", "source": "https://pubmed.ncbi.nlm.nih.gov/29741506/"}
+{"doc_id": "ebd455680a4ddeb606e9c2b94cd162c3", "sentence": "Possible differences between enalapril and captopril .", "spans": [{"span_id": 0, "text": "enalapril", "start": 29, "end": 38, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "captopril", "start": 43, "end": 52, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Possible differences between enalapril and captopril . Inhibitors of angiotensin converting enzyme block the conversion of angiotensin I to angiotensin II, the active hormone of the renin-angiotensin system. This inhibition leads to a reduction in angiotensin-mediated vasoconstriction and aldosterone production. Although converting enzyme inhibitors have other potential metabolic effects, their beneficial effects in hypertension and congestive heart failure appear to be, in large part, related to their ability to reduce angiotensin II. This causes an increase in plasma renin levels and a fall in plasma and urine aldosterone, which can be sustained for many years. As a consequence, converting enzyme inhibitors produce mild natriuresis and positive potassium balance. At conventionally used doses, enalapril more completely prevents posture-induced increases in aldosterone than does captopril, probably reflecting more complete inhibition of angiotensin II formation in vivo.", "source": "https://pubmed.ncbi.nlm.nih.gov/6089554/"}
+{"doc_id": "e4fd3f4f3543e792ba43e968cecc17af", "sentence": "Exposure of the saphenous veins to imipenem or imipenem combined with amphotericin B had no adverse effects on the viability of the endothelial cells with 12 h exposure .", "spans": [{"span_id": 0, "text": "imipenem", "start": 35, "end": 43, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "imipenem", "start": 47, "end": 55, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "amphotericin", "start": 70, "end": 82, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Effects of antibiotics on the endothelium of fresh and cryopreserved canine saphenous veins. To determine if antibiotic solutions for potential use in antimicrobial treatment of tissues were detrimental to cell viability, canine saphenous veins were exposed to three different antibiotic solutions at 37 degrees C for 12 h. Viability was determined by tissue culture, utilizing a limiting dilution assay. The antibiotic series included two formulations currently used for the preservation of heart valves and a new formulation containing imipenem, a broad spectrum beta-lactam. Currently used antibiotic regimes and imipenem with gentamicin resulted in a decrease of 30 to 50% of the viable endothelial cells within 12 h. Exposure of the saphenous veins to imipenem or imipenem combined with amphotericin B had no adverse effects on the viability of the endothelial cells with 12 h exposure . However, veins exposed to amphotericin B were more susceptible to subsequent damage during freezing and thawing than veins frozen after incubation with either imipenem alone or imipenem combined with flucytosine. These studies indicate that imipenem combined with flucytosine is suitable for use with vein grafts.", "source": "https://pubmed.ncbi.nlm.nih.gov/8319486/"}
+{"doc_id": "22e4c43526214a50dd7ba189ee96a40d", "sentence": "First-line chemotherapy was either R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine and prednisolone ) or CHOP-like-based regimen .", "spans": [{"span_id": 0, "text": "rituximab", "start": 44, "end": 53, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "cyclophosphamide", "start": 56, "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": 89, "end": 100, "token_start": 12, "token_end": 13}, {"span_id": 4, "text": "prednisolone", "start": 105, "end": 117, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "[Primary testicular non-Hodgkin's lymphoma: clinical analysis of 21 cases]. To explore the clinical characteristics and prognosis of patients with primary testicular non-Hodgkin's lymphoma. ### methods The clinical profiles and prognostic factors of 21 cases newly diagnosed as primary testicular non-Hodgkin's lymphoma at Peking University Cancer Hospital from January 2005 to December 2012 were retrospectively analyzed. ### results Their median age was 59 (34-86) years. And they were classified as Ann Arbor stage I (n = 8), stage II (n = 2) and stage IV (n = 11). There were B symptoms (n = 4), extranodal involvement outside testis (n = 12) and elevated lactate dehydrogenase (LDH) at diagnosis (n = 6). The scores of international prognostic index (IPI) were 0-1 point (n = 10), 3 points (n = 10) and 4 points (n = 1). The regimens included orchidectomy as the initial treatment (n = 15), chemotherapy followed by radiotherapy (n = 7) and CNS prophylaxis during treatment (n = 15). All patients were pathologically diagnosed as diffuse large B-cell lymphoma. And 11 cases belonged to the non-germinal center B cell-like subgroup. First-line chemotherapy was either R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine and prednisolone ) or CHOP-like-based regimen . Complete response was achieved in 85.7% of patients. The median follow-up period was 18 (6-58) months. The 1, 2 and 3-year survival rates were 100%, 80% and 60% respectively. Statistical analysis showed that the first-line chemotherapy with rituximab was a prognostic factor (P = 0.038).Other factors included stage (P = 0.275), LDH level (P = 0.179) , \u03b22-microglobulin level (P = 0.229) and IPI (P = 0.275) . ### conclusions The prognosis of primary testicular non-Hodgkin's lymphoma is usually poor. The first-line chemotherapy with rituximab is a prognostic factor.", "source": "https://pubmed.ncbi.nlm.nih.gov/24169330/"}
+{"doc_id": "cb3413a04ed145ab2ccfc3b8ba5675d8", "sentence": "The combination of rituximab with vincristine and 5-day cyclophosphamide is able to produce CR in patients with advanced follicular lymphoma , even in patients resistant to third-generation regimens .", "spans": [{"span_id": 0, "text": "rituximab", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "vincristine", "start": 34, "end": 45, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "cyclophosphamide", "start": 56, "end": 72, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Immunochemotherapy with rituximab, vincristine and 5-day cyclophosphamide for heavily pretreated follicular lymphoma. Therapeutic options for relapsed or refractory follicular lymphoma include combination chemotherapy, immunotherapy and, for selected patients, autotransplant. Because of the different mechanisms of action and non-overlapping toxicities, combination of rituximab with chemotherapy is a rational approach. ### methods 30 patients with follicular non-Hodgkin's lymphoma with advanced-stage disease were treated with four cycles of immunochemotherapy with rituximab 375 mg/m2 on day 1, vincristine 2 mg i.v. on day 2 and cyclophosphamide 400 mg/m2 i.v. from days 2 to 6, repeated at 3-week intervals. All patients had received multiple lines of therapy (median 3); 9 (30%) had relapses (2 after high-dose therapy with autologous transplant), and 21 (70%) were in relapse and refractory to salvage treatment (with an anthracycline-containing regimen in 19). ### results Of 29 patients evaluable for response, 16 (55 %) obtained a complete response (CR) and 3 (10%) a partial response (PR), with an overall response rate of 65% (19/29); 10 patients (35%) achieved less than PR. The median event-free survival was 16.1 months for all patients, being 22.8 months for responders. After a median follow-up of 2 years from the start of therapy (range 6 months to 3.8 years), of 16 patients who achieved CR, 10 remain free of disease. ### conclusion The combination of rituximab with vincristine and 5-day cyclophosphamide is able to produce CR in patients with advanced follicular lymphoma , even in patients resistant to third-generation regimens . The regimen designed on the basis of pharmacokinetics of the chimeric antibody seemed important for the clinical efficacy of the combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/16006752/"}
+{"doc_id": "989e4dbe95c2ec8043f087978dfa8204", "sentence": "The results showed that lamotrigine did not produce any change in cognitive function , while carbamazepine produced cognitive dysfunction .", "spans": [{"span_id": 0, "text": "lamotrigine", "start": 24, "end": 35, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "carbamazepine", "start": 93, "end": 106, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemical epileptogenesis in rats. The present study assessed the effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemically induced epileptogenesis in rats. Epileptogenesis was induced by administration of pentylenetetrazole (30 mg/kg, s.c.) on alternate days (three times/week) for 9-11 weeks or until stage 4 of seizure score was achieved. The neurobehavioural parameters used for cognitive assessment were step-down latency in continuous avoidance apparatus and transfer latency in elevated plus maze test paradigm. carbamazepine and lamotrigine were administered intraperitoneally in doses of 60 mg/kg and 25 mg/kg, respectively, according to the groups, once a day for 11 weeks. Oxidative stress was assessed in isolated homogenized whole brain samples and estimated for the levels of malondialdehyde, reduced glutathione, catalase and superoxide dismutase. The results showed that lamotrigine did not produce any change in cognitive function , while carbamazepine produced cognitive dysfunction . Cognitive decline seen in the carbamazepine-treated pentylenetetrazole-kindled group was also associated with increased oxidative stress. lamotrigine treatment had no effect on oxidative stress parameters alone, while it significantly decreased oxidative stress in the pentylenetetrazole-kindled group as compared to the pentylenetetrazole-kindled carbamazepine-treated group.", "source": "https://pubmed.ncbi.nlm.nih.gov/20002063/"}
+{"doc_id": "b0dcf3e3038370ed524af039d260b6ef", "sentence": "These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma .", "spans": [{"span_id": 0, "text": "decitabine", "start": 38, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "carboplatin", "start": 53, "end": 64, "token_start": 7, "token_end": 8}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma. Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma. ### methods To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction. ### results Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin. ### conclusions Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma .", "source": "https://pubmed.ncbi.nlm.nih.gov/29373959/"}
+{"doc_id": "08f60e955a6158992b104ff65ea478bd", "sentence": "[ Rhabdomyosarcoma of the urinary bladder : complete remission induced by vinblastine , cis-platinum , and bleomycin ] .", "spans": [{"span_id": 0, "text": "vinblastine", "start": 74, "end": 85, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "bleomycin", "start": 107, "end": 116, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "cis-platinum", "start": 88, "end": 100, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "[ Rhabdomyosarcoma of the urinary bladder : complete remission induced by vinblastine , cis-platinum , and bleomycin ] . Combination therapy consisting of vincristine, actinomycin-D, and cyclophosphamide with or without adriamycin is the most common chemotherapy for rhabdomyosarcoma in childhood. But the effective chemotherapy for rhabdomyosarcoma resistant to these four drugs has not been established. We report a case with rhabdomyosarcoma, which was resistant to these four drugs but responded completely to three drug combination chemotherapy consisting of vinblastine, cis-platinum, and bleomycin (VPB therapy). A 11-months-old boy was referred to us because of giant abdominal tumor. Postoperative diagnosis was Group III embryonal rhabdomyosarcoma of the urinary bladder. Partial resection was followed by vincristine, actinomycin-D, cyclophosphamide, and adriamycin, but his residual tumor was growing. Then VPB therapy was administered and the first course of the chemotherapy reduced the size of tumor. After three courses of VPB therapy the second-look operation was performed. At operation no residual tumor was found and a complete remission was confirmed. During the course of VPB therapy no severe adverse effect was detectable.", "source": "https://pubmed.ncbi.nlm.nih.gov/6191695/"}
+{"doc_id": "a3728ecff22176b9a5c91cf433c52ad7", "sentence": "Recent comparative studies suggest that atenolol ( 200 mg daily ) , metoprolol ( 200 mg daily ) ; acebutolol ( 400 mg daily ) , oxprenolol ( 160 mg daily ) , nadolol ( 80 mg daily ) and timolol ( 20 mg daily ) produce a beneficial clinical response equal to that seen with propranolol ( 160 mg daily ) .", "spans": [{"span_id": 0, "text": "atenolol", "start": 40, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "metoprolol", "start": 68, "end": 78, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "acebutolol", "start": 98, "end": 108, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "oxprenolol", "start": 128, "end": 138, "token_start": 26, "token_end": 27}, {"span_id": 4, "text": "nadolol", "start": 158, "end": 165, "token_start": 33, "token_end": 34}, {"span_id": 5, "text": "timolol", "start": 186, "end": 193, "token_start": 40, "token_end": 41}, {"span_id": 6, "text": "propranolol", "start": 273, "end": 284, "token_start": 56, "token_end": 57}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": false}], "paragraph": "Use of beta-adrenoceptor blocking drugs in hyperthyroidism. There is an increasing use and variety of beta-adrenoceptor blocking agents (beta-blockers) available for the treatment of hyperthyroidism. Recent comparative studies suggest that atenolol ( 200 mg daily ) , metoprolol ( 200 mg daily ) ; acebutolol ( 400 mg daily ) , oxprenolol ( 160 mg daily ) , nadolol ( 80 mg daily ) and timolol ( 20 mg daily ) produce a beneficial clinical response equal to that seen with propranolol ( 160 mg daily ) . Most beta-blockers reduce resting heart rate by approximately 25 to 30 beats/min, although a lesser reduction is seen with those possessing intrinsic sympathomimetic activity such as oxprenolol and pindolol. While earlier studies employing large doses of intravenous propranolol concluded that beta-blockade reduced myocardial contractility, more recent non-invasive studies suggest that the predominant cardiac effect is on heart rate. In patients with cardiac failure, beta-blockers may, however, produce a profound fall in cardiac output. Nevertheless, in combination with digoxin they may be useful in controlling the atrial fibrillation of thyrocardiac disease. beta-Blockers improve nervousness and tremor (although to a lesser extent with cardioselective agents) and severe myopathy, and they also reduce the frequency of paralysis in patients with thyrotoxic periodic paralysis. There is often subjective improvement in sweating but usually no major effect on eye signs. Recent studies show a 10% reduction in oxygen consumption/basal metabolic rate with long term oral use of selective or nonselective beta-blockers. In addition, many agents (propranolol, metoprolol, nadolol and sotalol but not acebutolol, atenolol or oxprenolol) reduce circulating tri-iodothyronine (T3) concentration by between 10 and 40%, although the clinical significance of this effect (if any) is not established. beta-Blockers may also have endocrinological effects on gastrin, cyclic AMP, catecholamines and other hormone levels. Given in adequate dosage, propranolol has been shown to control thyrotoxic hypercalcaemia. Minor side effects (nausea, headaches, tiredness, etc.) are quite common but overall beta-blockers are well tolerated by the thyrotoxic patient. The major use of these drugs is in symptomatic control while awaiting definitive diagnosis or treatment. As an adjunct to antithyroid drugs or radioactive iodine, beta-blockers will produce a satisfactory clinical response in the weeks to months before these forms of therapy produce a euthyroid state. beta-Blockers are more convenient than antithyroid drugs in the control of patients receiving therapeutic radioiodine, in that continuous therapy and assessment of biochemical response is possible.(ABSTRACT TRUNCATED AT 400 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/6144501/"}
+{"doc_id": "6940b79498c210d4948acbca8b303f0c", "sentence": "All the animals in the placebo group had tumors in each lobe compared with only 43 % each in the dorsolateral ( DLP ) and anterior prostate ( AP ) of the animals treated with raloxifene ( 10 mg/kg/day ) plus nimesulide .", "spans": [{"span_id": 0, "text": "raloxifene", "start": 175, "end": 185, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "nimesulide", "start": 208, "end": 218, "token_start": 41, "token_end": 42}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor. The chemopreventive efficacies of raloxifene and nimesulide, an anti-estrogen but with anti-androgen action and a cyclooxygenase-2 (COX-2) selective inhibitor, respectively, were evaluated in probasin/SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 p.p.m. in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 p.p.m.), and raloxifene (10 mg/kg/day) plus nimesulide (400 p.p.m.). Animals were killed at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure the testosterone levels. All the animals in the placebo group had tumors in each lobe compared with only 43 % each in the dorsolateral ( DLP ) and anterior prostate ( AP ) of the animals treated with raloxifene ( 10 mg/kg/day ) plus nimesulide . The total prostate weights and adenocarcinoma portions were significantly reduced in the three raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between the nimesulide alone and placebo groups or between the raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide group, suggesting a lack of cancer preventive effects of the COX-2 inhibitor in this animal model. PCNA positive rates in ventral prostate (VP) and DLP, and androgen receptor (AR) levels in VP were significantly reduced in the three raloxifene-treated groups. Furthermore, circulating testosterone was decreased after raloxifene (10 mg/kg/day) plus nimesulide treatment. These results demonstrate that raloxifene, but not nimesulide, inhibits prostate carcinogenesis in SV40 Tag TG rats associated with a decline in circulating testosterone levels and a loss of AR expression, as well as an inhibition of cell proliferation.", "source": "https://pubmed.ncbi.nlm.nih.gov/15731164/"}
+{"doc_id": "c68e463583257ffddef0e7d4b4325724", "sentence": "Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient .", "spans": [{"span_id": 0, "text": "dolutegravir", "start": 12, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "tenofovir", "start": 45, "end": 54, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient . A 21\u00a0year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay\u00ae) and tenofovir disaproxil fumarate/emtricitabine (Truvada\u00ae) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6\u00a0hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5\u00a0days after the day of intoxication, serum creatinine levels increased to high normal values (1.2\u00a0mg/dl). However, levels never exceeded the upper threshold. 8 and 12\u00a0weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments.", "source": "https://pubmed.ncbi.nlm.nih.gov/26045712/"}
+{"doc_id": "e464e3850c3026b2c1eb5be706e579ad", "sentence": "Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer : a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes .", "spans": [{"span_id": 0, "text": "Abiraterone", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "prednisone", "start": 24, "end": 34, "token_start": 3, "token_end": 4}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer : a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes . The aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes. ### methods This was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- ### results Overall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) \u2a7e 10 ng/ml ( ### conclusions Median PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series.", "source": "https://pubmed.ncbi.nlm.nih.gov/29383035/"}
+{"doc_id": "9e60e1297fe1d1a7991c6c60ce881374", "sentence": "Nivolumab plus ipilimumab combined therapy is among the most effective therapies for advanced melanoma .", "spans": [{"span_id": 0, "text": "Nivolumab", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "ipilimumab", "start": 15, "end": 25, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Increased serum CCL26 level is a potential biomarker for the effectiveness of anti-PD1 antibodies in patients with advanced melanoma.  Nivolumab plus ipilimumab combined therapy is among the most effective therapies for advanced melanoma . However, this therapy is also associated with a high frequency of immune-related adverse events (irAEs). To avoid such severe irAEs caused by additional administration of anti-CTLA4 antibodies, biomarkers to distinguish responders from non-responders among patients treated with anti-PD1 antibodies are important. The purpose of this study is to evaluate the increased serum levels of CCL11, CCL24, and CCL26 as a predictive biomarker for the efficacy of anti-PD1 antibodies in advanced cutaneous melanoma patients. This study analyzed increased serum levels of CCL11, CCL24, and CCL26 in 46 cases of advanced cutaneous melanoma treated with anti-PD1 antibodies. Serum levels on day 42 were compared to baseline (day 0) and analyzed statistically. Receiver operating characteristic curves were established to evaluate the correlation between serum levels of CCL11, CCL24, and CCL26 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 correlated significantly with the efficacy of anti-PD1 antibodies. In contrast, no significant correlations were seen between increased serum levels of CCL11 and CCL24 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 may be a useful biomarker for identifying those patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/32658051/"}
+{"doc_id": "615fe37e6e298fc0bc25eabe90123940", "sentence": "Cells that were sequentially exposed to rapamycin and topotecan had significantly higher levels of cleaved caspase-8 , -3 , and PARP compared to those treated with topotecan alone .", "spans": [{"span_id": 0, "text": "rapamycin", "start": 40, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "topotecan", "start": 54, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "topotecan", "start": 164, "end": 173, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Rapamycin-topotecan combination exhibited enhanced antitumor efficacy compared to topotecan used alone in cisplatin-resistant ovarian cancer cells. The present study aimed to investigate the antitumor efficacy of combination of topotecan with rapamycin, a\u00a0mTOR inhibitor, in cisplatin-resistant ovarian cancer cells A2780cis and COC1/DDP. Expressions of mTOR and its target molecules p70S6K and 4E-BP1 were determined in A2780cis and COC1/DDP and the parental cells A2780 and COC1 that are sensitive to cisplatin using Western blotting. Cell proliferation was examined using MTT assay in vitro and a\u00a0nude mouse model in vivo, respectively. Cell apoptosis and the relevant proteins were determined by flow cytometry and Western blotting. We found that the levels of phosphorylated mTOR, p70S6K, and 4E-BP1 were obviously higher in A2780cis and COC1/DDP cells than that in A2780 and COC1 cells. Pretreatment with rapamycin significantly enhanced the effects of topotecan in suppressing cell proliferation and soliciting cell apoptosis in A2780cis and COC1/DDP cells. Cells that were sequentially exposed to rapamycin and topotecan had significantly higher levels of cleaved caspase-8 , -3 , and PARP compared to those treated with topotecan alone . Mice co-administered rapamycin and topotecan had significantly decreased terminal tumor burden without additional loss of bodyweight compared to the mice received topotecan alone. The results suggested that rapamycin sensitized A2780cis and COC1/DDP cells to topotecan-induced apoptosis and rapamycin-topotecan combination might have a\u00a0value in treatment of cisplatin-resistant ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/26278147/"}
+{"doc_id": "cc4118b0a9d2cafa211a84e7363516a0", "sentence": "No cross-resistance was found with conventional drugs , being PNU-159548 active also in cells resistant to doxorubicin and with a multidrug resistance phenotype ( associated with MDR1 gene/P-glycoprotein overexpression ) , as well as in cells resistant to methotrexate or to cisplatin .", "spans": [{"span_id": 0, "text": "PNU-159548", "start": 62, "end": 72, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "doxorubicin", "start": 107, "end": 118, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "methotrexate", "start": 256, "end": 268, "token_start": 38, "token_end": 39}, {"span_id": 3, "text": "cisplatin", "start": 275, "end": 284, "token_start": 41, "token_end": 42}], "rels": [], "paragraph": "4-Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a promising new candidate for chemotherapeutic treatment of osteosarcoma patients. The effectiveness of the alkycycline 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548, ladirubicin), a new drug with high antitumour activity against a broad range of neoplasms, was evaluated by using a panel of 32 human osteosarcoma cell lines, including cell lines resistant to doxorubicin, methotrexate, or cisplatin. PNU-159548 resulted to be highly active in all cell lines. No cross-resistance was found with conventional drugs , being PNU-159548 active also in cells resistant to doxorubicin and with a multidrug resistance phenotype ( associated with MDR1 gene/P-glycoprotein overexpression ) , as well as in cells resistant to methotrexate or to cisplatin . Analysis of drug-drug interactions showed that PNU-159548 could be successfully used in combination with all the most important drugs currently used in OS chemotherapy. In fact, the simultaneous administration of PNU-159548 and doxorubicin, methotrexate, or cisplatin produced mostly additive or synergistic effects. Sequential exposure to PNU-159548 followed immediately by doxorubicin, methotrexate, or cisplatin was the most effective sequence of administration, invariably resulting in additive or synergistic effects in both drug-sensitive and drug-resistant osteosarcoma cell lines. In conclusion, the high in vitro effectiveness, the absence of cross-resistance with doxorubicin, methotrexate, or cisplatin and the possibility to be successfully used in combination with these drugs indicate PNU-159548 as a promising candidate to be considered for planning new therapeutic regimens for osteosarcoma patients, who show a decreased response to conventional chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/16140527/"}
+{"doc_id": "61e5eaac10e21ebad5a2d5e91724cf19", "sentence": "Synergistic cytotoxic effects of recombinant human tumor necrosis factor and Etoposide ( VP16 ) or Doxorubicin on A2774 human epithelial ovarian cancer cell line .", "spans": [{"span_id": 0, "text": "human tumor necrosis factor", "start": 45, "end": 72, "token_start": 5, "token_end": 9}, {"span_id": 1, "text": "Etoposide", "start": 77, "end": 86, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "Doxorubicin", "start": 99, "end": 110, "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}], "paragraph": "Synergistic cytotoxic effects of recombinant human tumor necrosis factor and Etoposide ( VP16 ) or Doxorubicin on A2774 human epithelial ovarian cancer cell line . Recombinant human tumor necrosis factor (rHuTNF) is a cytokine, with some antitumor activity, released by stimulated monocytes-macrophages. In vivo and in vitro cytotoxicity studies testing the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents have been carried out. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone or in combination with etoposide (VP16) or doxorubicin (Doxo), some topoisomerase II (Topo II) targeted drugs, or in combination with cisplatin (CDDP), a not Topo II interactive drug. Our results suggest that rHuTNF is directly cytotoxic and that it is also able to induce a potentiation of VP16- or Doxo-cytotoxicity, but it is unable to potentiate CDDP-cytotoxicity. These data represent a reasonable basis for combining rHuTNF with Topo II inhibitors within phase I studies. The combination regimen could be tested in ovarian cancer patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/11576250/"}
+{"doc_id": "1ab76019645a31da3b0448dcf00362c3", "sentence": "Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin ( p \uff1c 0.0001 ) and the quinolones nalidixic acid ( p\uff1d0.004 ) and ciprofloxacin ( p \uff1c 0.0001 ) than non-producers .", "spans": [{"span_id": 0, "text": "gentamicin", "start": 70, "end": 80, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "nalidixic", "start": 115, "end": 124, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "ciprofloxacin", "start": 146, "end": 159, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia. The purpose of this study was to investigate extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilities, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC)-typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin ( p \uff1c 0.0001 ) and the quinolones nalidixic acid ( p\uff1d0.004 ) and ciprofloxacin ( p \uff1c 0.0001 ) than non-producers . In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL-producing E. coli ST617 appear to have spread to Indonesia.", "source": "https://pubmed.ncbi.nlm.nih.gov/28003592/"}
+{"doc_id": "6d1750301095d2936cc280ebf081c991", "sentence": "The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine .", "spans": [{"span_id": 0, "text": "topotecan", "start": 18, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "amlodipine", "start": 88, "end": 98, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Effect of stealthy liposomal topotecan plus amlodipine on the multidrug-resistant leukaemia cells in vitro and xenograft in mice. Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy as the over-expressed MDR protein acts as an efflux pump, which leads to a reduction in the uptake of the anticancer agent by tumour cells. We combined topotecan and amlodipine together into the stealthy liposomes, in which amlodipine was applied as a MDR reversing agent to overcome the resistance. ### Materials And Methods Cytotoxicity, apoptosis and the signalling pathway assays were performed on human chronic myelogenous leukaemia K562, promyelocytic leukaemia HL-60 and MDR HL-60 cells, respectively. Pharmacokinetics and antitumour activity studies were performed on normal Kunming mice and female BALB/c nude mice with MDR HL-60 xenografts, respectively. ### results topotecan alone was effective in inhibiting the growth of non-resistant leukaemia cells, K562 and HL-60 cells but not the growth of MDR HL-60 cells. The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine . Moreover, amlodipine enhanced the apoptosis-inducing effect of topotecan synergistically. Apoptosis was through activating caspases in a cascade: first, the initiator caspase 8 and then effectors caspase 3/7 (total activity of caspases 3 and 7) were activated. Being encapsulated into the stealthy liposomes with an acidic internal medium, topotecan existed dominantly in an active lactone species, which was reversibly changed from an inactive carboxylate form via a pH-dependent reaction. After administration of stealthy liposomes to mice, the blood exposure of the lactone form was evidently increased and extended. The antitumour effects in the MDR HL-60 xenografted tumour were stealthy liposomal topotecan (SLT) plus amlodipine > SLT > un-encapsulated topotecan > blank control. ### conclusions The enhanced antitumour activity in the MDR HL-60 cells by the SLT plus amlodipine could be owing to multiple reasons: (a) synergistic apoptosis inducing effect, (b) reversing MDR by amlodipine and (c) increasing the availability of active lactone of topotecan by the stealthy liposomes. The apoptosis induced by amlodipine is through caspase 8 and then the 3/7 signalling pathway.", "source": "https://pubmed.ncbi.nlm.nih.gov/16684125/"}
+{"doc_id": "afc15f1af9a6d595687c65bfe26bec27", "sentence": "In separate studies , the electrocardiogram ( ECG ) and cardiovascular effects of loratadine ( 30 and 100 mg/kg , i.v . ) , terfenadine ( 10 mg/kg , i.v . ) , promethazine ( 5 mg/kg , i.v . ) and diphenhydramine ( 20 mg/kg , i.v . ) were evaluated .", "spans": [{"span_id": 0, "text": "loratadine", "start": 82, "end": 92, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "terfenadine", "start": 124, "end": 135, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "promethazine", "start": 159, "end": 171, "token_start": 33, "token_end": 34}, {"span_id": 3, "text": "diphenhydramine", "start": 196, "end": 211, "token_start": 42, "token_end": 43}], "rels": [], "paragraph": "Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea-pigs. Sedation limits the clinical utility of classical H1 antihistamines, while newer antihistamines such as loratadine and terfenadine are non-sedating. However, clinical use of the terfenadine has been associated with rare but severe cardiac arrhythmias, in particular torsades de pointes. ### objective To establish a quantitative experimental model for assessing the sedating and cardiotoxicity potential of non-sedating and sedating antihistamines. ### methods Drugs were administered intravenously and the integrated amplitude of the cortical electroencephalogram (EEG) signal was recorded. The threshold dose that depressed EEG activity was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by 10 micrograms/kg i.v., of histamine. In separate studies , the electrocardiogram ( ECG ) and cardiovascular effects of loratadine ( 30 and 100 mg/kg , i.v . ) , terfenadine ( 10 mg/kg , i.v . ) , promethazine ( 5 mg/kg , i.v . ) and diphenhydramine ( 20 mg/kg , i.v . ) were evaluated . ### results The sedating antihistamines, diphenhydramine and promethazine, depressed the integrated EEG at doses between 0.6 and 2.0 times their peripheral antihistamine doses. loratadine had no EEG depressant activity at 100 mg/kg, i.v., a dose more than 170 times its ED50 (0.58 mg/kg, i.v.) against histamine bronchospasm. We were unable to evaluate the EEG effects of terfenadine, because it produced cardiovascular collapse at 10 mg/kg, i.v. loratadine and promethazine did not produce adverse cardiovascular effects, nor did they alter normal ECG activity. diphenhydramine produced bradycardia followed by a transient hypertensive phase without affecting the QTc interval. In contrast, terfenadine elicited hypotension, bradycardia and significant arrhythmogenic activity, causing a prolongation of the QTc interval and a torsades de pointes--like ventricular arrhythmia. Pharmacokinetic studies after i.v. administration of loratadine (30 and 100 mg/kg) demonstrated plasma levels of loratadine and its major metabolite descarboethoxyloratadine to be several orders of magnitude greater than levels found in humans at the clinical dose of 10 mg. ### conclusion The CNS depressant effects of H1 antihistamines are promethazine approximately diphenhydramine >> loratadine = placebo. Of the non-sedating antihistamines, loratadine was devoid of adverse cardiovascular effects whereas terfenadine caused a pronounced disruption of the normal ECG, characterized by a torsades de pointes-like effect.", "source": "https://pubmed.ncbi.nlm.nih.gov/8556569/"}
+{"doc_id": "2e896861e22edcf2d90edc62272567a9", "sentence": "[ Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer -- comparative study of treatment with 2 and 4 cycles ] .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 68, "end": 78, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "paclitaxel", "start": 84, "end": 94, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer -- comparative study of treatment with 2 and 4 cycles ] . Neoadjuvant chemotherapy of epirubicin plus paclitaxel was administered to 75 patients (including a 2-cycle group of 39 patients and a 4-cycle group of 36 patients) with locally advanced breast cancer (35 cases of stage IIb, 28 of stage IIIa, 12 of stage IIIb) to compare efficacy and toxicity of 2 cycle and 4 cycle regimens. All patients were female. They were treated with epirubicin 60 mg/m2, on day 1, by i.v., followed by paclitaxel 150 mg/m2, by 3 hour continuous infusion on day 2 repeated every 3 weeks. Premedication with dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteritic and allergic reactions before chemotherapy. Thirty-nine patients were given 2 cycles and thirty-six were given 4 cycles of this regimen. One of 39 patients had complete response, 28 had partial response and 10 had no change in the 2-cycle group. In addition, 21 of 36 patients had complete response (including 9 who had pathologic complete response), 13 had partial response and 2 had no change. The response rates were 74% (29/39) in the 2-cycle group and 94% (34/36) in the 4-cycle group. There were no progressive disease in these 2 groups. However a higher proportion of PR was observed in stage II patients than in stage III patients. Twelve of 36 patients underwent breast conserving surgery, as tumor size had become smaller and down-staging was realized after neoadjuvant chemotherapy. In addition, axillary lymph nodes were palpable in all 75 patients before neoadjuvant chemotherapy with the ET regimen. But 46% (18/39) in the 2-cycle group and 75% (27/36) in the 4-cycle group became impalpable. Conversely, major toxicities (including leukopenia and gastroenteric reactions) were similar in both groups, but myalgia, arthralgia, neurotoxicity and alopecia were more severe in the 4-cycle group than in the 2-cycle group. In the present study, neoadjuvant chemotherapy with a 4-cycle ET regimen was more effective than with a 2-cycle regimen in down staging locally advanced breast cancer. Although major toxicities were more severe in the 4-cycle group than in the 2-cycle group, the regimen was tolerable and safe.", "source": "https://pubmed.ncbi.nlm.nih.gov/14997752/"}
+{"doc_id": "5933f7af6df7dcb19a1acf8b3630c4dd", "sentence": "When systemically active chemotherapy doses were reached , further dose escalation was discontinued , and a phase II dose-range was established ( pemetrexed 500 mg/m(2 ) and carboplatin AUC = 5 - 6 ) .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 146, "end": 156, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "carboplatin", "start": 174, "end": 185, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A phase I study of pemetrexed, carboplatin, and concurrent radiotherapy in patients with locally advanced or metastatic non-small cell lung or esophageal cancer. The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. ### Experimental Design Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m(2)); regimen 2 was pemetrexed (500 mg/m(2)) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). ### results Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m(2)). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m(2); AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached , further dose escalation was discontinued , and a phase II dose-range was established ( pemetrexed 500 mg/m(2 ) and carboplatin AUC = 5 - 6 ) . ### conclusions The combination of pemetrexed (500 mg/m(2)) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/17255273/"}
+{"doc_id": "ae5a3d41fe6197db7a7fa13e47a8af4f", "sentence": "Increased dose density is feasible : a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel , at 10- or 11-day intervals with filgrastim support in women with breast cancer .", "spans": [{"span_id": 0, "text": "epirubicin", "start": 63, "end": 73, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "cyclophosphamide", "start": 78, "end": 94, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "paclitaxel", "start": 107, "end": 117, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "filgrastim", "start": 152, "end": 162, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Increased dose density is feasible : a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel , at 10- or 11-day intervals with filgrastim support in women with breast cancer . Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. ### Experimental Design Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m(2) epirubicin and 600 mg/m(2) cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m(2) paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 microg s.c. daily) from day 2 to 24 h before the next treatment. ### results Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38 degrees C with absolute neutrophil count <1,000/microL. All febrile neutropenia was during therapy with EC. Other grade 3 toxicities included bone pain, hand and foot syndrome, neuropathy, mucositis, nausea, and vomiting. ### conclusions Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The approximately 30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/17200358/"}
+{"doc_id": "520dc3a18b14a57a368bcd964095071e", "sentence": "Those who test positive are treated with combinations of the following agents : omeprazole , clarithromycin , amoxicillin , tetracycline , and metronidazole .", "spans": [{"span_id": 0, "text": "omeprazole", "start": 80, "end": 90, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "clarithromycin", "start": 93, "end": 107, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "amoxicillin", "start": 110, "end": 121, "token_start": 17, "token_end": 18}, {"span_id": 3, "text": "tetracycline", "start": 124, "end": 136, "token_start": 19, "token_end": 20}, {"span_id": 4, "text": "metronidazole", "start": 143, "end": 156, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Pharmacist-managed Helicobacter pylori clinic. A pharmacist-managed Helicobacter pylori assessment clinic for ambulatory patients is described. The pharmacy service at a 400-bed Veterans Affairs Medical Center established a pharmacist-managed clinic to assess patients who were receiving long-term acid-suppressive medications (histamine H2-receptor antagonists, sucralfate, or omeprazole). Patients with active ulcer disease and those receiving ulcer prophylaxis are screened for the presence of H. pylori. Those who test positive are treated with combinations of the following agents : omeprazole , clarithromycin , amoxicillin , tetracycline , and metronidazole . The pharmacist also may adjust or discontinue acid-suppressive drug regimens. The pharmacist is responsible for ordering all appropriate laboratory tests, monitoring patients for adverse effects, collecting data on patient outcomes, and providing patient education. The clinic provides opportunities for pharmacists to study the clinical effectiveness and pharmacoeconomics of various regimens for treating H. pylori-associated disease and for pharmacy students and residents to interact with patients. As of fall 1994, 20 patients had been evaluated at the clinic: 12 tested positive for H. pylori and were treated with antimicrobials and all were pain-free without medication at the end of treatment. An H. pylori assessment clinic enabled pharmacists to assume a primary care role, document improvement in patient outcomes, and study the effectiveness of various antimicrobial regimens.", "source": "https://pubmed.ncbi.nlm.nih.gov/12879545/"}
+{"doc_id": "2f4440a6312f23fd7a3100bd25f39c1e", "sentence": "Patients can be treatment-na\u00efve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC ( ie , abiraterone or enzalutamide ) without evidence of progression at enrolment , and with no prior chemotherapy for mCRPC .", "spans": [{"span_id": 0, "text": "abiraterone", "start": 111, "end": 122, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "enzalutamide", "start": 126, "end": 138, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). ### Methods And Analysis Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-na\u00efve for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC ( ie , abiraterone or enzalutamide ) without evidence of progression at enrolment , and with no prior chemotherapy for mCRPC . Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. ### Ethics And Dissemination Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. ### Trial Registration Number NCT02730338.", "source": "https://pubmed.ncbi.nlm.nih.gov/29764892/"}
+{"doc_id": "f99dcdd01f6107affbfbbd94efa2f838", "sentence": "CYP2D6 metabolizes other opioid analgesics , including tramadol , dihydrocodeine , oxycodone and hydrocodone , although they have been less systematically studied .", "spans": [{"span_id": 0, "text": "tramadol", "start": 55, "end": 63, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "hydrocodone", "start": 97, "end": 108, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. codeine is a much weaker agonist at mu opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do not exist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics , including tramadol , dihydrocodeine , oxycodone and hydrocodone , although they have been less systematically studied . It is unclear whether these other pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PM with a history of problems with opioid analgesics. The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM and after the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Large case-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish that CYP2D6 genotyping has clinical relevance in the use of several opioid analgesics.", "source": "https://pubmed.ncbi.nlm.nih.gov/16631290/"}
+{"doc_id": "84a375ec840963d68895d36ecd84f3c3", "sentence": "Atracurium or vecuronium was given for intubation .", "spans": [{"span_id": 0, "text": "Atracurium", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "vecuronium", "start": 14, "end": 24, "token_start": 2, "token_end": 3}], "rels": [], "paragraph": "Prediction of oculocardiac reflex in strabismus surgery using neural networks. Successfully predicting an oculocardiac reflex (OCR) is difficult to achieve despite various proposed maneuvers. The aim of this study was to test the models built up by neural networks to predict the occurrence of OCR during strabismus surgery in children. Premedication was not given. atropine 0.01 mg/kg was medicated just before induction. Induction was performed with fentanyl or ketorolac, followed by propofol. Atracurium or vecuronium was given for intubation . Anesthesia was maintained with O2-N2O with continuous propofol infusion. Chi-square test was performed for induction agents, gender, weight, muscle blockade, repaired muscle, number of repaired muscles, duration of operation to detect any association between the occurrence of OCR and to develop the model of neural networks. The multi-layer perceptron, radial basis function and Bayesian backpropagation network were tested. The occurrence of OCR was significantly associated with gender and repaired muscle (p < 0.05). Gender, repaired muscle and age were considered as input for the multi-layer perceptron, radial basis function and Bayesian backpropagation network. Three neural networks had predicted the same correction rate in the occurrence of OCR as being 87.5% overall among 16 patients' records tested. These models are conceptually different in predicting compared to conventional maneuvers, and have the advantage of testing individually and foretelling the propensity. By comparison neural networks use grouped experiential data and predict OCR by the learning rule. Neural networks require a relatively abundant number of experienced and homogenous patients' records to establish an accurate model. The multi-layer perceptron, radial basis function and Bayesian backpropagation modeling network may be an alternative way, and preferable to vagal tone maneuvers if the associated relationships to the occurrence of OCR are more clearly defined.", "source": "https://pubmed.ncbi.nlm.nih.gov/10412336/"}
+{"doc_id": "76b596dbb2298d1ba4668068b940f4c9", "sentence": "The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine ( ACNU ) .", "spans": [{"span_id": 0, "text": "temozolomide", "start": 122, "end": 134, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "nimustine", "start": 139, "end": 148, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Rad51 and BRCA2--New molecular targets for sensitizing glioma cells to alkylating anticancer drugs. First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O(6)-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Rad51 and BRCA2, and for NHEJ we employed the DNA-PK inhibitor NU7026. We also assessed whether inhibition of poly(ADP)ribosyltransferase (PARP) by olaparib would enhance the killing effect. The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine ( ACNU ) . It did not sensitize to ionizing radiation (IR). The expression of O(6)-methylguanine-DNA methyltransferase (MGMT) abolished all these effects, indicating that O(6)-alkylguanine induced by these drugs is the primary lesion responsible for the formation of DSBs and increased sensitivity of glioma cells following knockdown of Rad51 and BRCA2. Inhibition of DNA-PK only slightly sensitized to temozolomide whereas a significant effect was observed with IR. A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect of temozolomide. The data provides evidence that down-regulation of Rad51 or BRCA2 is a reasonable strategy for sensitizing glioma cells to killing by O(6)-alkylating anti-cancer drugs. The data also provide proof of principle that a triple strategy involving down-regulation of HR, PARP inhibition and MGMT depletion may greatly enhance the therapeutic effect of temozolomide.", "source": "https://pubmed.ncbi.nlm.nih.gov/22073281/"}
+{"doc_id": "be817a111debcf11e63cf8c34861fed7", "sentence": "The systemic treatment in both studies consisted of a four-drug-regimen ( VACA = vincristine , actinomycin D , cyclophosphamide , and adriamycin ; or VAIA = vincristine , actinomycin D , ifosfamide , and adriamycin ) and a total number of four courses , each lasting nine weeks , was recommended by the protocol .", "spans": [{"span_id": 0, "text": "vincristine", "start": 81, "end": 92, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "actinomycin", "start": 95, "end": 106, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "cyclophosphamide", "start": 111, "end": 127, "token_start": 18, "token_end": 19}, {"span_id": 3, "text": "adriamycin", "start": 134, "end": 144, "token_start": 21, "token_end": 22}, {"span_id": 4, "text": "vincristine", "start": 157, "end": 168, "token_start": 26, "token_end": 27}, {"span_id": 5, "text": "actinomycin", "start": 171, "end": 182, "token_start": 28, "token_end": 29}, {"span_id": 6, "text": "ifosfamide", "start": 187, "end": 197, "token_start": 31, "token_end": 32}, {"span_id": 7, "text": "adriamycin", "start": 204, "end": 214, "token_start": 34, "token_end": 35}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}, {"class": "COMB", "spans": [4, 5, 6, 7], "is_context_needed": true}], "paragraph": "Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies. During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. ### Materials And Methods From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen ( VACA = vincristine , actinomycin D , cyclophosphamide , and adriamycin ; or VAIA = vincristine , actinomycin D , ifosfamide , and adriamycin ) and a total number of four courses , each lasting nine weeks , was recommended by the protocol . Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. ### results The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. ### conclusions The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.", "source": "https://pubmed.ncbi.nlm.nih.gov/9788419/"}
+{"doc_id": "a3e9deca9aeff608f039be706f6f2666", "sentence": "Rationale , design , and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive , nonhypercholesterolemic subjects with microalbuminuria ( the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [ PREVEND IT ] ) .", "spans": [{"span_id": 0, "text": "fosinopril", "start": 116, "end": 126, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "pravastatin", "start": 131, "end": 142, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Rationale , design , and baseline characteristics of a trial of prevention of cardiovascular and renal disease with fosinopril and pravastatin in nonhypertensive , nonhypercholesterolemic subjects with microalbuminuria ( the Prevention of REnal and Vascular ENdstage Disease Intervention Trial [ PREVEND IT ] ) . This study describes the rationale, design, and baseline characteristics of a trial to determine whether treatment with fosinopril 20 mg/day and/or pravastatin 40 mg/ day will prevent cardiovascular and renal disease in nonhypertensive (RR <160/100 mm Hg and not using antihypertensive medication) and nonhypercholesterolemic (total cholesterol <8.0 or <5.0 mmol/L in case of previous myocardial infarction and not using lipid lowering medication) men and women with persistent microalbuminuria (urinary albumin excretion >10 mg/L once in an early morning spot urine and 15 to 300 mg/24-hour at least once in two 24-hour urine collections). The Prevention of REnal and Vascular ENdstage Disease Intervention Trial is a single-center, double-blind, randomized, placebo-controlled trial with a 2 x 2 factorial design. The 864 randomized subjects will be monitored for a minimum of 4 years and a maximum of 5 years. The primary efficacy parameter is defined as the combined incidence of all-cause mortality or hospital admission for documented (1) nonfatal myocardial infarction, (2) myocardial ischemia, (3) heart failure, (4) peripheral vascular disease, (5) cerebrovascular accident and/or (6) end-stage renal disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/10980214/"}
+{"doc_id": "8aec468c4b89546f1205d002c2f46ab3", "sentence": "In the present study , rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administration on plasma corticosterone , catecholamine ( epinephrine , norepinephrine and dopamine ) and glucose responses to physical restraint stress .", "spans": [{"span_id": 0, "text": "nicotine", "start": 105, "end": 113, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "epinephrine", "start": 172, "end": 183, "token_start": 26, "token_end": 27}], "rels": [], "paragraph": "Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine. Habitual smokers frequently report that when they are stressed smoking helps them to relax. One potential explanation for the reported stress ameliorating effect of smoking is that cigarette consumption (nicotine self-administration) may decrease the sympathetic autonomic nervous system activity which is associated with the stress response. In the present study , rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administration on plasma corticosterone , catecholamine ( epinephrine , norepinephrine and dopamine ) and glucose responses to physical restraint stress . nicotine (0.025, 0.05 or 0.10 mg nicotine base/kg body weight) was administered for 10 days prior to the \"stress test\" to allow for the development of habituation/tolerance to its acute toxic effects. Independent administration of nicotine, or the application of the physical restraint stressor, resulted in increases in the plasma concentrations of corticosterone, epinephrine, norepinephrine, and glucose. nicotine administration during restraint stress enhanced the increase in plasma corticosterone and epinephrine, as compared to the responses induced by either factor alone. The results suggest that the stress ameliorating effect of continued cigarette smoking, as reported by habitual smokers, is not due to a reduction in the activity of the peripheral sympathetic autonomic nervous system.", "source": "https://pubmed.ncbi.nlm.nih.gov/2505296/"}
+{"doc_id": "2ff60aee3c52628cbf8ef1588d63a2cd", "sentence": "Phase III , randomized , double-blind , multicenter trial comparing orteronel ( TAK-700 ) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy : ELM-PC 5 .", "spans": [{"span_id": 0, "text": "TAK-700", "start": 80, "end": 87, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "prednisone", "start": 95, "end": 105, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "prednisone", "start": 124, "end": 134, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Phase III , randomized , double-blind , multicenter trial comparing orteronel ( TAK-700 ) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy : ELM-PC 5 . Orteronel (tak-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. ### Patients And Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], \u2265 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. ### results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). ### conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.", "source": "https://pubmed.ncbi.nlm.nih.gov/25624429/"}
+{"doc_id": "2696f2ed809244fe4362bf01ba2b9f1b", "sentence": "Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer ( mCRC ) with selection based on methyl-specific PCR ( MSP ) testing with modest results .", "spans": [{"span_id": 0, "text": "temozolomide", "start": 26, "end": 38, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "dacarbazine", "start": 42, "end": 53, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in\u00a0metastatic colorectal cancer patients. O(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer ( mCRC ) with selection based on methyl-specific PCR ( MSP ) testing with modest results . We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment. ### Patients And Methods Formalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS). ### results One hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p\u00a0<\u00a00.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p\u00a0<\u00a00.001) and a 77% in the hazard for death (p\u00a0=\u00a00.001). ### conclusion In mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/27997874/"}
+{"doc_id": "4d616b8b6d114e89d6958f931fe85aaa", "sentence": "Heparin infusion , followed by oral warfarin , is indicated for symptomatic thromboembolic disease as well as for asymptomatic patients with substantial proximal deep venous thrombosis or large pulmonary emboli .", "spans": [{"span_id": 0, "text": "Heparin", "start": 0, "end": 7, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "warfarin", "start": 36, "end": 44, "token_start": 6, "token_end": 7}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Therapy for postoperative thromboembolic disease:  indications and treatment. Postarthroplasty patients develop venous thromboembolic disease because of venous stasis, hypercoaguability, and vessel wall injury.  However, most venous thrombi are nonocclusive or small and elicit few symptoms; pulmonary emboli also tend to be asymptomatic.  Noninvasive techniques to detect deep vein thrombosis do not appear to be reliable in this population, so venography may be required.  Postoperative perfusion lung scans, with comparison to preoperative perfusion scans, are the best screen for asymptomatic pulmonary emboli. Heparin infusion , followed by oral warfarin , is indicated for symptomatic thromboembolic disease as well as for asymptomatic patients with substantial proximal deep venous thrombosis or large pulmonary emboli .", "source": "https://pubmed.ncbi.nlm.nih.gov/10147578/"}
+{"doc_id": "251f5f7c9560eb8b5c97eec74bfe8344", "sentence": "Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug , such as tamoxifen , by decreasing the formation of active metabolites of this drug .", "spans": [{"span_id": 0, "text": "Fluoxetine", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paroxetine", "start": 15, "end": 25, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "tamoxifen", "start": 153, "end": 162, "token_start": 24, "token_end": 25}], "rels": [{"class": "NEG", "spans": [1, 2], "is_context_needed": false}, {"class": "NEG", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Different antidepressant drugs are currently used for the treatment of depression in cancer patients, such as second-generation antidepressants and, recently, the extracts of Hypericum perforatum. These agents are susceptible to metabolically-based drug interactions with anticancer drugs. The aim of the present article is to provide an updated review of clinically relevant metabolic drug interactions between selected anticancer drugs and antidepressants, focusing on selective serotonin reuptake inhibitors (SSRIs) and Hypericum extract. SSRIs can cause pharmacokinetic interactions through their in vitro ability to inhibit one or more cytochrome P450 isoenzymes (CYPs). SSRIs differ in their potential for metabolic drug interactions with anticancer drugs. Fluoxetine and paroxetine are potent inhibitors of CYP2D6 and administration of these SSRIs reduces the clinical benefit of an anticancer drug , such as tamoxifen , by decreasing the formation of active metabolites of this drug . Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, including citalopram, escitalopram, are weak or negligible inhibitors of CYP2D6 and are less likely to interact with anticancer drugs, while sertraline causes significant inhibition of this isoform only at high doses. Hypericum extract, by inducing both the CYP3A4 and the P-glycoprotein (P-gp), can reduce the plasma concentrations of different antineoplastic agents such as imatinib, irinotecan and docetaxel, thus reducing the clinical efficacy of these drugs. Although these interactions are often predictable, the use of fluoxetine, paroxetine and Hypericum extract should be avoided in cancer patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/21395523/"}
+{"doc_id": "81dbb19a67ef1985983527cb474e4352", "sentence": "Epirubicin is an anthracyclin , analogous to doxorubicin , with a different toxicologic pattern .", "spans": [{"span_id": 0, "text": "Epirubicin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "doxorubicin", "start": 45, "end": 56, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "A phase II study evaluating the cisplatin and epirubicin combination in patients with unresectable malignant pleural mesothelioma. Few chemotherapeutic agents have demonstrated their efficacy in malignant mesothelioma. The cisplatin plus doxorubicin combination has one of the highest response rates. Epirubicin is an anthracyclin , analogous to doxorubicin , with a different toxicologic pattern . As there are no data on the activity of the combination cisplatin plus epirubicin in malignant mesothelioma, the European Lung Cancer Working Party (ELCWP) designed a phase II study with response rate as primary objective. Sixty-nine eligible patients with malignant pleural mesothelioma were centrally registered. The majority of the patients were male (n=59), had a Karnofsky performance status of 80 or more (n=62) and presented with an epithelial histologic subtype (n=43). Median age was 62 years. In nine patients, metastases were documented at the initial work-up, mainly in bone, lung and skin. Three hundred and twenty-four cycles of chemotherapy were administered. The main toxicities were nausea and vomiting, neutropenia and alopecia. Among 63 assessable patients, response rate was 19.0% (95% confidence interval [CI] 9-29%). Median survival was 13.3 months. In multivariate analysis, poor prognostic factors for survival were neutrophil count and CALGB groups 4-6. In conclusion, cisplatin plus epirubicin appears as an effective regimen in malignant mesothelioma, with a favourable toxicity profile. However, it does not demonstrate superior activity to other active regimens in this disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/16005104/"}
+{"doc_id": "6370dac70bb6f82f07d67292360f14ad", "sentence": "A total of 460 patients were randomized into four 10-day therapeutic schemes ( 115 patients per group ): ( i ) standard OCA , omeprazole , clarithromycin and amoxicillin ; ( ii ) triple OLA , omeprazole , levofloxacin and amoxicillin ; ( iii ) sequential OACM , omeprazole plus amoxicillin for 5 days , followed by omeprazole plus clarithromycin plus metronidazole for 5 days ; and ( iv ) modified sequential OALM , using levofloxacin instead of clarithromycin .", "spans": [{"span_id": 0, "text": "omeprazole", "start": 126, "end": 136, "token_start": 24, "token_end": 25}, {"span_id": 1, "text": "clarithromycin", "start": 139, "end": 153, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "amoxicillin", "start": 158, "end": 169, "token_start": 28, "token_end": 29}, {"span_id": 3, "text": "omeprazole", "start": 192, "end": 202, "token_start": 36, "token_end": 37}, {"span_id": 4, "text": "levofloxacin", "start": 205, "end": 217, "token_start": 38, "token_end": 39}, {"span_id": 5, "text": "amoxicillin", "start": 222, "end": 233, "token_start": 40, "token_end": 41}, {"span_id": 6, "text": "omeprazole", "start": 262, "end": 272, "token_start": 48, "token_end": 49}, {"span_id": 7, "text": "amoxicillin", "start": 278, "end": 289, "token_start": 50, "token_end": 51}, {"span_id": 8, "text": "omeprazole", "start": 315, "end": 325, "token_start": 57, "token_end": 58}, {"span_id": 9, "text": "clarithromycin", "start": 331, "end": 345, "token_start": 59, "token_end": 60}, {"span_id": 10, "text": "metronidazole", "start": 351, "end": 364, "token_start": 61, "token_end": 62}, {"span_id": 11, "text": "levofloxacin", "start": 422, "end": 434, "token_start": 75, "token_end": 76}, {"span_id": 12, "text": "clarithromycin", "start": 446, "end": 460, "token_start": 78, "token_end": 79}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "POS", "spans": [3, 4, 5], "is_context_needed": true}, {"class": "POS", "spans": [9, 10, 6, 7], "is_context_needed": true}], "paragraph": "Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication. Helicobacter pylori eradication rates with standard triple therapy have declined to unacceptable levels. ### aim To compare clarithromycin and levofloxacin in triple and sequential first-line regimens. ### methods A total of 460 patients were randomized into four 10-day therapeutic schemes ( 115 patients per group ): ( i ) standard OCA , omeprazole , clarithromycin and amoxicillin ; ( ii ) triple OLA , omeprazole , levofloxacin and amoxicillin ; ( iii ) sequential OACM , omeprazole plus amoxicillin for 5 days , followed by omeprazole plus clarithromycin plus metronidazole for 5 days ; and ( iv ) modified sequential OALM , using levofloxacin instead of clarithromycin . Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. ### results Per protocol cure rates were: OCA (66%; 95% CI: 57-74%), OLA (82.6%; 75-89%), OACM (80.8%; 73-88%) and OALM (85.2%; 78-91%). Intention-to-treat cure rates were: OCA (64%; 55-73%), OLA (80.8%; 73-88%), OACM (76.5%; 69-85%) and OALM (82.5%; 75-89%). Eradication rates were lower with OCA than with all the other regimens (P < 0.05). No differences in compliance or adverse effects were demonstrated among treatments. ### conclusions levofloxacin-based and sequential therapy are superior to standard triple scheme as first-line regimens in a setting with high clarithromycin resistance. However, all of these therapies still have a 20% failure rate.", "source": "https://pubmed.ncbi.nlm.nih.gov/20180787/"}
+{"doc_id": "1123d5ef9b6fdeb123b453991b3b6218", "sentence": "Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment .", "spans": [{"span_id": 0, "text": "Captopril", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "HYZ", "start": 30, "end": 33, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "captopril", "start": 166, "end": 175, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Testosterone increases blood pressure and cardiovascular and renal pathology in spontaneously hypertensive rats. The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment .", "source": "https://pubmed.ncbi.nlm.nih.gov/11055476/"}
+{"doc_id": "2f5b79becc8a6e69aaa31e1c49f396d2", "sentence": "Targeted therapy was administered to match the P1K3CA , c-MET , and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib .", "spans": [{"span_id": 0, "text": "sirolimus+", "start": 100, "end": 110, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "crizotinib", "start": 111, "end": 121, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "abraxane+", "start": 126, "end": 135, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "celecoxib", "start": 136, "end": 145, "token_start": 21, "token_end": 22}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine. Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy. ### Patients And Methods Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity\u00ae Pathway Analysis. ### results In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA , c-MET , and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib . In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFR\u03b1 amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFR\u03b1 and TP53 aberrations. Both the patients did not benefit from matched therapy. ### conclusions Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/26510912/"}
+{"doc_id": "6b6df6ff4095a8857ad554d4cf0c8f15", "sentence": "EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival .", "spans": [{"span_id": 0, "text": "ifosfamide", "start": 49, "end": 59, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "etoposide", "start": 64, "end": 73, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "postoperative chemotherapy", "start": 77, "end": 103, "token_start": 12, "token_end": 14}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (\u226510% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. ### methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m ### findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62\u00b71 months (IQR 46\u00b76-76\u00b76); 62\u00b73 months (IQR 46\u00b79-77\u00b71) for the MAP group and 61\u00b71 months (IQR 46\u00b75-75\u00b73) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0\u00b798 [95% CI 0\u00b778-1\u00b723]); hazards were non-proportional (p=0\u00b70003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. ### interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival . The results define standard of care for this population. New strategies are required to improve outcomes in this setting. ### funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.", "source": "https://pubmed.ncbi.nlm.nih.gov/27569442/"}
+{"doc_id": "10147e145cd0bdad159de619cec5c4f7", "sentence": "The focus of this study is to investigate , whether altered expression levels of potentially relevant microRNAs ( miRs ) in serum are associated with response to trastuzumab or lapatinib .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 162, "end": 173, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "lapatinib", "start": 177, "end": 186, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial. trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate , whether altered expression levels of potentially relevant microRNAs ( miRs ) in serum are associated with response to trastuzumab or lapatinib . Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p\u00a0=\u00a05.04e-08, p\u00a0=\u00a01.43e-10), miR-210 (p\u00a0=\u00a00.00151, p\u00a0=\u00a01.6e-05), and miR-373 (p\u00a0=\u00a07.87e-06, p\u00a0=\u00a01.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p\u00a0=\u00a05.73e-08), miR-210 (p\u00a0=\u00a00.000724), and miR-373 (p\u00a0=\u00a00.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p\u00a0<\u00a00.002). An association of miR-21 levels before (p\u00a0=\u00a00.0091) and after (p\u00a0=\u00a00.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21.", "source": "https://pubmed.ncbi.nlm.nih.gov/25086636/"}
+{"doc_id": "94f9dd27429e130f46f205da0891f4d4", "sentence": "These results suggest that the addition of intravenous ceftriaxone during the first 3 days of hospitalization does not improve the cost-efficacy of oral norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding and high risk of infection .", "spans": [{"span_id": 0, "text": "ceftriaxone", "start": 55, "end": 66, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "norfloxacin", "start": 153, "end": 164, "token_start": 23, "token_end": 24}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Parenteral antibiotic prophylaxis of bacterial infections does not improve cost-efficacy of oral norfloxacin in cirrhotic patients with gastrointestinal bleeding. Selective intestinal decontamination with norfloxacin is useful in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding. However, bleeding cirrhotic patients with ascites, encephalopathy, or shock are at high risk to develop bacterial infections in spite of prophylactic norfloxacin. The aim of this study was to assess whether the addition of intravenous ceftriaxone could improve the efficacy of prophylaxis with norfloxacin in these patients. ### methods Fifty-six cirrhotic patients with gastrointestinal hemorrhage and ascites, encephalopathy, or shock were randomized into two groups: Group 1 (n = 28) received oral norfloxacin 400 mg/12 h for 7 days, and group 2 (n = 28) received norfloxacin plus intravenous ceftriaxone 2 g daily during the first 3 days of admission. ### results Ten patients were excluded because of community-acquired infection, surgery, or death within the first 24 h. The incidence of bacterial infections during hospitalization was 18.1% in group 1 and 12.5% in group 2 (p = NS). The incidence of severe infections (spontaneous bacterial peritonitis, bacteremia, or pneumonia) was also similar in both groups: 9% in group 1 versus 8.3% in group 2 (p = NS). There were no statistical differences between the two groups with respect to duration of hospitalization or mortality. The cost of antibiotic therapy (including prophylaxis and treatment of infections) was significantly higher in group 2. ### conclusion These results suggest that the addition of intravenous ceftriaxone during the first 3 days of hospitalization does not improve the cost-efficacy of oral norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding and high risk of infection .", "source": "https://pubmed.ncbi.nlm.nih.gov/9860409/"}
+{"doc_id": "056c7e350cc7a5271279359bfcf3bc9d", "sentence": "However , clindamycin possesses only one of the two mechanisms of lincomycin action , which is bacteriostatic , against Escherichia coli .", "spans": [{"span_id": 0, "text": "clindamycin", "start": 10, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "lincomycin", "start": 66, "end": 76, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Microbial kinetics of drug action against gram-positive and gram-negative organisms. III: Effect of lincomycin and clindamycin combinations on Staphylococcus aureus and Escherichia coli. The functional dependencies of apparent first-order generation rate constants kapp, of drug-affected cultures on drug concentrations indicate that lincomycin and clindamycin possess the same mechanism of action, which is bacteriostatic, against Staphylococcus aureus. clindamycin also possesses another mechanism of action, which is bactericidal, at high concentration levels. However , clindamycin possesses only one of the two mechanisms of lincomycin action , which is bacteriostatic , against Escherichia coli . The relative potency of action of a clindamycin-lincomycin combination against Staph. aureus is variable, and the effective ratio ranges between 5:1 and 9:1; the effective ratio against E. coli is fixed at 6:1 over a wide concentration range. This difference is attributed to differences in bioavailability and/or binding characteristics of the drugs for bioreceptors, as a consequence of structural modifications in the drug molecules, and to differences in modes of action in the respective organisms. Mixtures containing equipotent fractions of clindamycin and lincomycin show \"equivalence\" or \"indifference\" of effects on Staph. aureus. The combined action of the mixtures can be quantitatively predicted from the separate dose-response curves of either component drug alone. Therefore, it is concluded that clindamycin and lincomycin may bind to the same receptor site that is engaged in microbial protein synthesis to inhibit the generation of Staph. aureus. However, combinations of clindamycin and lincomycin are less active than the a priori equipotent concentration of either drug alone in their action against E. coli, demonstrating unequivocally an antagonism of effects. Furthermore, the degree of antagonism is dependent on the order of addition of the drugs, which is attributed to the possibility that clindamycin and lincomycin bind differently on active and allosteric loci of the same receptor site functionally engaged in protein synthesis in E. coli. A rational approach to the quantification and prediction of combined antibiotic action must, therefore, be based not only on the kinetics and mechanisms of action as well as on the dose-response relationship over a wide concentration range for the separate antibiotics but also on the strain and species of the test organism.", "source": "https://pubmed.ncbi.nlm.nih.gov/1102659/"}
+{"doc_id": "64f929edb877af3cddf0c724ad66a1ba", "sentence": "This study evaluated the response rate of the combination therapy of aprinocarsen , gemcitabine , and carboplatin in previously untreated patients with advanced non-small cell lung cancer ( NSCLC ) .", "spans": [{"span_id": 0, "text": "aprinocarsen", "start": 69, "end": 81, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "gemcitabine", "start": 84, "end": 95, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "carboplatin", "start": 102, "end": 113, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase II study of PKC-alpha antisense oligonucleotide aprinocarsen in combination with gemcitabine and carboplatin in patients with advanced non-small cell lung cancer. The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen , gemcitabine , and carboplatin in previously untreated patients with advanced non-small cell lung cancer ( NSCLC ) . Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/16507327/"}
+{"doc_id": "e227b7bceedb8122b04c7d13e3ee098c", "sentence": "All patients were treated by surgical debridement followed by a combination of antibiotics ; ( ceftazidime , amoxy-clavulanic acid , co-trimoxazole and doxycycline ) for six months except for one who died due to fulminant septicemia .", "spans": [{"span_id": 0, "text": "ceftazidime", "start": 95, "end": 106, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "amoxy-clavulanic", "start": 109, "end": 125, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "co-trimoxazole", "start": 133, "end": 147, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "doxycycline", "start": 152, "end": 163, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Burkholderia pseudomallei musculoskeletal infections (melioidosis) in India. Melioidosis, an infection due to gram negative Burkholderia pseudomallei, is an important cause of sepsis in east Asia especially Thailand and northern Australia. It usually causes abscesses in lung, liver, spleen, skeletal muscle and parotids especially in patients with diabetes, chronic renal failure and thalassemia. Musculoskeletal melioidosis is not common in India even though sporadic cases have been reported mostly involving soft tissues. During a two-year-period, we had five patients with musculoskeletal melioidosis. All patients presented with multifocal osteomyelitis, recurrent osteomyelitis or septic arthritis. One patient died early because of septicemia and multi-organ failure. All patients were diagnosed on the basis of positive pus culture. All patients were treated by surgical debridement followed by a combination of antibiotics ; ( ceftazidime , amoxy-clavulanic acid , co-trimoxazole and doxycycline ) for six months except for one who died due to fulminant septicemia . All other patients recovered completely with no recurrences. With increasing awareness and better diagnostic facilities, probably musculoskeletal melioidosis will be increasingly diagnosed in future.", "source": "https://pubmed.ncbi.nlm.nih.gov/20419012/"}
+{"doc_id": "6d21b8fb44aec53cfdf566e8d7e95b68", "sentence": "To evaluate the eradication of Helicobacter pylori by therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin .", "spans": [{"span_id": 0, "text": "lansoprazole", "start": 90, "end": 102, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "clarithromycin", "start": 114, "end": 128, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Dual therapy with lansoprazole and clarithromycin for eradication of Helicobacter pylori.  To evaluate the eradication of Helicobacter pylori by therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin . ### Patients And Methods In an open therapeutic trial, 30 H. pylori-positive patients with active ulcer disease took 30 mg lansoprazole twice a day and 400 mg clarithromycin twice a day for the first 2 weeks, followed by 30 mg lansoprazole once a day for 4-6 weeks. Endoscopy was performed both before and at the end of therapy, and 4 weeks after the end of the therapy. H. pylori was detected by using a combination of smear, culture and tissue sections. ### results Complete pain relief occurred within 3 days in all patients and all ulcers were healed by the end of the therapy. The H. pylori clearance rate was 83.3% and the eradication rate was 73.3%. A minor side effect (metallic taste) was reported by only one patient (3.3%). ### conclusions Therapy with a combination of 60 mg lansoprazole and 800 mg clarithromycin is efficacious in the eradication of H. pylori and has the advantage of a low incidence of side effects and quick pain relief for patients with active ulcers.", "source": "https://pubmed.ncbi.nlm.nih.gov/8574739/"}
+{"doc_id": "91620a03f158f1956c52f44f1dcf437d", "sentence": "All patients were treated with vincristine , doxorubicin , cyclophosphamide and actinomycin-D , alternating with ifosfamide and etoposide every 3 weeks .", "spans": [{"span_id": 0, "text": "vincristine", "start": 31, "end": 42, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "doxorubicin", "start": 45, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "cyclophosphamide", "start": 59, "end": 75, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "actinomycin-D", "start": 80, "end": 93, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "ifosfamide", "start": 113, "end": 123, "token_start": 15, "token_end": 16}, {"span_id": 5, "text": "etoposide", "start": 128, "end": 137, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "Extraskeletal Ewing's sarcoma family of tumors in adults: prognostic factors and clinical outcome. The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. ### methods Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. ### results The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine , doxorubicin , cyclophosphamide and actinomycin-D , alternating with ifosfamide and etoposide every 3 weeks . In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size \u2265 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 \u2265 cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ### conclusions Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma.", "source": "https://pubmed.ncbi.nlm.nih.gov/22416252/"}
+{"doc_id": "512ff22c22b6761f2530a2a9e49dbf3c", "sentence": "We identified 49 and 220 patients treated with sorafenib and sunitinib , respectively , as first-line therapy in the Asan Medical Centre from April 2005 to March 2011 .", "spans": [{"span_id": 0, "text": "sorafenib", "start": 47, "end": 56, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "sunitinib", "start": 61, "end": 70, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. This study investigated the efficacy and toxicity of sorafenib and sunitinib as primary treatment for patients with metastatic renal cell carcinoma (mRCC). ### methods We identified 49 and 220 patients treated with sorafenib and sunitinib , respectively , as first-line therapy in the Asan Medical Centre from April 2005 to March 2011 . ### results Disease control rates of 71 and 74% were achieved with sorafenib and sunitinib, respectively (p = 0.687). After a median follow-up of 27.6 months, progression-free survival (PFS) and overall survival (OS) were not significantly different between the sorafenib and the sunitinib group (PFS 8.6 vs. 9.9 months, respectively, p = 0.948, and OS 25.7 vs. 22.6 months, p = 0.774). Patients treated with sorafenib required dose reduction due to toxicities less frequently than those treated with sunitinib (37 vs. 54%, p = 0.034). Haematological toxicity of grade 3 or 4 was more common in the sunitinib group than in the sorafenib group (45 vs. 4%, p < 0.001). Multivariate analysis showed old age, Heng's risk group, and bone and liver metastases, but not the type of vascular endothelial growth factor tyrosine kinase inhibitor, were independent prognostic factors affecting OS. ### conclusion The results of this study indicate that sorafenib has comparable efficacy to sunitinib in the treatment of mRCC patients and fewer and less severe toxicities, but the number of patients included in the study was small.", "source": "https://pubmed.ncbi.nlm.nih.gov/23548259/"}
+{"doc_id": "f14c3c8dadbef1d8912067d367d600b3", "sentence": "We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer .", "spans": [{"span_id": 0, "text": "pemetrexed", "start": 30, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "cetuximab", "start": 77, "end": 86, "token_start": 12, "token_end": 13}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer.  We studied the combination of pemetrexed , a multi-targeted antifolate , and cetuximab , an mAb against the epidermal growth factor receptor , with radiotherapy in poor prognosis head and neck cancer . ### Patients And Methods Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. ### results Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. ### conclusion The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/21363880/"}
+{"doc_id": "e0cba36b58781c2288d8448732651b68", "sentence": "Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice .", "spans": [{"span_id": 0, "text": "darunavir", "start": 9, "end": 18, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "ritonavir", "start": 24, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "cobicistat", "start": 50, "end": 60, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "darunavir", "start": 81, "end": 90, "token_start": 12, "token_end": 13}, {"span_id": 4, "text": "etravirine", "start": 114, "end": 124, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [3, 4], "is_context_needed": false}], "paragraph": "Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. ### methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150\u2009mg once daily (DRV cohort; n\u2009=\u200915) or etravirine 400\u2009mg once daily (ETR cohort; n\u2009=\u200915). etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. ### results etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. ### conclusions Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice .", "source": "https://pubmed.ncbi.nlm.nih.gov/29237008/"}
+{"doc_id": "6281f828d97fd01753786d649998ee0f", "sentence": "Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer ( ABC ) non-responsive to hormone therapy and without visceral crisis .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 13, "end": 23, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "vinorelbine", "start": 28, "end": 39, "token_start": 3, "token_end": 4}], "rels": [], "paragraph": "Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial).  Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer ( ABC ) non-responsive to hormone therapy and without visceral crisis . This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. ### methods Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80\u202fmg/m ### results The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. ### conclusion Oral vinorelbine and paclitaxel demonstrated similar DCRs (\u223c75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).", "source": "https://pubmed.ncbi.nlm.nih.gov/30802822/"}
+{"doc_id": "f2c019857efd32ae3b64a68ef6a2ecd0", "sentence": "Nal-IRI with 5-fluorouracil ( 5-FU ) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial ( AIO-YMO HEP-0315 )", "spans": [{"span_id": 0, "text": "5-fluorouracil", "start": 13, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "leucovorin", "start": 41, "end": 51, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "gemcitabine", "start": 55, "end": 66, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "cisplatin", "start": 72, "end": 81, "token_start": 11, "token_end": 12}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Nal-IRI with 5-fluorouracil ( 5-FU ) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial ( AIO-YMO HEP-0315 ) Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7\u2009months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. ### methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2\u2009\u00d7\u200946 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m ### discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. ### Trial Registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.", "source": "https://pubmed.ncbi.nlm.nih.gov/31646981/"}
+{"doc_id": "3d1b9b7ba6eec890228902c4011a7d7f", "sentence": "Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective , whereas only one dropped out of the budesonide group .", "spans": [{"span_id": 0, "text": "terbutaline", "start": 37, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "budesonide", "start": 140, "end": 150, "token_start": 21, "token_end": 22}], "rels": [], "paragraph": "Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. The presence of airway inflammation even in mild asthma points to the potential value of antiinflammatory therapy. We compared the effect of an inhaled corticosteroid, budesonide, with that of an inhaled beta 2-agonist, terbutaline, in the long-term treatment of newly detected asthma. ### methods We studied 103 patients (29 male and 74 female patients 15 to 64 years old) in whom asthma had appeared within the previous year. The patients were randomly assigned in blinded fashion to two treatment groups: one to receive 600 micrograms of inhaled budesonide twice a day, and the other to receive 375 micrograms of inhaled terbutaline twice a day. The study period was two years. ### results After six weeks of treatment, the patients treated with budesonide tolerated inhaled histamine better than the patients treated with terbutaline (a difference of one doubling dose step, P less than 0.001), and the difference was sustained. Patients' diaries kept during the first three months of the study and during the last month of the first and second years showed budesonide to be more effective than terbutaline in improving peak expiratory flow in the morning (average increase from the pretreatment value, 32.8 liters per minute for budesonide vs. 4.8 liters per minute for terbutaline; P less than 0.001) and in the evening (P less than 0.01). budesonide was also more effective in reducing the symptoms of asthma (P less than 0.01) and the use of supplemental beta 2-agonist medication (P less than 0.01). Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective , whereas only one dropped out of the budesonide group . The adverse reactions to both treatments were few and mild. ### conclusions Antiinflammatory therapy with inhaled budesonide is an effective first-line treatment for patients with newly detected, mild asthma, and it is superior to the use of terbutaline in such patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/2062329/"}
+{"doc_id": "d2ab326fb295d3755d481670624d8d1a", "sentence": "We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years , to compare the pain control effects of a single oral dose of two analgesic compounds ( drug A : propyphenazone mg 250 , ethylmorphine mg 5 , caffeine mg 5 ; drug B : dipyrone mg 500 , diphenhydramine mg 12.5 , adiphenine mg 5 , ethyl aminobenzoate mg 2.5 ) in an experimental pain model using stimulation of dental pulp .", "spans": [{"span_id": 0, "text": "propyphenazone", "start": 186, "end": 200, "token_start": 35, "token_end": 36}, {"span_id": 1, "text": "ethylmorphine", "start": 210, "end": 223, "token_start": 39, "token_end": 40}, {"span_id": 2, "text": "caffeine", "start": 231, "end": 239, "token_start": 43, "token_end": 44}, {"span_id": 3, "text": "dipyrone", "start": 256, "end": 264, "token_start": 50, "token_end": 51}, {"span_id": 4, "text": "diphenhydramine", "start": 274, "end": 289, "token_start": 54, "token_end": 55}, {"span_id": 5, "text": "adiphenine", "start": 300, "end": 310, "token_start": 58, "token_end": 59}, {"span_id": 6, "text": "aminobenzoate", "start": 324, "end": 337, "token_start": 63, "token_end": 64}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [3, 4, 5, 6], "is_context_needed": true}], "paragraph": "[Electric stimulation of the dental pulp in the evaluation of the central effect of analgesics].  We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years , to compare the pain control effects of a single oral dose of two analgesic compounds ( drug A : propyphenazone mg 250 , ethylmorphine mg 5 , caffeine mg 5 ; drug B : dipyrone mg 500 , diphenhydramine mg 12.5 , adiphenine mg 5 , ethyl aminobenzoate mg 2.5 ) in an experimental pain model using stimulation of dental pulp . Constant voltage stimuli were delivered through silver chloride electrodes placed in contact with the vestibular surface of the upper medial incisor. At the beginning of the session, the pain input was graded by asking the subject to identify the weakest stimulus perceived (threshold level) and the strongest stimulus endurable (tolerance level). The range between threshold and tolerance level was divided in nine steps plus a subliminal step. The ten steps were delivered randomly, and each series of steps was repeated eight times. The subjects were instructed to rate the pain sensation in an arbitrary scale of 5 degrees. The procedure was repeated at 60 min and 180 min after drug administration. Each subject received two tablets of drug A or drug B in two different sessions at weekly intervals. Statistical analysis of the procedures showed that neither drug A nor drug B significantly affected the pain threshold. Drug A significantly reduced the total pain score (P less than 0.01) and its action peaked 60 min after administration.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/1979494/"}
+{"doc_id": "dbd8e4b1986c862f4f6959bc01ba9a08", "sentence": "Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study .", "spans": [{"span_id": 0, "text": "cetuximab", "start": 39, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "panitumumab", "start": 52, "end": 63, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Hypomagnesemia is a reliable predictor for efficacy of anti-EGFR monoclonal antibody used in combination with first-line chemotherapy for metastatic colorectal cancer. Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy. ### methods Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study . All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events. ### results The incidence rates of hypomagnesemia and acneiform rash were 32.6\u00a0% (grade 1: 20.9\u00a0%, grade 2: 11.6\u00a0%) and 93.0\u00a0% (grade 1: 41.9\u00a0%, grade 2: 41.9\u00a0%, grade 3: 9.3\u00a0%), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5\u00a0%, P\u00a0=\u00a00.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash. ### conclusion Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/27106835/"}
+{"doc_id": "34d2058b1f46a61ed6efa1e0d2cc049f", "sentence": "Furthermore , 11 AML patients at primary diagnosis , including five AML patients with P-gp overexpression , who were treated with idarubicin , vepesid , and cytarabine V ( ara-C ) showed a complete remission .", "spans": [{"span_id": 0, "text": "idarubicin", "start": 130, "end": 140, "token_start": 21, "token_end": 22}, {"span_id": 1, "text": "vepesid", "start": 143, "end": 150, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "cytarabine", "start": 157, "end": 167, "token_start": 26, "token_end": 27}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Clinical importance of P-glycoprotein-related resistance in leukemia and myelodysplastic syndromes--first experience with their reversal. P-glycoprotein (P-gp) expression in mononuclear bone marrow cells was analyzed in 119 patients, including 60 with chronic myelogenous leukemia (CML), 48 with myelodysplastic syndromes (MDS), and 11 with acute myelogenous leukemia (AML). For P-gp measurement an immunocytological method using monoclonal antibodies C219, 4E3, and MRK 16 and the reverse transcription-polymerase chain reaction technique were applied. According to our results obtained in healthy volunteers using the immunocytological method, the limit for P-gp overexpression was set at > or = 10% P-gp-positive mononuclear bone marrow cells and at > or = 30% P-gp-positive mononuclear peripheral blood cells. All 42 CML patients in chronic phase had normal P-gp expression. P-gp overexpression was demonstrated in four of six patients in accelerated myelogenous blast cell phase and in four of 12 CML-BC patients. Of eight CML patients in blast crisis (BC) with normal P-gp expression, partial remission was achieved in three and minor response in five after prednisone/vindesine therapy. All four of the 12 CML-BC patients with P-gp overexpression did not respond to this therapy. Normal P-gp expression was seen in 41 (85.4%) of 48 untreated MDS patients. While P-gp overexpression did not develop during therapy in any of the myelodysplastic syndrome patients treated with low-dose ara-C alone, four of eight treated with low-dose ara-C plus GM-CSF and four of 11 treated with low-dose ara-C and IL-3 developed P-gp overexpression after therapy. Furthermore , 11 AML patients at primary diagnosis , including five AML patients with P-gp overexpression , who were treated with idarubicin , vepesid , and cytarabine V ( ara-C ) showed a complete remission . Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months. Our results suggest that in CML patients in BC, P-gp expression influences outcome after therapy. Further more, studies in a larger series of patients are necessary to prove the efficacy and toxicity of idarubicin/vepesid and cytardbine--or dexniguldipine-containing--therapy in relation to P-gp expression of AML patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/7914749/"}
+{"doc_id": "26b52a93d8e856f6c5071f06c51f1393", "sentence": "Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer .", "spans": [{"span_id": 0, "text": "Bavituximab", "start": 18, "end": 29, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "Carboplatin", "start": 35, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "Pemetrexed", "start": 51, "end": 61, "token_start": 8, "token_end": 9}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer . bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non-small-cell lung cancer (NSCLC). ### Patients And Methods Patients with advanced nonsquamous NSCLC and performance status 0 or 1 were treated with pemetrexed 500 mg/m ### results Between March 29, 2011 and December 30, 2013, 26 patients were enrolled. Three patients each were enrolled into dose escalation cohorts of bavituximab (0.3, 1, and 3 mg/kg). Therapy was well tolerated with no DLTs, and toxicities were consistent with those expected from pemetrexed/carboplatin. Overall response was 28%, with a median progression-free and overall survival of 4.8 months and 12.2 months, respectively. ### conclusion The combination of pemetrexed, carboplatin, bavituximab is well tolerated. However, with toxicities and preliminary efficacy signal similar to pemetrexed/carboplatin alone, further studies of bavituximab should focus on ways to enhance its immunomodulatory role.", "source": "https://pubmed.ncbi.nlm.nih.gov/29631965/"}
+{"doc_id": "d6601173b0972a426b9ca45a7a4f091c", "sentence": "In this multicenter study , the reliability of two nonradiometric , fully automated systems , the MB/BacT and BACTEC MGIT 960 systems , for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid , rifampin , ethambutol , and streptomycin was evaluated in comparison with the radiometric BACTEC 460 TB system .", "spans": [{"span_id": 0, "text": "isoniazid", "start": 213, "end": 222, "token_start": 33, "token_end": 34}, {"span_id": 1, "text": "rifampin", "start": 225, "end": 233, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "ethambutol", "start": 236, "end": 246, "token_start": 37, "token_end": 38}, {"span_id": 3, "text": "streptomycin", "start": 253, "end": 265, "token_start": 40, "token_end": 41}], "rels": [], "paragraph": "Multicenter laboratory evaluation of the MB/BacT Mycobacterium detection system and the BACTEC MGIT 960 system in comparison with the BACTEC 460TB system for susceptibility testing of Mycobacterium tuberculosis.  In this multicenter study , the reliability of two nonradiometric , fully automated systems , the MB/BacT and BACTEC MGIT 960 systems , for testing the susceptibilities of 82 Mycobacterium tuberculosis strains to isoniazid , rifampin , ethambutol , and streptomycin was evaluated in comparison with the radiometric BACTEC 460 TB system . The arbitration of discrepant results was done by the reanalysis of the strain, the determination of the MIC, and the molecular characterization of some resistance determinants. The overall level of agreement with BACTEC 460TB results was 96% with the MB/BacT test and 97.2% with the BACTEC MGIT 960 system. With both methods, the level of agreement with BACTEC 460TB results was 96.3% for isoniazid, 98.8% for rifampin, and 98.8% for ethambutol. The level of agreement for streptomycin was 90.2% with MB/BacT and 97.5% with BACTEC MGIT 960. Overall, there were 11 very major errors and 2 major errors with the MB/BacT method and 5 very major errors and 2 major errors with the BACTEC MGIT 960 system. In general, the MB/BacT and BACTEC MGIT 960 systems showed good performance for susceptibility testing with first-line antituberculosis drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/17442793/"}
+{"doc_id": "6201ec7c59b896456b430a50bd41c74f", "sentence": "Most frequent first line therapy was Sunitinib ( 66 % ) , followed by Sorafenib ( 20 % ) and Pazopanib ( 10 % ) .", "spans": [{"span_id": 0, "text": "Sunitinib", "start": 37, "end": 46, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "Sorafenib", "start": 70, "end": 79, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "Pazopanib", "start": 93, "end": 102, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort. Tyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN). ### objective To assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting. ### methods Overall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS). ### results Overall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib ( 66 % ) , followed by Sorafenib ( 20 % ) and Pazopanib ( 10 % ) . After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P\u202f=\u202f0.04 and P\u202f=\u202f0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis. ### conclusion The role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/32576526/"}
+{"doc_id": "cac8b6d7e0e9cff86690aeac01a51b77", "sentence": "Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors , imatinib and sunitinib being first-line and second-line drugs .", "spans": [{"span_id": 0, "text": "imatinib", "start": 97, "end": 105, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "sunitinib", "start": 110, "end": 119, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "A gastrointestinal stromal tumour with pulmonary metastases mimicking unilateral gynaecomastia. Gastrointestinal stromal tumours (GISTs) represent 1% of primary gastrointestinal cancers. These neoplasms most frequently metastasise to the liver and peritoneum and rarely to the lungs and bones. Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors , imatinib and sunitinib being first-line and second-line drugs . We report the case of a 52-year-old man with GIST who developed a right-sided subareolar breast swelling and subsequently discovered to be an invasive metastatic pulmonary GIST. Given that gynaecomastia is a known adverse effect of imatinib and sunitinib, this case report illustrates the importance of including metastatic disease in the differential diagnosis of patients with GIST and with the new onset of soft tissue masses.", "source": "https://pubmed.ncbi.nlm.nih.gov/24343802/"}
+{"doc_id": "2bcb0a1c13e14733a47a2ce01f58095f", "sentence": "Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan , and carboplatin plus doxorubicin .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 33, "end": 43, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "topotecan", "start": 91, "end": 100, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "carboplatin", "start": 107, "end": 118, "token_start": 14, "token_end": 15}, {"span_id": 3, "text": "doxorubicin", "start": 124, "end": 135, "token_start": 16, "token_end": 17}, {"span_id": 4, "text": "carboplatin/cisplatin", "start": 64, "end": 85, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 4], "is_context_needed": true}, {"class": "POS", "spans": [0, 2, 3], "is_context_needed": true}], "paragraph": "Role of weekly paclitaxel in the treatment of advanced ovarian cancer. Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a 1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than 3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20-65%. Combination therapy with weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60-88%. Triple-drug combination therapy has produced response rates of 42-67.5%. Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan , and carboplatin plus doxorubicin . In an attempt to avoid problems with high corticosteroid doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/12505598/"}
+{"doc_id": "5b73032843858b59999366946c1e2aeb", "sentence": "This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma .", "spans": [{"span_id": 0, "text": "temozolomide", "start": 98, "end": 110, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "docetaxel", "start": 115, "end": 124, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group. temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma . ### Patients And Methods Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. ### results Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. ### conclusion The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases.", "source": "https://pubmed.ncbi.nlm.nih.gov/11786569/"}
+{"doc_id": "0cad00d5e84694cb17717fc3f749e2aa", "sentence": "Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer .", "spans": [{"span_id": 0, "text": "verapamil", "start": 12, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "tamoxifen", "start": 26, "end": 35, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer . Based on experimental observations that verapamil and tamoxifen reverse multiple drug resistance, the authors investigated the feasibility of combining both agents with the initial chemotherapy of extensive small cell lung cancer. Overall, in a consecutive series of 58 patients the most important toxicity was myelosuppression, and there was a 24% rate of severe infections. Therapeutic results included 24% complete and 34% partial response rates, median time to disease progression of 32 weeks, and median survival of 46 weeks. In three consecutive cohorts of patients the dose of either tamoxifen or verapamil were escalated by 25% and 33%, respectively. The cohort of patients receiving verapamil 360 mg/day and tamoxifen 100 mg/day (level 2) had slightly more toxicity but also more responses than the other groups. Therefore, the authors recommend that these doses be used in controlled trials to confirm the promising results of their study.", "source": "https://pubmed.ncbi.nlm.nih.gov/2164872/"}
+{"doc_id": "86b8b2e11fa8569ee780430cc83fa446", "sentence": "In a scenario analysis comparing pembrolizumab with ipilimumab , the estimated ICER was USD8,904 .", "spans": [{"span_id": 0, "text": "pembrolizumab", "start": 33, "end": 46, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "ipilimumab", "start": 52, "end": 62, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Cost-effectiveness analysis of pembrolizumab compared to standard of care as first line treatment for patients with advanced melanoma in Hong Kong. pembrolizumab has been shown to improve overall survival (OS) and progression free survival (PFS) compared to ipilimumab in patients with ipilimumab-na\u00efve advanced melanoma; however, there are no published data on the cost-effectiveness for pembrolizumab compared to standard-of-care treatments currently used in Hong Kong for advanced melanoma. ### methods A partitioned-survival model based on data from a recent randomized phase 3 study (KEYNOTE-006) and meta-analysis was used to derive time in PFS, OS, and post-progression survival for pembrolizumab and chemotherapy, such as dacarbazine (DTIC), temozolomide (TMZ), and the paclitaxel-carboplatin combination (PC). A combination of clinical trial data, published data, results of meta-analysis, and melanoma registry data was used to extrapolate PFS and OS curves. The base-case time horizon for the model was 30\u00a0years with costs and health outcomes discounted at a rate of 5% per year. Individual patient level data on utilities and frequencies of adverse events were obtained from the final analysis of KEYNOTE-006 (cut-off date: 3-Dec-15) for pembrolizumab. Cost data included drug acquisition, treatment administration, adverse event management, and clinical management of advanced melanoma. The distribution of patient weight from the Hong Kong population was applied to calculate the drug costs. Analyses were performed from a payer's perspective. The incremental cost effectiveness ratio (ICER) expressed as cost in US Dollars (USD) per quality-adjusted life years (QALYs) was the main outcome. ### results In base-case scenario, the ICER for pembrolizumab as a first-line treatment for advanced melanoma was USD49,232 compared to DTIC, with the ICER values lower than cost-effectiveness threshold in Hong Kong. Results comparing pembrolizumab to TMZ and to PC were similar to that when compared to DTIC. Probability sensitivity analyses showed that 99% of the simulated ICERs were below three times the Gross Domestic Product (GDP) per capita for Hong Kong (currently at $119,274//QALY threshold). In a scenario analysis comparing pembrolizumab with ipilimumab , the estimated ICER was USD8,904 . ### conclusions pembrolizumab is cost-effective relative to chemotherapy (DTIC, TMZ and PC), and highly-cost-effective compared to ipilimumab, for the first-line treatment of advanced melanoma in Hong Kong.", "source": "https://pubmed.ncbi.nlm.nih.gov/31969794/"}
+{"doc_id": "0d17f81c5efb1b73b80eb287f32c69e0", "sentence": "Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial .", "spans": [{"span_id": 0, "text": "lapatinib", "start": 96, "end": 105, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "trastuzumab", "start": 113, "end": 124, "token_start": 15, "token_end": 16}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial . Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. ### methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T\u2009+\u2009L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. ### results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T\u2009+\u2009L arm vs. 197 (9.3%) in T arm (OR\u2009=\u20090.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset\u2009=\u20096.6 months [IQR\u2009=\u20093.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF\u2009<\u200955% (vs\u2009>\u200964%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI\u2009>\u200930\u2009kg/m ### conclusions Dual HER2 blockade with T\u2009+\u2009L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. ### Trial Registration Number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.", "source": "https://pubmed.ncbi.nlm.nih.gov/32203207/"}
+{"doc_id": "f2c24cda6984f8af1fd4c57784983b09", "sentence": "To determine the current status of ivermectin , abamectin and praziquantel combined , and fenbendazole resistance to Parascaris spp . in horses in Saudi Arabia .", "spans": [{"span_id": 0, "text": "ivermectin", "start": 35, "end": 45, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "abamectin", "start": 48, "end": 57, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "praziquantel", "start": 62, "end": 74, "token_start": 10, "token_end": 11}, {"span_id": 3, "text": "fenbendazole", "start": 90, "end": 102, "token_start": 14, "token_end": 15}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "A field study on the anthelmintic resistance of Parascaris spp. in Arab foals in the Riyadh region, Saudi Arabia. In the last decade, Parascaris spp. resistance to anthelmintics has been recorded in many countries. In Saudi Arabia, there are limited data available on Parascaris spp. resistance to anthelmintics. ### objective To determine the current status of ivermectin , abamectin and praziquantel combined , and fenbendazole resistance to Parascaris spp . in horses in Saudi Arabia . ### methods Three hundred and forty-one foals from eleven different farms were examined by faecal egg count (FEC). The foals were all Arab horses aged 17.2 \u00b1 4.5 (SD) months. ivermectin (n = 46 foals), abamectin and praziquantel combined (n = 46), and fenbendazole (n = 46) were administered on day 0 and faeces were collected on day 14. The study comprised 41 untreated foals as controls. Animals that have FEC of \u2265100 eggs per gram (EPG) were used to measure anthelmintic efficacy. Parascaris spp. populations were considered susceptible when faecal egg count reduction (FECR) was \u226595% associated with a lower 95% confidence limit (LCL) >90%, suspected resistant when FECR \u226490% or LCL <90% and resistant when FECR <90% and LCL <90%. ### results Prevalence of Parascaris spp. infection was 53% (179/341 horses). Anthelmintic resistance to Parascaris spp. were highest following fenbendazole (55% of farms and 65% of foals) and to a lower extent following ivermectin or the combination of abamectin and praziquantel which comprised 27% of farms (and 46% of foals) and 18% of farms (and 10% of foals), respectively. ### conclusion These data indicate that anthelmintics-resistant Parascaris spp. populations are present on horse farms in Saudi Arabia.", "source": "https://pubmed.ncbi.nlm.nih.gov/28537782/"}
+{"doc_id": "65d4616fe9641bc48a437be91566e364", "sentence": "To determine the response rate ( RR ) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer ( ESCLC ) .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 63, "end": 74, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "gemcitabine", "start": 77, "end": 88, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Results of a Phase II study of carboplatin plus gemcitabine in patients with untreated extensive small cell lung cancer.  To determine the response rate ( RR ) and survival produced by carboplatin + gemcitabine therapy in patients with untreated extensive small cell lung cancer ( ESCLC ) . ### Patients And Methods Treatment consisted of carboplatin (AUC = 5) on day 1 and gemcitabine (1100 mg/m(2)) on days 1 and 8 of each 21-day cycle for 4 planned cycles (additional cycles allowed as per treating physician). ECOG performance status 0/1/2 was 29, 58, and 13%. Median age was 66.5 years (range: 41.3-83.1), 94% were white, and 50.7% were female. ### results Between August 2000 and February 2002, 69 patients with ESCLC were enrolled. All 69 patients were included in the safety analysis, and 66 patients were evaluable for response. There were 2 CR (3.0%), 26 PR (39.5%), 23 SD (34.8%), and 15 PD (22.7%) resulting in a RR of 42.5%. The median survival was 9.2 months (range: <1-22.6), and the estimated 1-year survival was 33%. The median TTP was 3.9 months (range: <1-12.8), and the estimated 6-month progression free survival was 24%. The median duration of response was 3.8 months (range: 1.0-9.9). Out of 69 patients, 29, 3, and 16 received 4, 5, and 6 cycles of therapy, respectively. The major Grade 3, 4 toxicities included neutropenia (39.1%), thrombocytopenia (31.9%), anemia (13.0%), and fatigue (4.3%). ### conclusion This regimen resulted in survival data that was similar to other regimens for ESCLC and treatment appeared to be well tolerated. gemcitabine in combination with carboplatin or other active drugs in ESCLC may be worth further investigation.", "source": "https://pubmed.ncbi.nlm.nih.gov/15541823/"}
+{"doc_id": "fa9ec0fb6b4851232e80bbb0f13f1bab", "sentence": "The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain -- a pattern found with other reversal agents .", "spans": [{"span_id": 0, "text": "chloroquine", "start": 19, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "citalopram", "start": 35, "end": 45, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo. citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain -- a pattern found with other reversal agents . citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo.", "source": "https://pubmed.ncbi.nlm.nih.gov/9655857/"}
+{"doc_id": "dcd33444812f986d077de2eb9f79e65e", "sentence": "Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide .", "spans": [{"span_id": 0, "text": "Isoniazid", "start": 86, "end": 95, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "Pyrazinamide", "start": 100, "end": 112, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Interfacial Phenomenon Based Biocompatible Alginate-Chitosan Nanoparticles Containing Isoniazid and Pyrazinamide . Tuberculosis (TB) is one of the major health challenge in the world. The current treatment of TB needs daily administration of combined drug therapy for six or more months. Sometime non-adherence and less bioavailability from current therapy develops multidrug resistance, as a result, high dose requirement and subsequent intolerable toxicity are seen. Therefore, nanotechnology gained special attention as it has potential to improve patient compliance, bioavailability and reduction in dosing frequency. ### objective The aim of this study is to fabricate alginate-chitosan nanoparticles (AL-CS NPs) under appropriate conditions using ionic gelation method. The use of natural polymers in nanoparticle fabrication has a vast application due to their biodegradability, biocompatibility and nontoxic nature. Ionic gelation method involves the interaction between macromolecules with opposite charged ionizable groups forming polyelectrolyte complex. Hence, it is rational to formulate natural polymerbased sustained release nano-particulate matrix to improve patient adherence, reducing dose frequency and drug toxicity. ### method The formulations were based on 32 factorial designs. Nanoparticles of combined drug (isoniazid- INH and pyrazinamide-PYZ) were fabricated using natural polymer. Formulation process involved the use of pregelated sodium alginate followed by ionic gelation with chitosan. Pregelation of sodium alginate included calcium chloride. The effects of sodium alginate concentration and chitosan concentration on particle size, zeta potential, entrapment efficiency and in vitro drug release were studied. ### results Optimized Batch-3s showed particle size 539.7 \u00b1 2.33 nm, zeta potential -26.4 \u00b1 0.55 mV, and entrapment efficiency is 70.21 \u00b1 0.24% and 73.45 \u00b1 0.21% of INH and PYZ, respectively. Dissolution release study of Batch-3s in 7.4 pH phosphate buffer exhibited the initial burst of 5.04 \u00b10.45% and 19.68 \u00b1 0.87% at 0.25 hrs followed by slow, sustained release of drug 74.53 \u00b1 2.53 and 57.87 \u00b1 2.04% at 10 hrs of INH and PYZ, respectively. ### conclusion It concluded that chitosan (CS) and sodium alginate (AL) concentration are rate-limiting factors in formulation development. Natural polymer based combined drug nano-particulate system could be an innovative and optimistic approach in the treatment of TB.", "source": "https://pubmed.ncbi.nlm.nih.gov/29938624/"}
+{"doc_id": "576c8ac8cc0fa93c995c35b5e17b8c95", "sentence": "In a 27-day inpatient study , 10 methamphetamine-dependent individuals participated in a double-blind , placebo-controlled , cross-over design , with oral doses of topiramate ( 0 , 100 , and 200 mg ) administered as a pretreatment before intravenous doses of methamphetamine ( 0 , 15 , and 30 mg ) .", "spans": [{"span_id": 0, "text": "topiramate", "start": 164, "end": 174, "token_start": 23, "token_end": 24}, {"span_id": 1, "text": "methamphetamine", "start": 259, "end": 274, "token_start": 41, "token_end": 42}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals. Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study , 10 methamphetamine-dependent individuals participated in a double-blind , placebo-controlled , cross-over design , with oral doses of topiramate ( 0 , 100 , and 200 mg ) administered as a pretreatment before intravenous doses of methamphetamine ( 0 , 15 , and 30 mg ) . The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.", "source": "https://pubmed.ncbi.nlm.nih.gov/17184890/"}
+{"doc_id": "6226da15ba7f4d73c2d17792fe9e79af", "sentence": "Synergism between penicillin , clindamycin , or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups .", "spans": [{"span_id": 0, "text": "penicillin", "start": 18, "end": 28, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "clindamycin", "start": 31, "end": 42, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "metronidazole", "start": 48, "end": 61, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "gentamicin", "start": 66, "end": 76, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Synergism between penicillin , clindamycin , or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups . Clinical isolates of the Bacteroides melaninogenicus and Bacteroides fragilis groups were tested for in vitro and in vivo susceptibility to penicillin, clindamycin, and metronidazole, used singly or in combination with gentamicin. The in vitro tests consisted of determinations of minimal inhibitory concentrations (MICs) carried out with or without constant amounts of gentamicin. When used alone, gentamicin had negligible effects on the bacteria but significantly reduced the MICs of penicillin, clindamycin, and metronidazole against 11, 10, and 3, of the 15 strains of the B. melaninogenicus group, respectively. The 15 strains of the B. fragilis group were all beta-lactamase producers and were highly resistant to penicillin or the combination of penicillin and gentamicin. However, gentamicin reduced the MICs of clindamycin and metronidazole against 1 and 7 strains of this group, respectively. The in vivo tests were carried out in mice and consisted of measurements of the effects of the antimicrobial agents on the sizes and bacterial content of abscesses induced by subcutaneous injection of bacterial suspensions. The results of the in vivo tests were generally consistent with those obtained in vitro with strains of the B. melaninogenicus group. Synergism between gentamicin and penicillin, clindamycin, or metronidazole was shown in 13, 10, and 3 strains of this group, respectively. In vivo synergism was not clearly demonstrated with the strains of the B. fragilis group, possibly because clindamycin and metronidazole used alone were highly efficacious. We suggest that the synergistic effect of gentamicin is due to its increased transport into the bacterial cell in the presence of penicillin and, possibly, other antimicrobial agents. The newly recognized in vitro and in vivo synergism between penicillin and other antimicrobial agents and an aminoglycoside in B. melaninogenicus may have clinical implications that deserve to be investigated.", "source": "https://pubmed.ncbi.nlm.nih.gov/6142680/"}
+{"doc_id": "363c8fe1e1792237985df9fbfb8e1a58", "sentence": "Thirty-one animals were allocated randomly to three groups , all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min , 17 mg/kg aspirin intravenously , and heparin ( as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h ) , hirudin ( as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h ) , or Yagin ( as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h ) .", "spans": [{"span_id": 0, "text": "aspirin", "start": 145, "end": 152, "token_start": 26, "token_end": 27}, {"span_id": 1, "text": "heparin", "start": 173, "end": 180, "token_start": 30, "token_end": 31}, {"span_id": 2, "text": "heparin", "start": 237, "end": 244, "token_start": 43, "token_end": 44}], "rels": [], "paragraph": "Enhancement of recombinant tissue-type plasminogen activator thrombolysis with a selective factor Xa inhibitor derived from the leech Hirudo medicinalis: comparison with heparin and hirudin in a rabbit thrombosis model. To compare the efficacy of Yagin, a factor Xa inhibitor derived from the leech Hirudo medicinalis, with those of heparin and hirudin as adjuncts to recombinant tissue-type plasminogen activator (rTPA) thrombolysis in a rabbit thrombosis model. ### methods Thirty-one animals were allocated randomly to three groups , all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min , 17 mg/kg aspirin intravenously , and heparin ( as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h ) , hirudin ( as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h ) , or Yagin ( as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h ) . ### results Administration of Yagin was associated with a significant acceleration of the reflow time, this time being 14.5 +/- 1.2 min with Yagin, 25.8 +/- 5.2 min with heparin (P < 0.0001, versus Yagin), and 28.7 +/- 16.0 min with hirudin (P = 0.012, versus Yagin). Overall patency did not differ significantly among the three groups. ### conclusions At the indicated single doses, inhibition of factor Xa by a relatively low concentration of Yagin was found to be superior than that with either heparin or hirudin for accelerating rTPA thrombolysis.", "source": "https://pubmed.ncbi.nlm.nih.gov/9116933/"}
+{"doc_id": "bd1b614a9a5b0c1225075c98f84ca619", "sentence": "In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth .", "spans": [{"span_id": 0, "text": "evofosfamide", "start": 8, "end": 20, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "paclitaxel", "start": 81, "end": 91, "token_start": 13, "token_end": 14}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models. Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth . Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone.", "source": "https://pubmed.ncbi.nlm.nih.gov/26749324/"}
+{"doc_id": "366808bdb989ebd4b56210b53fb3e265", "sentence": "Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "vinorelbine", "start": 15, "end": 26, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Phase I/II study of paclitaxel and vinorelbine in metastatic breast cancer.  Paclitaxel and vinorelbine are among the most active new agents in metastatic breast cancer . Both in vitro and in vivo studies have shown that the combined administration of these two microtubule-targeting agents is feasible and worthwhile. Based on the promising preclinical data, patients with metastatic breast cancer no longer amenable to conventional treatment were entered into a phase I/II study in which the vinorelbine dose was fixed at 30 mg/sqm and paclitaxel was started at 90 mg/sqm and then subsequently escalated by 30 mg/sqm per step. Cycles were repeated every 21 days. Hematopoietic growth factor support was provided from the 4th dose level onwards. Grade III neutropenia was observed only in 2 patients treated at the 5th dose level. Thrombocytopenia never reached grade 3. Neurotoxicity was considered dose-limiting, since grade 3 peripheral neuropathy occurred in all three patients treated at the 6th dose level. Other toxicities were mild. paclitaxel 210 mg/sqm and vinorelbine 30 mg/sqm was the selected combination for phase II. Overall response rate in 34 evaluable patients was 38% (95% confidence interval (C.I.), 22% to 54%). In particular, 3 complete responses (9%) and 10 partial responses (29%) were observed. The observed level of antitumor activity, with an overall response rate of 38% and a median duration of response of 12 months, is of interest, since the study was targeted only to anthracycline-pretreated patients, most of whom had adverse prognostic features. The evaluation of a combination of vinorelbine and paclitaxel as first-line therapy in metastatic breast cancer seems worthwhile and is currently undergoing.", "source": "https://pubmed.ncbi.nlm.nih.gov/9493980/"}
+{"doc_id": "5a93666939620e4a5416bd80da463252", "sentence": "Treatments included recombinant human leptin ( 10 - 100nM ) , recombinant human IL-6 ( 0.3 - 3nM ) , or recombinant human erythropoietin ( Epo ) ( 10mU/ml ) .", "spans": [{"span_id": 0, "text": "leptin", "start": 38, "end": 44, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "erythropoietin", "start": 122, "end": 136, "token_start": 23, "token_end": 24}], "rels": [], "paragraph": "Leptin receptor JAK2/STAT3 signaling modulates expression of Frizzled receptors in articular chondrocytes. Differentiated articular chondrocytes express a functional bisoform of the leptin receptor (LRb); however, leptin-LRb signaling in these cells is poorly understood. We hypothesized that leptin-LRb signaling in articular chondrocytes functions to modulate canonical Wnt signaling events by altering the expression of Frizzled (FZD) receptors. ### methods Human chondrocyte cell lines and primary articular chondrocytes were grown in serum containing growth media for 24h, followed by a media change to Dulbecco's modified Eagle's medium (DMEM) containing 1% Nutridoma-SP to obtain a serum-deficient environment for 24h before treatment. Treatments included recombinant human leptin ( 10 - 100nM ) , recombinant human IL-6 ( 0.3 - 3nM ) , or recombinant human erythropoietin ( Epo ) ( 10mU/ml ) . Cells were harvested 30min-48h after treatment and whole cell lysates were analyzed using immunoblots or luciferase assays. ### results Treatment of cells with leptin resulted in activation of Janus kinase 2 (JAK2) and subsequent phosphorylation of specific tyrosine residues on LRb, followed by dose- and time-dependent increases in the expression of Frizzled-1 (FZD1) and Frizzled-7 (FZD7). leptin-mediated increases in the expression of FZD1 were blocked by pre-treatment with the protein synthesis inhibitor cycloheximide or the JAK2 inhibitor AG490. Experiments using a series of hybrid Epo extracellular domain-leptin intracellular domain receptors (ELR) harboring mutations of specific tyrosine residues in the cytoplasmic tail showed that increases in the expression of FZD1 were dependent on LRb-mediated phosphorylation of STAT3, but not ERK1/2 or STAT5. leptin pre-treatment of chondrocytes prior to Wnt3a stimulation resulted in an increased magnitude of canonical Wnt signaling. ### conclusion These experiments show that leptin-LRb signaling in articular chondrocytes modulates expression of canonical Wnt signaling receptors and suggests that direct cross-talk between these pathways is important in determining chondrocyte homeostasis.", "source": "https://pubmed.ncbi.nlm.nih.gov/20868760/"}
+{"doc_id": "0cc39e9cd43eed735fbf93fa813da8a0", "sentence": "Lenalidomide is currently being tested in combination with both standard and novel agents , including bortezomib , for patients with relapsed/refractory multiple myeloma .", "spans": [{"span_id": 0, "text": "Lenalidomide", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "bortezomib", "start": 102, "end": 112, "token_start": 15, "token_end": 16}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide. The immunomodulatory drug (IMiD) lenalidomide is a more potent immunomodulator than thalidomide with respect to its effects on cytokine modulation and increased T-cell proliferation. Of all the IMiDs, clinical trial data are most mature for lenalidomide. In phase I studies, dose-limiting toxicities of lenalidomide were limited to myelosuppression and a response rate of 72% was seen in relapsed/refractory patients. Three phase II studies subsequently evaluated the efficacy of single-agent lenalidomide or lenalidomide in combination with dexamethasone. As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44%. For patients with relapsed/refractory multiple myeloma, the MM-007 study has shown that lenalidomide alone or in combination with dexamethasone provides response rates between 37% and 41%. In MM-007, median progression-free survival was 5.5 months at early analysis and the median overall survival has yet to be reached. Preliminary data for the single-arm, multicenter, open-label MM-014 study showed that median time to progression was 5.6 months. Response rates indicate that 70% of patients had stable disease or better as the best response to treatment. Two randomized, phase III trials (MM-009 and MM-010) evaluated lenalidomide with high-dose dexamethasone versus high-dose dexamethasone alone for the treatment of relapsed/refractory multiple myeloma. Both MM-009 and MM-010 provided remarkably similar response rates for patients receiving lenalidomide and dexamethasone. In both trials response rates with the combination were greater than twice the response rates seen with high-dose dexamethasone alone. Indeed, an independent Data Monitoring Committee determined that both trials exceeded the prespecified efficacy value of P<.0015, recommending that the trials be discontinued and that lenalidomide be offered to patients on the dexamethasone arm of the trial if clinically indicated. Toxicities observed in studies of lenalidomide alone were low; the incidence of peripheral neuropathy was significantly lower than those noted in trials using thalidomide. Thrombocytopenia was a significant grade 3 or 4 toxicity observed; however, it was manageable with dose reduction. In contrast with high-dose dexamethasone, deep vein thrombosis has emerged as an important toxicity. Lenalidomide is currently being tested in combination with both standard and novel agents , including bortezomib , for patients with relapsed/refractory multiple myeloma .", "source": "https://pubmed.ncbi.nlm.nih.gov/16344100/"}
+{"doc_id": "edbe761e468cedddb1012894057a128a", "sentence": "[ Efficacy of fluvoxamine combined with extended-release methylphenidate on treatment-refractory obsessive-compulsive disorder ] .", "spans": [{"span_id": 0, "text": "fluvoxamine", "start": 14, "end": 25, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "methylphenidate", "start": 57, "end": 72, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[ Efficacy of fluvoxamine combined with extended-release methylphenidate on treatment-refractory obsessive-compulsive disorder ] . To observe the clinical efficacy of dopamine modulator methylphenidate (MPH) of extended-release formulations (MPH-ER) augmentation of ongoing fluvoxamine treatment in refractory obsessive-compulsive disorder (OCD) and its effects on patient's anxiety and sleep quality.\u2029 Methods: A pilot randomized, placebo-controlled, and double-blind trial was conducted at an outpatient, single-center academic setting. Participants included 44 adults with serotonin reuptake inhibitor treatment-refractory OCD and they received a stable fluvoxamine pharmacotherapy with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores higher than 20. The 44 patients were randomly assigned into a study group and a control group, with 22 patiencs in each group. fluvoxamine and MPH-ER were given to the study group, while fluvoxamine and placebo were given to the control group, with 8 weeks of the treatment course. Y-BOCS, Hamilton Anxiety Scale (HAMA) were used to assess the efficacy, Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality, and Treatment Emergent Symptom Scale (TESS) was used to evaluate the side effects. Data were analyzed in the intention-to-treat sample.\u2029 Results: The improvement in the Y-BOCS total score, Y-BOCS obsession subscale score and HAMA score were more prominent in the study group than those in the control group (P<0.001). There was no significant difference in PSQI score and TESS score between the two groups. MPH-ER was well tolerated.\u2029 Conclusion: fluvoxamine combined with MPH-ER is effective in the treatment of refractory obsessive-compulsive disorder. It can improve anxiety and has no adverse effect on sleep quality.", "source": "https://pubmed.ncbi.nlm.nih.gov/30643068/"}
+{"doc_id": "9b59233ac22acf3f6df19738ee0dccee", "sentence": "Analysis of HER Family ( HER1 - 4 ) Expression as a Biomarker in Combination Therapy with Pertuzumab , Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer .", "spans": [{"span_id": 0, "text": "Pertuzumab", "start": 90, "end": 100, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "Trastuzumab", "start": 103, "end": 114, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "Docetaxel", "start": 119, "end": 128, "token_start": 21, "token_end": 22}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Analysis of HER Family ( HER1 - 4 ) Expression as a Biomarker in Combination Therapy with Pertuzumab , Trastuzumab and Docetaxel for Advanced HER2-positive Breast Cancer . Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1-4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen. ### Patients And Methods The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015. The expression levels of estrogen receptor (ER), progesterone receptor (PgR), Ki67, HER1, HER2, HER3 and HER4 were evaluated using immunostaining employing needle biopsy specimens. ### results The overall response rate (ORR) was significantly higher in the HER3-positive group than in the HER3-negative group (p=0.002). In prognostic analysis, the HER3-positive group showed a significant progression-free survival extension over the HER3-negative group (p=0.042, log-rank). In univariate analysis, objective response (p=0.004, hazard ratio(HR)=0.123) and positive HER3 expression (p=0.023, HR=0.279) significantly contributed to extension of progression-free survival interval. ### conclusion HER3 expression may be a useful factor for predicting the response of HER2-positive breast cancer to chemotherapy with the TPD regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/29599351/"}
+{"doc_id": "5ed89d28b16c808ded0f444bde90dc63", "sentence": "Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin .", "spans": [{"span_id": 0, "text": "floxuridine", "start": 29, "end": 40, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "gemcitabine", "start": 72, "end": 83, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "oxaliplatin", "start": 88, "end": 99, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. ### objective To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. ### Design Setting And Participants A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. ### interventions Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin . ### Main Outcomes And Measures The primary outcome was progression-free survival (PFS) of 80% at 6 months. ### results For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P\u2009=\u2009.66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P\u2009=\u2009.01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). ### Conclusions And Relevance Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.", "source": "https://pubmed.ncbi.nlm.nih.gov/31670750/"}
+{"doc_id": "3ed64085bfe928c461f9c17f9f8f5ac1", "sentence": "Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6 % of patients had taken rofecoxib 50 mg/day for longer than recommended .", "spans": [{"span_id": 0, "text": "celecoxib", "start": 81, "end": 90, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "rofecoxib", "start": 106, "end": 115, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "rofecoxib", "start": 205, "end": 214, "token_start": 32, "token_end": 33}], "rels": [], "paragraph": "Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6 % of patients had taken rofecoxib 50 mg/day for longer than recommended . Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.", "source": "https://pubmed.ncbi.nlm.nih.gov/15813652/"}
+{"doc_id": "22cc4576d56fdf21b9fcd4001d2e46f9", "sentence": "Chemoimmunotherapy with cyclophosphamide , doxorubicin , vincristine , and prednisolone combined with rituximab ( R-CHOP ) is currently the first-line therapy for diffuse large B-cell lymphoma ( DLBCL ) .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 24, "end": 40, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "doxorubicin", "start": 43, "end": 54, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "vincristine", "start": 57, "end": 68, "token_start": 6, "token_end": 7}, {"span_id": 3, "text": "prednisolone", "start": 75, "end": 87, "token_start": 9, "token_end": 10}, {"span_id": 4, "text": "rituximab", "start": 102, "end": 111, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": false}], "paragraph": "Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma.  Chemoimmunotherapy with cyclophosphamide , doxorubicin , vincristine , and prednisolone combined with rituximab ( R-CHOP ) is currently the first-line therapy for diffuse large B-cell lymphoma ( DLBCL ) . However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them. ### methods At our institute, for DLBCL patients aged 65-79 and \u226580 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP. ### results Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p\u2009<\u20090.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60-80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups. ### Discussion And Conclusions Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity.", "source": "https://pubmed.ncbi.nlm.nih.gov/30101679/"}
+{"doc_id": "f840117cf09b1a62ab954e23e6ccdf3a", "sentence": "The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A ( CsA ) or tacrolimus .", "spans": [{"span_id": 0, "text": "cyclosporine", "start": 108, "end": 120, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "tacrolimus", "start": 134, "end": 144, "token_start": 24, "token_end": 25}], "rels": [], "paragraph": "Tacrolimus versus cyclosporine induction therapy in pulmonary transplantation in miniature swine. tacrolimus has been shown to provide superior immunosuppression in various solid organ transplant settings. The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A ( CsA ) or tacrolimus . ### methods Single lung transplantation from MHC mismatched donors was performed in 10 minipigs. Immunosuppression included 1.5 mg/kg per day methylprednisolone and 1.0 mg/kg per day azathioprine. CsA (n=5) was adjusted to trough levels of 300-500 ng/ml, tacrolimus (n=5) was adjusted to 16-26 ng/ml. All immunosuppressive drugs were discontinued on postoperative day (POD) 28. Allograft survival was monitored by sequential chest radiographs, bronchoscopy and transbronchial biopsy histology. Peripheral blood leukocytes were scanned for donor chimerism and CD3, CD4, CD8 and CD25 expression. ### results The animals survived a 4-week course of immunosuppression without radiological or histological signs of rejection on POD 28. Median allograft survival in CsA-treated animals was 55+/-15 days and all animals rejected their grafts within 42 days after withdrawal of immunosuppression. In tacrolimus-treated animals, median survival was 152+/-65 days with the longest survivor being electively sacrificed on POD 390 (P=0.0064). The degree of donor leukocyte chimerism and the frequency of CD4+CD25+ T-cells were higher in the tacrolimus group, however, these differences were not statistically significant. ### conclusion The results of our study show that primary immunosuppression with tacrolimus is superior to cyclosporine after pulmonary allotransplantation in a large animal model.", "source": "https://pubmed.ncbi.nlm.nih.gov/16054825/"}
+{"doc_id": "69ce1c75c42d853e74eec788b249f146", "sentence": "Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer : A Case Report and Literature Review .", "spans": [{"span_id": 0, "text": "Paclitaxel", "start": 44, "end": 54, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "Bevacizumab", "start": 59, "end": 70, "token_start": 8, "token_end": 9}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer : A Case Report and Literature Review . We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/28868019/"}
+{"doc_id": "fb1cdc336bfa44facd7d223ab0910933", "sentence": "The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 63, "end": 74, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "S-1", "start": 79, "end": 82, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "oxaliplatin", "start": 142, "end": 153, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "irinotecan", "start": 158, "end": 168, "token_start": 24, "token_end": 25}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Phase II Study of Third-Line Combination Chemotherapy with Bevacizumab Plus S-1 for Metastatic Colorectal Cancer with Mutated KRAS (SAVIOR Study). No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC. ### methods Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR). ### results In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade \u22653, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade \u22653, 17%). ### conclusions The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS .", "source": "https://pubmed.ncbi.nlm.nih.gov/27229742/"}
+{"doc_id": "4aa4b4fdad3c2ed039c5ce33e2f3cef5", "sentence": "In accordance with their different pharmacological profiles , the three NLs iloperidone , clozapine , and haloperidol have different effects in this preclinical cognitive task .", "spans": [{"span_id": 0, "text": "iloperidone", "start": 76, "end": 87, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "clozapine", "start": 90, "end": 99, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "haloperidol", "start": 106, "end": 117, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Differential effects of iloperidone, clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm. Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available. ### objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol. ### methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0-64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured. ### results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance. ### conclusion In accordance with their different pharmacological profiles , the three NLs iloperidone , clozapine , and haloperidol have different effects in this preclinical cognitive task . These results might provide important information for the development of NLs with beneficial effects on cognition.", "source": "https://pubmed.ncbi.nlm.nih.gov/12827343/"}
+{"doc_id": "38e0f18b20644a73a11a219785d8e7bf", "sentence": "In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin , the RR was 1 and its 95 % CI remained within a post-hoc margin of \u00b1 15 % .", "spans": [{"span_id": 0, "text": "ticagrelor", "start": 63, "end": 73, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "aspirin", "start": 76, "end": 83, "token_start": 10, "token_end": 11}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "New oral anticoagulants in acute coronary syndrome: is there any advantage over existing treatments? After an acute coronary syndrome, dual antiplatelet therapy with clopidogrel plus aspirin is still a standard of care, but several new approaches have been investigated. ### objectives The present study re-examined the studies published thus far on this topic to evaluate the effectiveness of dual antiplatelet therapy in comparison to some of these new approaches (mainly, ticagrelor + aspirin and dual therapy plus a new oral anticoagulant [NOAC]; i.e., \"triple therapy\"). ### Materials And Methods The clinical material was directly derived from that reported in recent meta-analyses. Our re-analysis relied on standard equivalence methods in which interpretation is based on Relative Risks (RRs) along with their 95% Confidence Intervals (CI). The equivalence margins employed in our statistical testing were directly derived from those reported in randomized studies. ### results The equivalence margins were initially set at RR ranging from 0.775 to 1.29. According to these margins, triple therapy based on any NOAC proved to be superior to dual therapy alone, but at the same time demonstrated its equivalence with dual therapy. The results for apixaban-based triple therapy were inconclusive (not superior, not not-inferior, not equivalent and, of course, not inferior to the controls). Those for rivaroxaban-based triple therapy showed that this combination treatment was superior to dual therapy alone and failed to meet the criterion of equivalence. In the comparison between rivaroxaban-based triple therapy and ticagrelor + aspirin , the RR was 1 and its 95 % CI remained within a post-hoc margin of \u00b1 15 % . ### conclusions Even if one considers the most effective NOAC in combination with clopidogrel + ticagrelor, this triple therapy is not more effective than ticagrelor + aspirin. On the other hand, the increased risk of bleeding with triple regimens is well demonstrated. We therefore conclude that these triple regimens did not play any important roles in the patients experiencing an acute coronary syndrome.", "source": "https://pubmed.ncbi.nlm.nih.gov/25177676/"}
+{"doc_id": "ffeb8dccbb9425bef2c952f8290978d5", "sentence": "The incidence of cross-resistance between indinavir , nelfinavir , ritonavir and saquinavir was high ( 60 - 90 % ) .", "spans": [{"span_id": 0, "text": "indinavir", "start": 42, "end": 51, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "nelfinavir", "start": 54, "end": 64, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "ritonavir", "start": 67, "end": 76, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "saquinavir", "start": 81, "end": 91, "token_start": 11, "token_end": 12}], "rels": [], "paragraph": "Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. To assess the patterns of HIV phenotypic cross-resistance to protease inhibitors (PI) in patients experiencing viral load rebound on combination therapy including a PI. ### methods Phenotypic analysis of sensitivity to indinavir, nelfinavir, saquinavir, ritonavir and amprenavir was carried out using a single-cycle recombinant virus assay. Viral protease was sequenced by automated dideoxynucleotide chain termination. ### results Of the 108 patients studied, 68 had received indinavir, 50 ritonavir, 25 saquinavir and eight nelfinavir. The majority (71%) had received only one PI. The incidence of cross-resistance between indinavir , nelfinavir , ritonavir and saquinavir was high ( 60 - 90 % ) . Cross-resistance to amprenavir was less frequent (37-40%). However there was some correlation between levels of sensitivity to amprenavir and indinavir (r2 = 0.34; P < 0.01). Conversely, the correlation between levels of sensitivity to indinavir and saquinavir was poor (r2 = 0.25), particularly for patients who had not received saquinavir. The degree of cross-resistance correlated with the level of resistance and with the total number of mutations in the protease gene (P < 0.05, chi square test) but could not be significantly correlated to any one particular mutation or combination of mutations. Mutation 184V was significantly associated with cross-resistance to amprenavir, with no mutations at codon 50 observed, while mutations associated with cross-resistance to saquinavir differed according to the treatment received. ### conclusions These results suggest that, although the total number of protease mutations correlates with the degree of cross-resistance, the specific mechanisms accounting for primary resistance and for cross-resistance may be different.", "source": "https://pubmed.ncbi.nlm.nih.gov/10546858/"}
+{"doc_id": "bd9e3e4a321fffdb4c4e9ccdaf754cc3", "sentence": "Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis .", "spans": [{"span_id": 0, "text": "Mercaptopurine", "start": 36, "end": 50, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "Allopurinol", "start": 71, "end": 82, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis . mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/26878433/"}
+{"doc_id": "a43b30fbecc655bb6b300d1ce1cb8cf2", "sentence": "The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment ( with capecitabine or with a two-drug regimen including irinotecan ) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression .", "spans": [{"span_id": 0, "text": "capecitabine", "start": 125, "end": 137, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "irinotecan", "start": 175, "end": 185, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Second-Line Chemotherapy of Advanced Colorectal Cancer: Predictive and Prognostic Factors. Colorectal cancer progression presents a significant clinical problem. After its dissemination, the foundation of its treatment comprises of palliative chemotherapy. ### objectives The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment ( with capecitabine or with a two-drug regimen including irinotecan ) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression . ### Material And Methods The retrospective analysis of 164 patients with advanced colorectal cancer treated in 2001- -2008 included chosen clinical, pathological and follow-up data. ### results Response to second-line chemotherapy was observed in 34 out of 164 patients: In 18/82 in the irinotecan group (22%) and in 16/82 in the capecitabine group (19.5%). The mean survival time to progression following the second line of treatment amounted to 5.85 and 6.2 months respectively. Statistically, a higher number of patients in good condition of 0 to 1 was documented in the group responding to treatment. Significant correlation was documented between primary stage of the disease and time to progression in patients treated with capecitabine (p = 0.0258). The recurrence of the disease was observed in 44/45 patients following operation with radical intention but with an insufficient number of excised lymph nodes. A significantly longer time to progression was observed in women treated with capecitabine. In logistic regression, lack of treatment response was found to be an independent factor affecting the time to disease progression. Patients who did not respond to the second line of treatment demonstrated a significantly shorter time to disease progression than patients who responded to it and they showed a significantly higher number of patients with leucopenia during treatment. ### conclusions Clinical response to treatment in both treated groups is of significant importance for the probability of local recurrence of the disease, preservation of a good patient's condition and the higher level of leukocytes during treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/27629847/"}
+{"doc_id": "2e00802dc163aa6e6be87ebdb2ca208f", "sentence": "An 8-week , randomized , parallel-group , double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg ( T/A ; n = 352 ) with once-daily amlodipine 10 mg ( A ; n = 354 ) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension ( systolic BP [ SBP ] > 150 mm Hg ) .", "spans": [{"span_id": 0, "text": "telmisartan", "start": 127, "end": 138, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "amlodipine", "start": 149, "end": 159, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "amlodipine", "start": 200, "end": 210, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial. Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. ### objective The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. ### methods An 8-week , randomized , parallel-group , double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg ( T/A ; n = 352 ) with once-daily amlodipine 10 mg ( A ; n = 354 ) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension ( systolic BP [ SBP ] > 150 mm Hg ) . ### results Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. ### conclusions In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).", "source": "https://pubmed.ncbi.nlm.nih.gov/22386829/"}
+{"doc_id": "63e916e263ec45ae78e3b37282fa746f", "sentence": "Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers .", "spans": [{"span_id": 0, "text": "tenofovir", "start": 57, "end": 66, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "didanosine", "start": 71, "end": 81, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effect of tenofovir on didanosine absorption in patients with HIV. To evaluate the pharmacokinetic interaction between tenofovir and didanosine when used in combination as a highly active antiretroviral therapy regimen. ### Data Sources Literature retrieval was accessed through MEDLINE (1966-January 2003) using the terms tenofovir and didanosine. Abstracts from recent meetings, including the International AIDS Society, Interscience Conference on Antimicrobial Agents and Chemotherapy, and the Infectious Diseases Society of America, were reviewed for relevant abstracts and poster presentations. ### Data Synthesis Pharmacokinetic studies evaluating the concurrent use of tenofovir and didanosine have been performed in healthy volunteers . tenofovir 300 mg administered concurrently with 400 mg didanosine results in a 48-64% increase in the didanosine maximum plasma concentration and AUC with no significant alterations in the tenofovir pharmacokinetic parameters. tenofovir 300 mg and didanosine 250 mg has been compared with didanosine 400 mg alone. The results demonstrated equivalent didanosine AUCs. ### conclusions When used concurrently, tenofovir significantly increases the maximum plasma concentration and the AUC of didanosine. Additional data in HIV-infected patients are needed to determine the long-term toxicities of this combination therapy. didanosine dose reduction should be considered when these 2 agents are used concurrently.", "source": "https://pubmed.ncbi.nlm.nih.gov/12921517/"}
+{"doc_id": "14e658c0964fbb5b76fbaf6250621d8a", "sentence": "This comparative phase III trial of mitoxantrone+vinorelbine ( MV ) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin ( FAC/FEC ) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy , while resulting in an improved tolerance in relation to alopecia and nausea/vomiting .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 114, "end": 125, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "epirubicin", "start": 129, "end": 139, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer.  This comparative phase III trial of mitoxantrone+vinorelbine ( MV ) versus 5-fluorouracil+cyclophosphamide+either doxorubicin or epirubicin ( FAC/FEC ) in the treatment of metastatic breast cancer was conducted to determine whether MV would produce equivalent efficacy , while resulting in an improved tolerance in relation to alopecia and nausea/vomiting . This multicentre study recruited and randomised 281 patients with metastatic breast cancer; 280 were evaluable for response survival and toxicity (138 received FAC/FEC, 142 received MV). Patient characteristics were matched in each arm and stratification for prior exposure to adjuvant therapy was made prospectively. The overall response rate (ORR) was equivalent in the two arms (33.3% for FAC/FEC versus 34.5% for MV), but MV was more effective in patients who had received prior adjuvant therapy (13% (95% confidence interval (CI) 3-23) for FAC/FEC versus 33% (95% CI 20-47) for MV P=0.025) with a better progression-free survival (PFS) (5 months (range 1-18 months) versus 8 months (range 1-27 months); P=0.0007 for FAC/FEC versus MV, respectively) while FAC/FEC was more effective in previously untreated patients (ORR 43% (95% CI 33-53) versus 35% (95% CI 25-45), P=0.26; PFS 9 months (range 0-29 months) versus 6 months (range 0-26 months) P=0.014). Toxicity was monitored through the initial six cycles of therapy; febrile neutropenia and delayed haematological recovery was more frequent for MV (P=0.001), while nausea/vomiting of grades 3-4 was greater for FAC/FEC (P=0.031), as was alopecia (P=0.0001), cardiotoxicity was the same for the two regimens. MV represents a chemotherapy combination with equivalent efficacy to standard FAC/FEC and improved results for patients who have previously received adjuvant chemotherapy. Toxicity must be balanced to allow for increased haematological suppression and risk of febrile neutropenia with MV compared with a higher risk of subjectively unpleasant side-effects such as nausea/vomiting and alopecia with FAC/FEC.", "source": "https://pubmed.ncbi.nlm.nih.gov/11378344/"}
+{"doc_id": "a4a0e2aa03eb1a3c7b02ab4d991eca20", "sentence": "Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males ( age range : 18 - 26 years ) to compare with trait measures of trust and aggressive behavior .", "spans": [{"span_id": 0, "text": "oxytocin", "start": 18, "end": 26, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "vasopressin", "start": 31, "end": 42, "token_start": 4, "token_end": 5}], "rels": [], "paragraph": "Oxytocin, vasopressin and trust: Associations with aggressive behavior in healthy young males. oxytocin enhances trust during social interactions and reduces the tendency for social betrayal. Animal studies have revealed that oxytocin is also an important factor in the establishment and regulation of aggression, for which social interaction is a critical precondition. In humans, however, the effects of oxytocin appear more nuanced and influenced by social context and personality traits. Moreover, the pro-social effects of oxytocin are not mirrored by vasopressin, despite their high chemical similarity. Rather, vasopressin has been associated with an increase of aggressive responses. Therefore, we sought to investigate the association of oxytocin and vasopressin with trust and aggressive behavior. Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males ( age range : 18 - 26 years ) to compare with trait measures of trust and aggressive behavior . We found a significant interaction of oxytocin and trust on aggression in which low trait measures of trust, in combination with low levels of oxytocin, were associated with a history of aggressive behavior. Notably, we found no significant associations for vasopressin. Although both oxytocin and vasopressin have been shown to be important in the emergence of violent behavior, our study suggests that oxytocin may be particularly modified by affiliative behaviors. These findings provide insights into the neuropsychological influences of oxytocin, and highlights the potential for clinical translation regarding the treatment of patients who exhibit recurrent aggressive behavior.", "source": "https://pubmed.ncbi.nlm.nih.gov/30802507/"}
+{"doc_id": "a852ffe5eeabb1b66257d24e56fa70bf", "sentence": "Additionally , the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated .", "spans": [{"span_id": 0, "text": "Lapatinib", "start": 38, "end": 47, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "Herceptin", "start": 62, "end": 71, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "Cetuximab", "start": 75, "end": 84, "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": "Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines. lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of lapatinib for therapy of ESCC patients, we evaluated the effect of lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally , the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated . lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of lapatinib. Cumulatively, the data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of lapatinib and cetuximab/Herceptin is a promising strategy in ESCC.", "source": "https://pubmed.ncbi.nlm.nih.gov/21207425/"}
+{"doc_id": "aa87c9c97af30d5f0c6ba4db662cd97d", "sentence": "In a case-control study , we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy .", "spans": [{"span_id": 0, "text": "aspirin", "start": 90, "end": 97, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "clopidogrel", "start": 102, "end": 113, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "aspirin", "start": 143, "end": 150, "token_start": 22, "token_end": 23}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Preoperative platelet aggregation predicts perioperative blood loss and rethoracotomy for bleeding in patients receiving dual antiplatelet treatment prior to coronary surgery. Patients scheduled for coronary artery bypass graft surgery (CABG) are commonly treated with clopidogrel. We sought to assess the relation between preoperative platelet aggregation and bleeds in CABG patients on clopidogrel. ### Material And Methods In a case-control study , we compared 52 consecutive patients undergoing isolated CABG on aspirin and clopidogrel 75mg/d versus 50 controls on aspirin monotherapy . Platelet aggregation induced by 10\u03bcmol/l adenosine di-phosphate (ADP) in platelet-rich plasma was measured in subjects on clopidogrel within 5days prior to surgery. ADP-induced aggregation of \u226550% was used to define subjects with satisfactory inhibition of platelet reactivity. ### results In 29 patients with preoperative ADP-induced aggregation \u226550%, compared with 23 subjects with aggregation <50%, lower chest-tube drainage volumes (after 6h, p=0.002; and 12h, p=0.001) and fewer rethoracotomies were observed (p=0.03). The former group was characterized with lower transfusion rates of packed red blood cells (p=0.009), platelet concentrate (p=0.04) and fresh frozen plasma (p=0.001). Patients with ADP-induced aggregation \u226550% did not differ from untreated controls regarding the postoperative drainage, transfusions and rethoracotomy. The incidence of thromboembolic events and death during perioperative period were similar in all groups. Multivariate logistic regression identified ADP-induced aggregation <50% as the only independent predictor of rethoracotomy (OR=2.94 [1.12-7.75], p=0.029). ### conclusions Patients on aspirin and clopidogrel <5days before CABG who had preoperative ADP-induced platelet aggregation \u226550% have bleeding risk similar to those receiving aspirin monotherapy. Reduced platelet reactivity to ADP can predict postoperative bleeding in CABG patients on dual antiplatelet therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/26003782/"}
+{"doc_id": "53063ff66fc71e61d0f3a62bb493d9fe", "sentence": "The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin , 1 to 3 tubes higher than the broth dilution MICs for ofloxacin , 1 to 3 tubes higher than the broth dilution MICs for erythromycin , and the same as the broth dilution MICs for rifampin .", "spans": [{"span_id": 0, "text": "levofloxacin", "start": 67, "end": 79, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "erythromycin", "start": 200, "end": 212, "token_start": 40, "token_end": 41}, {"span_id": 2, "text": "rifampin", "start": 259, "end": 267, "token_start": 51, "token_end": 52}], "rels": [], "paragraph": "Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila. The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml). The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin , 1 to 3 tubes higher than the broth dilution MICs for ofloxacin , 1 to 3 tubes higher than the broth dilution MICs for erythromycin , and the same as the broth dilution MICs for rifampin . In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin. At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L. pneumophila. In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin. Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h. In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy. Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L. pneumophila when it was studied alone or in a combination with rifampin.", "source": "https://pubmed.ncbi.nlm.nih.gov/7486896/"}
+{"doc_id": "e7607395b589a9d6a885823a4bdd8d74", "sentence": "Ketanserin ( a 5-HT2 antagonist , 10 mumol/L ) and tropisetron ( a 5-HT3 antagonist , 1 mumol/L ) had no effect .", "spans": [{"span_id": 0, "text": "Ketanserin", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "tropisetron", "start": 51, "end": 62, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Ketotifen modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional nonhistamine receptor. In guinea pig airways, electrical field stimulation (50 V, 0.5 msec, 8 Hz for 20 seconds) produces a rapid contraction, which is followed by a long-lasting contraction, at least in the lower part of the trachea and in the bronchi. The latter contraction is due to the release of neuropeptides from airway sensory nerves. ketotifen fumarate has been demonstrated to inhibit the noncholinergic contraction in guinea pig airways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate which receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. ketotifen (3 to 100 mumol/L) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 74% +/- 7% at 8 Hz stimulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 mumol/L) or thioperamide (10 mumol/L) or phentolamine (10 mumol/L) did not prevent the inhibitory effect of ketotifen (10 mumol/L). cetirizine (10 mumol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 mumol/L) and methysergide (1 mumol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 mumol/L). Ketanserin ( a 5-HT2 antagonist , 10 mumol/L ) and tropisetron ( a 5-HT3 antagonist , 1 mumol/L ) had no effect . Ketoifen (100 mumol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 mumol/L to 10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/8064073/"}
+{"doc_id": "6f5e628682c1f970cc1c941f78c757f9", "sentence": "This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam .", "spans": [{"span_id": 0, "text": "zidovudine", "start": 107, "end": 117, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "oxazepam", "start": 122, "end": 130, "token_start": 16, "token_end": 17}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient.  This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam . Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. zidovudine concentrations were determined by radioimmunoassay. oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)", "source": "https://pubmed.ncbi.nlm.nih.gov/8417175/"}
+{"doc_id": "5fb6d683308d65ef5c0f0d786b1bd4cf", "sentence": "Patients with apical CFTR protein showed higher residual chloride secretion than those without ( amiloride to isoprenaline value of 4.59 and 0.56 mV , respectively , p = 0.01 ) .", "spans": [{"span_id": 0, "text": "amiloride", "start": 97, "end": 106, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "isoprenaline", "start": 110, "end": 122, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Correlation between nasal potential difference measurements, genotype and clinical condition in patients with cystic fibrosis. In cystic fibrosis (CF), the clinical condition of patients correlates poorly with genotype. One possible explanation is that clinical status is influenced by net preserved chloride secretion rather than the CF mutation. We tested the relationships between residual chloride secretion, as measured by nasal potential difference (PD) and the type of mutation (genotypes expressing apical cystic fibrosis transmembrane conductance regulator (CFTR) protein versus those that do not) and clinical status. Twenty two CF patients (mean age 25.7 yrs, 11 females and 11 males, mean forced expiratory volume in one second (FEV1) 53.1% of predicted) with defined genotypes were recruited. Nasal PD was measured using a standard protocol involving the perfusion of the nasal epithelium with a sodium channel blocker (amiloride), followed by a solution of low chloride and finally with isoprenaline. Patients with apical CFTR protein showed higher residual chloride secretion than those without ( amiloride to isoprenaline value of 4.59 and 0.56 mV , respectively , p = 0.01 ) . There was no correlation between mutation type and clinical condition. When these patients were recategorized as \"high\" (> 10 mV amiloride to isoprenaline response) or \"low\" (10 mV or less) chloride secretors, we found that the former group had a significantly higher FEV1 (67.7 versus 48.3% pred) and a better pulmonary radiological score (4.14 versus 7.07, by Northern scoring system). These results suggest that some cystic fibrosis patients, regardless of genotype, have an ability to secrete chloride when stimulated with chloride secretatagogues, and this is correlated with a better lung function. These results also have implications for the use of potential difference measurements in novel cystic fibrosis transmembrane conductance regulator replacement trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/9311495/"}
+{"doc_id": "74c0e16ee5db2c1c5de0863213b10cdd", "sentence": "African American men were more likely to receive ketoconazole than abiraterone , enzalutamide , or docetaxel ( AME , 2.8 % ; 95 % CI , 0.7%-4.9 % ) .", "spans": [{"span_id": 0, "text": "ketoconazole", "start": 49, "end": 61, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "abiraterone", "start": 67, "end": 78, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "enzalutamide", "start": 81, "end": 93, "token_start": 12, "token_end": 13}, {"span_id": 3, "text": "docetaxel", "start": 99, "end": 108, "token_start": 15, "token_end": 16}], "rels": [], "paragraph": "Factors influencing treatment of veterans with advanced prostate cancer. Treatments for metastatic castration-resistant prostate cancer (CRPC) differ in toxicity, administration, and evidence. In this study, clinical and nonclinical factors associated with the first-line treatment for CRPC in a national delivery system were evaluated. ### methods National electronic laboratory and clinical data from the Veterans Health Administration were used to identify patients with CRPC (ie, rising prostate-specific antigen [PSA] on androgen deprivation) who received abiraterone, enzalutamide, docetaxel, or ketoconazole from 2010 through 2017. It was determined whether clinical (eg, PSA) and nonclinical factors (eg, race, facility) were associated with the first-line treatment selection using multilevel, multinomial logistic regression. The average marginal effects (AMEs) were calculated of patient, disease, and facility characteristics on ketoconazole versus more appropriate CRPC therapy. ### results There were 4998 patients identified with CRPC who received first-line ketoconazole, docetaxel, abiraterone, or enzalutamide. After adjustment, increasing age was associated with receipt of abiraterone (adjusted odds ratio [aOR], 1.07; 95% credible interval [CrI], 1.06-1.09) or enzalutamide (aOR, 1.10; 95% CrI, 1.08-1.11) versus docetaxel. Greater preexisting comorbidity was associated with enzalutamide versus abiraterone (aOR, 1.53; 95% CrI, 1.23-1.91). Patients with higher PSA values at the start of treatment were more likely to receive docetaxel than oral agents and less likely to receive ketoconazole than other oral agents. African American men were more likely to receive ketoconazole than abiraterone , enzalutamide , or docetaxel ( AME , 2.8 % ; 95 % CI , 0.7%-4.9 % ) . This effect was attenuated when adjusting for facility characteristics (AME, 1.9%; 95% CI, -0.4% to 4.1%). ### conclusions Clinical factors had an expected effect on the first-line treatment selection. Race may be associated with the receipt of a guideline-discordant first-line treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/33764537/"}
+{"doc_id": "5fb2877fd458b4bee2e72b3106d5a0a8", "sentence": "These observations are important in the development of vorinostat , and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen .", "spans": [{"span_id": 0, "text": "vorinostat", "start": 55, "end": 65, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "exemestane", "start": 175, "end": 185, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "ibuprofen", "start": 190, "end": 199, "token_start": 29, "token_end": 30}], "rels": [], "paragraph": "Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. ### methods Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. ### results Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. ### conclusion UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat , and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen .", "source": "https://pubmed.ncbi.nlm.nih.gov/21849928/"}
+{"doc_id": "bb7ddd4997f0951a2d47cc6d0d000cc5", "sentence": "Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939 , but combination treatment with everolimus ( mTOR inhibitor ) and erlotinib resulted in synergistic cell growth inhibition .", "spans": [{"span_id": 0, "text": "XAV939", "start": 149, "end": 155, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "everolimus", "start": 189, "end": 199, "token_start": 26, "token_end": 27}, {"span_id": 2, "text": "erlotinib", "start": 223, "end": 232, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "POS", "spans": [0, 2], "is_context_needed": false}], "paragraph": "Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Tyrosine kinase inhibitors (TKIs) against EGFR and c-Met are initially effective when administered individually or in combination to non-small cell lung cancer (NSCLC) patients. However, the overall efficacies of TKIs are limited due to the development of drug resistance. Therefore, it is important to elucidate mechanisms of EGFR and c-Met TKI resistance in order to develop more effective therapies. Model NSCLC cell lines H1975 and H2170 were used to study the similarities and differences in mechanisms of EGFR/c-Met TKI resistance. H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TKI therapies, while H2170 cells are EGFR wild-type. Previously, H2170 cells were made resistant to the EGFR TKI erlotinib and the c-Met TKI SU11274 by exposure to progressively increasing concentrations of TKIs. In H2170 and H1975 TKI-resistant cells, key Wnt and mTOR proteins were found to be differentially modulated. Wnt signaling transducer, active \u03b2-catenin was upregulated in TKI-resistant H2170 cells when compared to parental cells. GATA-6, a transcriptional activator of Wnt, was also found to be upregulated in resistant H2170 cells. In H2170 erlotinib resistant cells, upregulation of inactive GSK3\u03b2 (p-GSK3\u03b2) was observed, indicating activation of Wnt and mTOR pathways which are otherwise inhibited by its active form. However, in H1975 cells, Wnt modulators such as active \u03b2-catenin, GATA-6 and p-GSK3\u03b2 were downregulated. Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939 , but combination treatment with everolimus ( mTOR inhibitor ) and erlotinib resulted in synergistic cell growth inhibition . Thus, in H2170 cells and H1975 cells, simultaneous inhibition of key Wnt or mTOR pathway proteins in addition to EGFR and c-Met may be a promising strategy for overcoming EGFR and c-Met TKI resistance in NSCLC patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/26301867/"}
+{"doc_id": "a07c1da8ac6e880d708e348dee854111", "sentence": "The addition of dexmedetomidine to bupivacaine 0.5 % in EUS-CPN demonstrated beneficial effects as regards the degree and duration of pain relieve with negligible effect on the patient survival .", "spans": [{"span_id": 0, "text": "dexmedetomidine", "start": 16, "end": 31, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "bupivacaine", "start": 35, "end": 46, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Value of Adding Dexmedetomidine in Endoscopic Ultrasound-Guided Celiac Plexus Neurolysis for Treatment of Pancreatic Cancer-Associated Pain. Abdominal and back pain is present in up to 80% of patients with pancreatic cancer and represents a significant cause of morbidity. Celiac plexus neurolysis (CPN) demonstrated good results in relief of pain of upper abdominal malignancy. Dexmedetomidine is alpha-2 adrenoceptor highly selective agonist approved for procedural sedation use. ### Patients And Methods Fifty patients divided in two groups with locally advanced pancreatic cancer-associated abdominal pain underwent endoscopic ultrasound (EUS)-guided CPN using bupivacaine 0.5% alone with alcohol for the first group and bupivacaine 0.5% plus dexmedetomidine in the second. Patients scored their pain according to the Numeric Rating Scale (NRS-11) before, 2, 4, 6, 8, 12, 16, and 24\u00a0week after the procedure. ### results The study has included 50 patient in two groups. There was no significant difference between the two groups as regards medical, laboratory, or tumor characters. The median pain score decreases from 8.32\u2009\u00b1\u20090.75 before the procedure to 3.75\u2009\u00b1\u20093.72 24\u00a0week after the procedure in group 1 and from 8.08\u2009\u00b1\u20090.86 before to 1.67\u2009\u00b1\u20092.3 24\u00a0week after the procedure in group 2. However, there was no significant difference between the two groups in the median pain score during the first 4\u00a0weeks. There was no statistically significant difference between the two groups as regards the median survival time. ### conclusion The addition of dexmedetomidine to bupivacaine 0.5 % in EUS-CPN demonstrated beneficial effects as regards the degree and duration of pain relieve with negligible effect on the patient survival .", "source": "https://pubmed.ncbi.nlm.nih.gov/32621112/"}
+{"doc_id": "ee28ea04905713e9b380ad3cbd796d56", "sentence": "The incidence of carcinoma , confirmed microscopically , was : control 14/20 ( 70 % ) ; high-dose gefitinib , 7/20 ( 35 % ) ; low-dose gefitinib , 7/20 ( 35 % ) ; high-dose meloxicam 7/21 ( 33 % ) ; and low-dose meloxicam , 12/20 ( 60 % ) .", "spans": [{"span_id": 0, "text": "gefitinib", "start": 98, "end": 107, "token_start": 18, "token_end": 19}, {"span_id": 1, "text": "gefitinib", "start": 135, "end": 144, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "meloxicam", "start": 173, "end": 182, "token_start": 36, "token_end": 37}, {"span_id": 3, "text": "meloxicam", "start": 212, "end": 221, "token_start": 45, "token_end": 46}], "rels": [{"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis. To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model. ### Materials And Methods The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips. ### results The incidence of carcinoma , confirmed microscopically , was : control 14/20 ( 70 % ) ; high-dose gefitinib , 7/20 ( 35 % ) ; low-dose gefitinib , 7/20 ( 35 % ) ; high-dose meloxicam 7/21 ( 33 % ) ; and low-dose meloxicam , 12/20 ( 60 % ) . The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects. ### conclusion Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects.", "source": "https://pubmed.ncbi.nlm.nih.gov/16469040/"}
+{"doc_id": "94de76aa894156859854546a83ca433f", "sentence": "Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy ( more than 200 mg/d of oral morphine equivalent ) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine , ropivacaine , and clonidine .", "spans": [{"span_id": 0, "text": "ziconotide", "start": 271, "end": 281, "token_start": 39, "token_end": 40}, {"span_id": 1, "text": "morphine", "start": 296, "end": 304, "token_start": 42, "token_end": 43}, {"span_id": 2, "text": "ropivacaine", "start": 307, "end": 318, "token_start": 44, "token_end": 45}, {"span_id": 3, "text": "clonidine", "start": 325, "end": 334, "token_start": 47, "token_end": 48}], "rels": [{"class": "NEG", "spans": [0, 1, 2, 3], "is_context_needed": false}], "paragraph": "Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Ziconotide is a new analgesic agent administered intrathecally. It is challenging to use and can induce several and sometimes serious adverse events. A low initial dosage followed by slow titration may reduce serious adverse events. ### objective To determine whether a low starting dosage of ziconotide, followed by slow titration, decreases the incidence of major adverse events associated with ziconotide when used for intractable cancer pain. ### Study Design Observational cohort study. ### setting Three French cancer centers. ### methods Patients with incurable cancer causing chronic pain rated above 6/10 on a numerical scale while receiving high-dose opioid therapy ( more than 200 mg/d of oral morphine equivalent ) and/or exhibiting severe opioid-related adverse events received intrathecal infusions of ziconotide combined with morphine , ropivacaine , and clonidine . ### results Seventy-seven patients were included. Adverse events were recorded in 57% of them; moderate adverse events occurred in 51%. Adverse events required treatment discontinuation in 7  (9%) including 5  (6%) for whom a causal role for ziconotide was highly likely; among them 4  (5%) were serious. All patients experienced a significant and lasting decrease in pain intensity  (by 48%) in response to intrathecal analgesic therapy that included ziconotide. ### limitations Limitations include the nonrandomized, observational nature of the study. Determining the relative contributions of each drug to adverse events was difficult, and some of the adverse events manifested as clinical symptoms of a subjective nature. ### conclusions The rates of minor and moderate adverse events were consistent with previous reports. However, the rate of serious adverse events was substantially lower. Our study confirms the efficacy of intrathecal analgesia with ziconotide for relieving refractory cancer pain. These results indicate that multimodal intrathecal analgesia in patients with cancer pain should include ziconotide from the outset in order to provide time for subsequent slow titration.", "source": "https://pubmed.ncbi.nlm.nih.gov/22996851/"}
+{"doc_id": "68c9547776b2824a3e90e1f59b9b4366", "sentence": "Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage .", "spans": [{"span_id": 0, "text": "adalimumab", "start": 5, "end": 15, "token_start": 1, "token_end": 2}, {"span_id": 1, "text": "etanercept", "start": 20, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 2, "text": "methotrexate", "start": 56, "end": 68, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment of rheumatoid arthritis (RA) in adults. ### Data Sources Electronic databases were searched up to February 2005. ### Review Methods Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. ### results Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (<or=3 years) who were na\u00efve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage . etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were na\u00efve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around pound30,000 per quality-adjusted life-year (QALY) in early RA and pound50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is pound24,000 per QALY, substantially lower than for adalimumab ( pound30,000 per QALY) or infliximab ( pound38,000 per QALY). First line use as monotherapy generates ICERs around pound50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. ### conclusions adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality.", "source": "https://pubmed.ncbi.nlm.nih.gov/17049139/"}
+{"doc_id": "5386d10522b4ceab39a95e1adbc57b27", "sentence": "Combination chemotherapy with gemcitabine ( Gem ) , doxorubicin ( Dox ) , and paclitaxel ( Pac ) ( GAT ) has been considered attractive as first-line treatment in metastatic breast cancer .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 30, "end": 41, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doxorubicin", "start": 52, "end": 63, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "paclitaxel", "start": 78, "end": 88, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Evaluation of a gemcitabine-doxorubicin-paclitaxel combination schedule through flow cytometry assessment of apoptosis extent induced in human breast cancer cell lines.  Combination chemotherapy with gemcitabine ( Gem ) , doxorubicin ( Dox ) , and paclitaxel ( Pac ) ( GAT ) has been considered attractive as first-line treatment in metastatic breast cancer . We compared the potential of various schedules of GAT to induce apoptosis on MDA-MB-231, MCF7, and T47D human breast cancer cell lines. The extent of apoptotic induction was analyzed by flow cytometry with 7-aminoactinomycin D (7AAD) staining. Differences between various schedules in terms of apoptotic induction were statistically significant (P < 0.05). The most effective apoptotic induction regimen was achieved by the sequence: Dox for 16 h followed by Pac + Gem. Schedules employing a 16-h interval between drug administrations induced higher levels of apoptosis in human breast cancer cell lines compared with schedules using a 4-h interval. The therapeutic efficacy of the experimental results shown in this paper has been clinically corroborated in a phase II trial in metastatic breast cancer patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/12036452/"}
+{"doc_id": "e9da5f1b64d56f794f15c5887995e662", "sentence": "Anti-cancer agents like adriamycin , mitomycin-C , bleomycin , and etoposide express their cell-killing activity partly through oxygen radicals .", "spans": [{"span_id": 0, "text": "adriamycin", "start": 24, "end": 34, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "mitomycin-C", "start": 37, "end": 48, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "bleomycin", "start": 51, "end": 60, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "etoposide", "start": 67, "end": 76, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Overcoming of cross-resistance to the cell-killing activity of oxygen radicals in VCR-resistant hematologic cell lines with cyclosporin-A.  Anti-cancer agents like adriamycin , mitomycin-C , bleomycin , and etoposide express their cell-killing activity partly through oxygen radicals . Since vincristine (VCR)-resistant cells show cross-resistance to oxygen radicals, this study was designed to study whether the combined effects of oxygen radicals derived from hypoxanthine-xanthine oxidase plus enhancers of anti-cancer drugs such as verapamil (Ver), dipyridamole (Dip), and cyclosporin-A (Cy-A) overcome the cross-resistance for oxygen radicals in VCR-resistant human leukemia/lymphoma cell lines. We found that 3 micrograms/mL Cy-A enhances the cidal effect of oxygen radicals on two of five types of wild type and two of five VCR-resistant cell lines and it could overcome the cross-resistance to oxygen radicals in VCR-resistant cells. Neither Ver nor Dip showed any effect on the cidal activity of oxygen radicals. Thus, it was suggested that Cy-A works with different mechanisms from those of Ver or Dip, and Cy-A may be useful in reducing the doses of anti-neoplastic agents that exert their activity via oxygen radicals in the clinical treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/9673368/"}
+{"doc_id": "5f1a3d2c3e4b6683bc6cb633081ad7a6", "sentence": "The efficacy and safety of isepamicin compared with amikacin in the treatment of intra-abdominal infections .", "spans": [{"span_id": 0, "text": "isepamicin", "start": 27, "end": 37, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "amikacin", "start": 52, "end": 60, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "The efficacy and safety of isepamicin compared with amikacin in the treatment of intra-abdominal infections . This multicentre, randomised, open-label, parallel group study compared the efficacy and safety of isepamicin (15 mg/kg once daily) and amikacin (7.5 mg/kg twice daily) when given intravenously in combination with metronidazole to 267 hospitalised adults with intra-abdominal infections. Clinical cure or improvement was achieved in 96.3% (130/135) evaluable patients (efficacy population) in the isepamicin group and 94.3% (66/70) patients in the amikacin group. Bacteriological elimination occurred in 93.3% (126/135) evaluable isepamicin patients and 95.7% (67/170) amikacin patients. there was not statistically significant differences between the groups. Adverse events were reported by 9% of patients in the isepamicin group (16/178) and 10% of patients in the amikacin group (9/89). Events considered to be related to treatment occurred in 6% of patients in both groups. The most frequent adverse events were diarrhoea, nausea and vomiting. Renal problems caused three patients (2 isepamicin, 1 amikacin) to withdraw from the study. Ototoxicity (detected by audiometric testing) occurred in one patient (treated with isepamicin). In conclusion, isepamicin at a dose of 15 mg/kg once daily was shown to be as effective as amikacin (7.5 mg/kg twice daily) in the treatment of intra-abdominal infections in hospitalised adults also treated with metronidazole. Both treatments were well tolerated.", "source": "https://pubmed.ncbi.nlm.nih.gov/8622103/"}
+{"doc_id": "796ef671b82d8b62f17e74d857fe5411", "sentence": "Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph . aureus and Str . faecalis , respectively .", "spans": [{"span_id": 0, "text": "Imipenem", "start": 0, "end": 8, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "nafcillin", "start": 27, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "penicillin", "start": 46, "end": 56, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "gentamicin", "start": 62, "end": 72, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Imipenem therapy of experimental Staphylococcus aureus and Streptococcus faecalis endocarditis. imipenem was very active in vitro against 36 Staphylococcus aureus isolates from cases of infective endocarditis; the MBC90 was 0.06 mg/l (four- to eight-fold more active than nafcillin). The in-vitro activity of imipenem against 22 Streptococcus faecalis isolates from proven endocarditis cases was similar to that of penicillin G (MBC90 = 8 mg/l). Imipenem was compared with nafcillin and with penicillin plus gentamicin in the therapy of experimental endocarditis induced in rabbits by Staph . aureus and Str . faecalis , respectively . The dosages were chosen to simulate closely serum antibiotic concentrations found in humans receiving standard parenteral regimens. imipenem was more rapidly bactericidal than nafcillin in experimental staphylococcal endocarditis. The mean +/- S.D. Staph. aureus concentrations within aortic valve vegetations (log10 cfu/g) after 5 days of therapy were as follows: imipenem = 1.39 +/- 0.61 versus nafcillin 2.39 +/- 0.36 (P less than 0.02). Both the imipenem and nafcillin regimens resulted in 'sterile' vegetations in congruent to 50% of rabbits with experimental staphylococcal endocarditis after 5 days of therapy (P greater than 0.05). imipenem was also equivalent to penicillin plus gentamicin in the therapy of experimental enterococcal endocarditis for 5 days, as assessed by the mean cfu/g vegetation and the percentage of vegetations rendered sterile. However, 7 days of therapy cured experimental enterococcal endocarditis in 72% of rabbits receiving penicillin plus gentamicin versus 20% for imipenem alone (P less than 0.05). imipenem deserves further evaluation in the therapy of infective endocarditis, both in experimental animal models of infection and in humans. This agent may prove useful in the therapy of staphylococcal endocarditis in a variety of difficult clinical situations. Therapy of enterococcal endocarditis with imipenem alone is not advisable, pending further data.", "source": "https://pubmed.ncbi.nlm.nih.gov/6421794/"}
+{"doc_id": "2ffc3bc4a2d4cef091142559f41db561", "sentence": "The total dose of paclitaxel ( 175 - 200 mg/m2 ) ; cisplatin ( 75 mg/m2 ) ; and etoposide ( 175 - 200 mg/m2 ) was divided into five daily doses administered over 3 h with cycles repeated at 21 - 28 days .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 18, "end": 28, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "cisplatin", "start": 51, "end": 60, "token_start": 12, "token_end": 13}, {"span_id": 2, "text": "etoposide", "start": 80, "end": 89, "token_start": 19, "token_end": 20}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Paclitaxel, cisplatin, etoposide combination chemotherapy: a multifractionated bolus dose schedule for non-small cell lung cancer. In this phase II study, paclitaxel was added to the combination of cisplatin and etoposide (TPE regimen), in 37 patients with advanced non-small cell lung cancer, using a multifractionated dosing schedule. The total dose of paclitaxel ( 175 - 200 mg/m2 ) ; cisplatin ( 75 mg/m2 ) ; and etoposide ( 175 - 200 mg/m2 ) was divided into five daily doses administered over 3 h with cycles repeated at 21 - 28 days . 15 patients had stage III A or B disease and 22 stage IV disease. 32 patients were evaluable for toxicity and 37 for response. Neutropenia was the most prominent toxicity. Grade 3 or grade 4 neutropenia was observed in 12 (38%) and 9 (25%) of the patients, respectively and 11 patients required hospitalisation. 3 patients died secondary to chemotherapy related sepsis. Diarrhoea (grade 3, 3 patients; grade 4, 2 patients) was the only other significant non-haematological acute toxicity. The optimal dose rate for this multifractionated regimen was paclitaxel 35 or 40 mg/m2/fraction; cisplatin 15 mg/m2/fraction; etoposide 35 or 40 mg/m2/fraction. Responses were observed in 28 of 37 evaluable patients (3 complete response; 25 partial responses [76%]. 22 patients are alive; 8 with stage III B disease received radiation or surgery (3 had minimal or no tumour in the pathology specimen). TPE is a highly active regimen for non-small cell lung cancer and multifractionated dose scheduling is a feasible and well tolerated system.", "source": "https://pubmed.ncbi.nlm.nih.gov/9713270/"}
+{"doc_id": "d3d3065094bd69c0fc64085832f1d55a", "sentence": "In this phase 3 trial , we randomly assigned ( in a 1:1:1 ratio ) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib ( 20 mg orally once daily ) plus pembrolizumab ( 200 mg intravenously once every 3 weeks ) , lenvatinib ( 18 mg orally once daily ) plus everolimus ( 5 mg orally once daily ) , or sunitinib ( 50 mg orally once daily , alternating 4 weeks receiving treatment and 2 weeks without treatment ) .", "spans": [{"span_id": 0, "text": "lenvatinib", "start": 154, "end": 164, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "pembrolizumab", "start": 198, "end": 211, "token_start": 37, "token_end": 38}, {"span_id": 2, "text": "lenvatinib", "start": 258, "end": 268, "token_start": 48, "token_end": 49}, {"span_id": 3, "text": "everolimus", "start": 302, "end": 312, "token_start": 57, "token_end": 58}, {"span_id": 4, "text": "sunitinib", "start": 345, "end": 354, "token_start": 67, "token_end": 68}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. ### methods In this phase 3 trial , we randomly assigned ( in a 1:1:1 ratio ) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib ( 20 mg orally once daily ) plus pembrolizumab ( 200 mg intravenously once every 3 weeks ) , lenvatinib ( 18 mg orally once daily ) plus everolimus ( 5 mg orally once daily ) , or sunitinib ( 50 mg orally once daily , alternating 4 weeks receiving treatment and 2 weeks without treatment ) . The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. ### results A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P\u2009=\u20090.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P\u2009=\u20090.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. ### conclusions lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).", "source": "https://pubmed.ncbi.nlm.nih.gov/33616314/"}
+{"doc_id": "6f0476440606d257ae4a2266a30878d1", "sentence": "Only chemotherapy by intravenous administration of 2 courses of 120 - 150 mg ACNU ( 1.7 - 2.2 mg/kg ) and 4 mg vincristine ( 0.06 mg/kg ) with intrathecal administration of methotrexate was given at this time .", "spans": [{"span_id": 0, "text": "ACNU", "start": 77, "end": 81, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "vincristine", "start": 111, "end": 122, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "methotrexate", "start": 173, "end": 185, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "A long surviving case of recurrent medulloblastoma displaying effectiveness of ACNU/vincristine chemotherapy. A favorable case of recurrent medulloblastoma, in which 19 years has elapsed with combination therapy due to surgery, radiation and chemotherapy since the initial operation, is reported. The case was a male of age 12 who was admitted due to medulloblastoma of the classical type. Tumor recurrences were observed 3 times within 7 years after the initial operation and radiation treatment. At the 3rd recurrence, a large tumor was found in the cerebellar vermis and left cerebellar hemisphere on CT with CSF dissemination and a high NSE level in the CSF (62 ng/ml). Only chemotherapy by intravenous administration of 2 courses of 120 - 150 mg ACNU ( 1.7 - 2.2 mg/kg ) and 4 mg vincristine ( 0.06 mg/kg ) with intrathecal administration of methotrexate was given at this time . The tumor image and gait disturbance with radicular pain disappeared completely and the NSE level in the CSF improved to within the normal range (5.4 ng/ml). The patient continues in complete remission, with a Karnovsky performance status of 100% at 4 years after the 3rd recurrence. We report full details of this case in which active treatments consisting mainly of chemotherapy proved to be effective for recurrent medulloblastoma, even though its prognosis is generally very unfavorable.", "source": "https://pubmed.ncbi.nlm.nih.gov/8057133/"}
+{"doc_id": "fac270cf9d9f839bc49728d2d4f38fc7", "sentence": "In first-line treatment of intermediate- to poor-risk patients , the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 139, "end": 148, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "ipilimumab", "start": 153, "end": 163, "token_start": 21, "token_end": 22}, {"span_id": 2, "text": "sunitinib", "start": 171, "end": 180, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A Cost-Effectiveness Analysis of Nivolumab and Ipilimumab Versus Sunitinib in First-Line Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma. The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first-line treatment of intermediate- to poor-risk patients , the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib . The high cost of combined immune-modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab and ipilimumab compared with sunitinib for first-line treatment of intermediate- to poor-risk advanced RCC from the U.S. payer perspective. ### Materials And Methods A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first-line treatment of intermediate- to poor-risk advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. ### results The total mean cost per-patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost-effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. ### conclusion Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness-to-pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost-effective. ### Implications For Practice This article assessed the cost-effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate- to poor-risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality-adjusted life-year with nivolumab and ipilimumab versus sunitinib in these patients.", "source": "https://pubmed.ncbi.nlm.nih.gov/30710066/"}
+{"doc_id": "b050c4f05066a38a88314ba7a6cf1d3a", "sentence": "In addition , docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux .", "spans": [{"span_id": 0, "text": "docetaxel", "start": 14, "end": 23, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "paclitaxel", "start": 72, "end": 82, "token_start": 13, "token_end": 14}], "rels": [], "paragraph": "Preclinical pharmacology of the taxanes: implications of the differences. Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to beta-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition , docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux . Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio- and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons.", "source": "https://pubmed.ncbi.nlm.nih.gov/15161985/"}
+{"doc_id": "0cf78118eeb04f8f121db21b6dd8b17a", "sentence": "The total sample size was 103 , consisting of 31 , 23 , and 19 patients in olanzapine , risperidone , and clozapine groups , respectively and 30 controls .", "spans": [{"span_id": 0, "text": "olanzapine", "start": 75, "end": 85, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "risperidone", "start": 88, "end": 99, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "clozapine", "start": 106, "end": 115, "token_start": 22, "token_end": 23}], "rels": [], "paragraph": "Comparative study of sexual dysfunction and serum prolactin level associated with olanzapine, risperidone, and clozapine in patients with remitted schizophrenia. Sexual dysfunctions have been a major side effect of the second generation anti-psychotic drugs which often affects treatment compliance in patients with schizophrenia. There is no/few systematic review or research addressing sexual dysfunction and their effect on serum prolactin level among different atypical antipsychotics in India. ### aims To determine and compare the frequency of sexual dysfunction associated with olanzapine, risperidone, and clozapine and their effect on serum prolactin level in remitted patients with schizophrenia. ### Settings And Design Cross-sectional hospital-based study. Recruitment by purposive sampling. Estimation of serum prolactin was done using enzyme-linked immunosorbent assay technique. ### Materials And Methods The total sample size was 103 , consisting of 31 , 23 , and 19 patients in olanzapine , risperidone , and clozapine groups , respectively and 30 controls . A Brief Psychiatric Rating Scale, Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and Sexual Functioning Questionnaire were administered. Analysis of variance was used to compare clinical variables. Chi-square test was used to identify the frequency of sexual dysfunction. Kruskal-Wallis test was used to compare UKU side effect, sexual dysfunction, and blood parameters across the study groups. ### Results And Conclusion Eighty-six percentage reported sexual dysfunction in one or more domains of sexual functioning in risperidone group as compared to 48.3% in olanzapine and 31% in clozapine groups, respectively. Prolactin level elevation was statistically significant in risperidone group followed by clozapine and olanzapine groups, respectively.", "source": "https://pubmed.ncbi.nlm.nih.gov/26816428/"}
+{"doc_id": "3602ecfca299c3ee0a85bc8259f20cae", "sentence": "The relative analgesic potency ratios were 0.65 ( 0.56 - 0.76 ) for ropivacaine : bupivacaine , 0.80 ( 0.70 - 0.92 ) for ropivacaine : levobupivacaine , and 0.81 ( 0.69 - 0.94 ) for levobupivacaine : bupivacaine .", "spans": [{"span_id": 0, "text": "ropivacaine", "start": 68, "end": 79, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "bupivacaine", "start": 82, "end": 93, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "ropivacaine", "start": 121, "end": 132, "token_start": 24, "token_end": 25}, {"span_id": 3, "text": "levobupivacaine", "start": 135, "end": 150, "token_start": 26, "token_end": 27}, {"span_id": 4, "text": "levobupivacaine", "start": 182, "end": 197, "token_start": 36, "token_end": 37}, {"span_id": 5, "text": "bupivacaine", "start": 200, "end": 211, "token_start": 38, "token_end": 39}], "rels": [], "paragraph": "Minimum local analgesic doses of ropivacaine, levobupivacaine, and bupivacaine for intrathecal labor analgesia. Doses for intrathecal opioid-local anesthetic mixtures have been arbitrarily chosen. The aim of this study was to compare the analgesic efficacies of intrathecal ropivacaine, levobupivacaine, and bupivacaine for labor analgesia and to determine the analgesic potency ratios for these three drugs. For this purpose, the authors used the up-down sequential allocation model, which estimates the minimum local analgesic dose for intrathecal local anesthetic. ### methods Ninety-seven nulliparous term parturients in spontaneous labor, requesting combined spinal-epidural analgesia, were randomly allocated to one of three groups to receive 0.25% spinal ropivacaine, levobupivacaine, or bupivacaine. The initial dose of the local anesthetic drug was chosen to be 2.5 mg, and the testing interval was set at 0.25 mg. The subsequent doses were determined by the response of the previous parturient. Efficacy was accepted if the visual analog pain score decreased to 10 mm or less on a 100-mm scale within 30 min. The minimum local analgesic dose was calculated using the method of Dixon and Massey. ### results The intrathecal minimum local analgesic dose was 3.64 mg (95% confidence interval, 3.33-3.96 mg) for ropivacaine, 2.94 (2.73-3.16) mg for levobupivacaine, and 2.37 (2.17-2.58) mg for bupivacaine. The relative analgesic potency ratios were 0.65 ( 0.56 - 0.76 ) for ropivacaine : bupivacaine , 0.80 ( 0.70 - 0.92 ) for ropivacaine : levobupivacaine , and 0.81 ( 0.69 - 0.94 ) for levobupivacaine : bupivacaine . There were significant trends (P bupivacaine and levobupivacaine. ### conclusions This study suggests a potency hierarchy of spinal bupivacaine > levobupivacaine > ropivacaine.", "source": "https://pubmed.ncbi.nlm.nih.gov/15731605/"}
+{"doc_id": "0e92133c9b682a28ac91ea5d2c6fcb9d", "sentence": "Lapatinib ( LPT ) could sensitize human epidermal growth factor receptor-2 ( HER-2 ) positive breast cancer to paclitaxel ( PTX ) and induce synergetic action with PTX in preclinical test and phase II/III trial .", "spans": [{"span_id": 0, "text": "Lapatinib", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "paclitaxel", "start": 111, "end": 121, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A novel combined micellar system of lapatinib and Paclitaxel with enhanced antineoplastic effect against human epidermal growth factor receptor-2 positive breast tumor in vitro.  Lapatinib ( LPT ) could sensitize human epidermal growth factor receptor-2 ( HER-2 ) positive breast cancer to paclitaxel ( PTX ) and induce synergetic action with PTX in preclinical test and phase II/III trial . In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with \u00b9H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 \u00b1 0.47 nm and zeta potential of -3.17 \u00b1 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/25421492/"}
+{"doc_id": "32a61c25a4ad01c272675f512c603206", "sentence": "Two of nine patients received 15 mg/kg bevacizumab IV , 90 mg/m(2 ) irinotecan orally for five consecutive days , 100 mg/m(2)/day temozolomide IV for 5 days , and 1.5 mg/m(2 ) vincristine IV , each administered every 21 days .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 39, "end": 50, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "irinotecan", "start": 68, "end": 78, "token_start": 13, "token_end": 14}, {"span_id": 2, "text": "temozolomide", "start": 130, "end": 142, "token_start": 22, "token_end": 23}, {"span_id": 3, "text": "vincristine", "start": 176, "end": 187, "token_start": 32, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience. Chemotherapy for relapsed medulloblastoma has been inadequate, and most patients succumb to disease. ### methods We retrospectively reviewed nine cases of relapsed medulloblastoma treated with bevacizumab, irinotecan, \u00b1\u2009temozolomide. Patients received one to three prior therapeutic regimens. Five patients received 10 mg/kg bevacizumab and 125-150 mg/m(2) irinotecan IV every 2 weeks, with temozolomide, starting at a median dose of 150 mg/m(2) orally for 5 days monthly. Two patients received bevacizumab and irinotecan, but not temozolomide, due to provider preference. Two of nine patients received 15 mg/kg bevacizumab IV , 90 mg/m(2 ) irinotecan orally for five consecutive days , 100 mg/m(2)/day temozolomide IV for 5 days , and 1.5 mg/m(2 ) vincristine IV , each administered every 21 days . ### results Median time to progression was 11 months. Median overall survival was 13 months. Objective tumor response at 3 months was 67 %, including six patients with partial response (PR) and three patients with stable disease (SD). At 6 months, objective response was 55 %, with two patients with PR and three with complete response. Additionally, one patient had SD and three had PD. Two patients remain alive and progression free at 15 and 55 months; another is alive with disease at 20 months. Toxicities included two patients with grade III neutropenia, two with grade III thrombocytopenia, one with grade III elevation of liver function tests, and one patient with grade III diarrhea. ### conclusions The combination of bevacizumab and irinotecan, with or without temozolomide, produces objective responses with minimal toxicity in children with recurrent medulloblastoma. Prospective clinical trials are needed to evaluate the efficacy of this strategy.", "source": "https://pubmed.ncbi.nlm.nih.gov/23296323/"}
+{"doc_id": "8153038603c4967e7f15cff9488531d3", "sentence": "These findings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneficial .", "spans": [{"span_id": 0, "text": "acamprosate", "start": 62, "end": 73, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "naltrexone", "start": 78, "end": 88, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Baseline trajectories of drinking moderate acamprosate and naltrexone effects in the COMBINE study. The COMBINE study evaluated the effects of acamprosate, naltrexone, and the Combined Behavioral Intervention (CBI). In secondary analyses, our goals were to identify trajectories of any drinking prior to randomization, to characterize subjects in these trajectories, and to assess whether prerandomization trajectories predict drinking outcomes and moderate treatment response. ### methods We analyzed daily indicators of any drinking in 90 days prior to randomization using a trajectory-based approach. General linear models and generalized logistic regression assessed main and interactive effects of prerandomization drinking trajectories and treatment on summary drinking measures during active treatment. ### results We identified five trajectories of any drinking prior to randomization: \"T1: frequent drinkers\", \"T2: very frequent drinkers\", \"T3: nearly daily drinkers\", \"T4: consistent daily drinkers\", and \"T5: daily drinkers stopping early\". During treatment, \"T3: nearly daily drinkers\" and \"T4: consistent daily drinkers\" had significantly worse drinking outcomes than \"T1: frequent drinkers\", while \"T5: daily drinkers stopping early\" had comparable drinking outcomes to \"T1: frequent drinkers\". acamprosate significantly increased the chance of abstinence from heavy drinking for the \"T2: very frequent drinking\" trajectory but decreased the chance of abstinence from heavy drinking for \"T5: daily drinkers stopping early\". naltrexone differentially improved rates of continuous abstinence for very frequent drinkers. ### conclusions acamprosate benefited very frequent drinkers and contrary to expectations was associated with poorer response compared to placebo for consistent daily drinkers who had longer durations of pretreatment abstinence (e.g., \u226514 days). Baseline drinking trajectories also moderated naltrexone effects. These findings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneficial .", "source": "https://pubmed.ncbi.nlm.nih.gov/21143249/"}
+{"doc_id": "26cdeb8104e8e3213f01593e3d4ec34a", "sentence": "From August 2002 to August 2004 , 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2 ) intravenously ( i.v . ) on day 1 and vinorelbine 30 mg/m(2 ) i.v . on days 1 and 15 every 4 weeks .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 130, "end": 141, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "vinorelbine", "start": 191, "end": 202, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Multicenter phase II study of pegylated liposomal doxorubicin in combination with vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. This multicenter phase II trial was conducted to analyze the clinical activity and toxicity of the combination of pegylated liposomal doxorubicin and vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. ### Patients And Methods From August 2002 to August 2004 , 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2 ) intravenously ( i.v . ) on day 1 and vinorelbine 30 mg/m(2 ) i.v . on days 1 and 15 every 4 weeks . ### results The median age of the patients in this trial was 68 years (range 60-82). 40% of patients had 2 or more sites of metastasis, 33 (78%) had predominantly visceral metastasis, and 7 (16%) mostly bone metastasis. Just 2 (5%) patients had only lymphogenous or soft tissue metastasis. All patients had an ECOG performance status of 0-1, but 70% of the patients had relevant comorbidities. In an intention-to-treat analysis, the overall clinical response rate was 36%, the complete response rate was 2%, and the rate of partial remissions was 34%; stable disease occurred in 30%, and progressive disease was observed in 36%. Median duration of response was 10 months. Median time to progression was 4 months, and median overall survival time was 24 months. ### conclusion The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well tolerated regimen in elderly patients with metastatic breast cancer in first-line treatment.", "source": "https://pubmed.ncbi.nlm.nih.gov/19209014/"}
+{"doc_id": "3bc93c0827679996e6c214c767d3824d", "sentence": "The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells .", "spans": [{"span_id": 0, "text": "simvastatin", "start": 72, "end": 83, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "exemestane", "start": 88, "end": 98, "token_start": 15, "token_end": 16}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells. Breast cancer is associated with high levels of incidence, morbidity and mortality; therefore, the identification of effective chemopreventive strategies is crucial. It is important for clinicians to be able to identify the populations at risk who would benefit from chemoprevention, and the interventions that are effective and safe. The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells . The anti-proliferative effects of simvastatin and exemestane, alone and in combination, on the growth of MCF-7 human breast cancer cells were assessed by MTT assay. The synergism between the two drugs was determined in vitro using the combination index (CI) analysis. Cell cycle distribution and apoptosis were analyzed by flow cytometry, and alterations to the signaling pathway in MCF-7 cells were examined by immunoblotting following treatment with various regimens. The results of the MTT assay indicated that the combined treatment of simvastatin and exemestane significantly decreased the viability of MCF-7 estrogen receptor-positive (ER+) human breast cancer cells, as compared with those that were treated with the individual drugs (CI<1). In addition, coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug-treated cells. Furthermore, the results of the present study indicated that these synergistic effects may be associated with the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein apoptotic pathway and the mitogen-activated protein kinase/mammalian target of rapamycin/p70S6 kinase growth pathway. The combination of exemestane and simvastatin generated synergistic effects on MCF-7 ER+ breast cancer cells, indicating that the combination of these drugs may be a potential therapeutic strategy for the treatment of hormone-dependent breast cancer. The combination of the two inhibitors markedly increased the efficacy, as compared with the single-agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer. The results of the present study suggested that this combination of drugs has therapeutic potential, and requires further mechanistic and biomarker investigations in clinical trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/25738757/"}
+{"doc_id": "65bcf2e8ba4bd0911cf6a8ed3352e2e9", "sentence": "Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms .", "spans": [{"span_id": 0, "text": "Omeprazole", "start": 11, "end": 21, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "Praziquantel", "start": 26, "end": 38, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms . Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis. ### methodology We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay. ### Principal Findings We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect. ### conclusions Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.", "source": "https://pubmed.ncbi.nlm.nih.gov/26402251/"}
+{"doc_id": "1ed70d4deb51eaba9be4d2bdbada5d16", "sentence": "Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all \u03b2-lactams and treated with the association of at least aztreonam plus cefepime .", "spans": [{"span_id": 0, "text": "aztreonam", "start": 155, "end": 164, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "cefepime", "start": 170, "end": 178, "token_start": 27, "token_end": 28}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Use of aztreonam in association with cefepime for the treatment of nosocomial infections due to multidrug-resistant strains of Pseudomonas aeruginosa to \u03b2-lactams in ICU patients: A pilot study. Resistance to all \u03b2-lactams is emerging among Pseudomonas aeruginosa (PA) clinical isolates. aztreonam and cefepime act synergistically in vitro against AmpC overproducing PA isolates. The objective of this study was to evaluate the clinical efficacy of this treatment in ICU patients infected with multidrug-resistant PA. ### Material And Methods Retrospective study (2 years, 2 ICUs) in a tertiary university hospital. Inclusion criteria were proven infection with evidence of a bacterial strain of PA resistant to all \u03b2-lactams and treated with the association of at least aztreonam plus cefepime . Treatment was considered effective for pneumonia using CPIS scores at the end of treatment and for other infections, using the SOFA score and signs of infection improvement at the end of treatment. Infectious episodes were classified as cure or failure. ### results Thirteen patients were included (10 nosocomial pneumonia, 3 nosocomial intra-abdominal infections). The median [25th-75th percentiles] admission SAPS2 score was 54 [51-69] and the median SOFA score at the beginning of infection was 7 [4-8]. The median CPIS scores for pneumonia at the beginning and end of treatment were 9 [7-10.5] and 2 [0.75-5.5]. The duration of treatment with the combination of aztreonam plus cefepime was 14 days [9.5-16]. Nine episodes were classified as cures and 4 as failures, indicating a clinical efficacy of 69.2%. Overall mortality was 38.5%. ### discussion These data suggest that the association of cefepime plus aztreonam could be an attractive alternative in the treatment of infections with multidrug-resistant PA to all \u03b2-lactams with a clinical efficacy rate of 69%.", "source": "https://pubmed.ncbi.nlm.nih.gov/26004874/"}
+{"doc_id": "92445f629c7c8fa9a5f669f9895c4ca4", "sentence": "Comparison of the additive effects of nipradilol and carteolol to latanoprost in open-angle glaucoma .", "spans": [{"span_id": 0, "text": "nipradilol", "start": 38, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "carteolol", "start": 53, "end": 62, "token_start": 8, "token_end": 9}, {"span_id": 2, "text": "latanoprost", "start": 66, "end": 77, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Comparison of the additive effects of nipradilol and carteolol to latanoprost in open-angle glaucoma . To compare the effects of nipradilol and carteolol on intraocular pressure (IOP) when added to latanoprost treatment for glaucoma patients. ### methods Fifty patients with primary open-angle glaucoma were treated with latanoprost 0.005% once daily for 3 months. Then they were assigned to one of two groups randomly. One group received nipradilol 0.25% twice daily (nipradilol preceding group; n = 25), and the other carteolol hydrochloride 2% twice daily (carteolol preceding group; n = 25), for 3 months in addition to latanoprost. Then, nipradilol and carteolol were switched, and the subjects were treated for 3 more months. One eye was selected randomly for analysis. ### results In the nipradilol preceding group, IOP was 21.4 +/- 2.3 mmHg (mean +/- SD) at baseline, and 16.8 +/- 1.9 mmHg at the end of latanoprost monotherapy (P < 0.01). The addition of nipradilol decreased IOP to 15.8 +/- 1.7 mmHg, and the change to carteolol, to 15.3 +/- 2.0 mmHg. In the carteolol preceding group, IOP was 21.2 +/- 2.0 mmHg at baseline, and 17.0 +/- 2.1 mmHg at the end of latanoprost monotherapy (P < 0.01). The addition of carteolol decreased IOP to 15.4 +/- 1.8 mmHg, and the change to nipradilol, to 16.3 +/- 1.9 mmHg. Additional IOP reduction was greater with carteolol than with nipradilol (cross-over analysis of variance; P = 0.0005). ### conclusions Both nipradilol and carteolol have additive effects when used in combination with latanoprost. carteolol, however, may have a more potent effect than nipradilol.", "source": "https://pubmed.ncbi.nlm.nih.gov/16453185/"}
+{"doc_id": "c02a93b4a7110fb9bc0dc35cbaf0cd6e", "sentence": "The poly(ADP-ribose ) polymerase ( PARP ) inhibitor olaparib has recently received approval from the Food and Drug Administration ( FDA ) and European Medicines Agency ( EMA ) , with a second agent ( rucaparib ) likely to be approved in the near future .", "spans": [{"span_id": 0, "text": "olaparib", "start": 52, "end": 60, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "rucaparib", "start": 200, "end": 209, "token_start": 35, "token_end": 36}], "rels": [], "paragraph": "Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer. : High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents. ### Implications For Practice The poly(ADP-ribose ) polymerase ( PARP ) inhibitor olaparib has recently received approval from the Food and Drug Administration ( FDA ) and European Medicines Agency ( EMA ) , with a second agent ( rucaparib ) likely to be approved in the near future . However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.", "source": "https://pubmed.ncbi.nlm.nih.gov/27022037/"}
+{"doc_id": "d2cc5f8f48a70aafe4eb86abc0c90963", "sentence": "Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine , clomipramine , amitriptyline and diazepam .", "spans": [{"span_id": 0, "text": "Fluvoxamine", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "imipramine", "start": 148, "end": 158, "token_start": 23, "token_end": 24}, {"span_id": 2, "text": "clomipramine", "start": 161, "end": 173, "token_start": 25, "token_end": 26}, {"span_id": 3, "text": "amitriptyline", "start": 176, "end": 189, "token_start": 27, "token_end": 28}, {"span_id": 4, "text": "diazepam", "start": 194, "end": 202, "token_start": 29, "token_end": 30}], "rels": [{"class": "COMB", "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": "Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. The potent CYP1A2 inhibitor fluvoxamine has recently been shown also to be an effective inhibitor of the CYP2C19-mediated metabolism of the antimalarial drug proguanil in vivo. The purpose of the present study was to confirm this interaction in vitro. ### methods A high-performance liquid chromatography (HPLC) method was developed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from proguanil by microsomes prepared from human liver. The limit of detection was 0.08 nmol mg-'. h-I. ### results The formation of 4-CPBG and cycloguanil could be described by one-enzyme kinetics, indicating that the formation of the two metabolites is almost exclusively catalysed by a single enzyme, i.e. CYP2C19 within the concentration range used, or that the contribution of an alternative low-affinity enzyme, probably CYP3A4, is very low. This notion was confirmed by the lack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocriptine, midazolam and dihydroergotamine. fluvoxamine was a very effective inhibitor of the oxidation of proguanil, displaying Ki values of 0.69 micromol x l(-1) for the inhibition of cycloguanil formation and 4.7 micromol x l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omeprazole inhibited the formation of both metabolites with an IC50 of 10 micromol x l(-1). Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki values of 7.3-16 micromol x l(-1), suggesting that the two compounds are moderate inhibitors of CYP2C19. ### conclusions Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine , clomipramine , amitriptyline and diazepam . The combination of fluvoxamine and proguanil can not be recommended.", "source": "https://pubmed.ncbi.nlm.nih.gov/9923577/"}
+{"doc_id": "8d5eb6f039e442f59bb27170b6806920", "sentence": "We have compared amphotericin B , flucytosine , ketoconazole and fluconazole susceptibilities of 40 clinical isolates of Candida albicans by broth microdilution in two different media : RPMI 1640 ( RPMI ) and the same medium supplemented with 18 g of glucose per L ( RPMI-2 % glucose ) .", "spans": [{"span_id": 0, "text": "amphotericin", "start": 17, "end": 29, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "flucytosine", "start": 34, "end": 45, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "ketoconazole", "start": 48, "end": 60, "token_start": 8, "token_end": 9}, {"span_id": 3, "text": "fluconazole", "start": 65, "end": 76, "token_start": 10, "token_end": 11}], "rels": [], "paragraph": "Defining conditions for microbroth antifungal susceptibility tests: influence of RPMI and RPMI-2% glucose on the selection of endpoint criteria.  We have compared amphotericin B , flucytosine , ketoconazole and fluconazole susceptibilities of 40 clinical isolates of Candida albicans by broth microdilution in two different media : RPMI 1640 ( RPMI ) and the same medium supplemented with 18 g of glucose per L ( RPMI-2 % glucose ) . Preparation of media, drugs and inocula, as well as incubation temperature, followed the recommendations of the National Committee for Clinical Laboratory Standards (Villanova, PA, USA) antifungal agent working group for broth macrodilution tests with antifungal agents. Microtitre plates were agitated for 5 min before spectrophotometric readings were performed with an automatic plate reader. MIC endpoints were defined in three different ways: (i) MIC-100% for amphotericin B and flucytosine; (ii) MIC-80% for azole-drugs and also for flucytosine; (iii) IC1/2 for azole-drugs. The MIC endpoints were compared between the two different media in order to ascertain which was the best criterion. For amphotericin B, 100% of strains had a maximum difference of a twofold dilution in both media. For flucytosine, MIC values were very similar in both media, irrespective of the MIC endpoint chosen, MIC-100% or MIC-80%. For azole-drugs the (MIC-80%)50 and (MIC-80%)90 in RPMI were higher than those in RPMI-2% glucose. However, (IC1/2)50 and (IC1/2)90 were identical in both media as well as (MIC-80%)50 and (MIC-80%)90 in RPMI-2% glucose, The limited growth of yeasts in RPMI precludes the selection of an azole-MIC-80% endpoint, although the MIC determination was performed with an objective turbidimetric method (spectrophotometric reading plus mathematical MIC calculation). The use of RPMI-2% glucose produces the same MIC whatever methods was used, IC1/2 or MIC-80%. However, some minor discrepancies can be expected between IC1/2 and MIC-80% when strains with higher \"trailing effect\" are being tested. Therefore, we recommended IC1/2 in RPMI-2% glucose as the method of choice for MIC calculation, until more studies correlating in-vitro results with clinical outcome have been performed.", "source": "https://pubmed.ncbi.nlm.nih.gov/7559186/"}
+{"doc_id": "a0ac50dcdd622cfc2511df4110f4c9c2", "sentence": "Over the past decade , paclitaxel , docetaxel , vinorelbine , gemcitabine , irinotecan , and topotecan have been introduced into the clinic .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 23, "end": 33, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "docetaxel", "start": 36, "end": 45, "token_start": 7, "token_end": 8}, {"span_id": 2, "text": "vinorelbine", "start": 48, "end": 59, "token_start": 9, "token_end": 10}, {"span_id": 3, "text": "gemcitabine", "start": 62, "end": 73, "token_start": 11, "token_end": 12}, {"span_id": 4, "text": "irinotecan", "start": 76, "end": 86, "token_start": 13, "token_end": 14}, {"span_id": 5, "text": "topotecan", "start": 93, "end": 102, "token_start": 16, "token_end": 17}], "rels": [], "paragraph": "Is cisplatin required for the treatment of non-small-cell lung cancer? Experience and preliminary results of a phase I/II trial with topotecan and vinorelbine. Platinum-based chemotherapy is considered standard treatment for advanced non-small-cell lung cancer (NSCLC). However, toxicity of most platinum-based regimens is substantial and requires close monitoring and supportive care. Over the past decade , paclitaxel , docetaxel , vinorelbine , gemcitabine , irinotecan , and topotecan have been introduced into the clinic . These newer agents have shown promising activity against NSCLC with a favorable toxicity profile as single agents. For patients with metastatic NSCLC, palliation is the main goal of therapy. Therefore, treatment should be easy to administer on an outpatient basis. We explored a novel combination therapy avoiding platinum. Patients with recurrent or metastatic NSCLC were treated with intravenous (i.v.) topotecan (0.5-1.0 mg/m(2)/day x 5) and i.v. vinorelbine (20-30 mg/m(2)/day on day 1 and day 5) in 21-day cycles. Dose-limiting toxicity (DLT) was defined separately with or without the addition of granulocyte colony-stimulating factor (G-CSF) support. Twenty-nine patients have been enrolled to date. At i.v. topotecan doses of 0.75-1.0 mg/m(2)/day and i.v. vinorelbine of 25 mg/m(2)/day, neutropenia was frequent but of short duration (<7 days). The DLT of i.v. topotecan (0.85 mg/m(2)) in the absence of G-CSF support was based on myelosuppression with neutropenic fever. With the addition of G-CSF, a DLT has not been reached. Nonhematologic toxicities included mild to moderate fatigue and constipation. An overall clinical response rate of 42% was achieved, with responses noted at all dose levels. At a short median follow-up of 15 months, the median survival for all patients is 13 months. In conclusion, the combination regimen of topotecan and vinorelbine is feasible for outpatient administration and is well tolerated with less toxicity than platinum-based regimens. Preliminary response data demonstrate good tumor activity, suggesting that this regimen could make an excellent palliative treatment for advanced NSCLC.", "source": "https://pubmed.ncbi.nlm.nih.gov/11598413/"}
+{"doc_id": "85cf1d136acd78cbd2c0e0e7ba8af4a6", "sentence": "Alternatively , it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both beta 1- and beta 2-adrenoceptors .", "spans": [{"span_id": 0, "text": "pindolol", "start": 54, "end": 62, "token_start": 10, "token_end": 11}, {"span_id": 1, "text": "propranolol", "start": 67, "end": 78, "token_start": 12, "token_end": 13}], "rels": [], "paragraph": "Central propranolol and pindolol, but not atenolol nor metoprolol, inhibit sexual behavior in male rats. Are the anti-sexual effects of propranolol and pindolol due to actions within the brain? To answer this, these agents were administered directly into the brain ventricular system (ICV). Additionally, atenolol and metoprolol were evaluated to see whether differential delivery to the brain contributed to the observed lack of effect of systemically administered beta 1-adrenoceptor antagonists. ICV administration of pindolol (45 or 90 micrograms) was followed by a suppression of copulation. At 45 micrograms, inhibition was limited to performance aspects of copulation, whereas at 90 micrograms, decrements in motivational and performance aspects of copulation were evident. ICV administration of propranolol also suppressed copulatory behavior. At 45 micrograms, no significant effects were observed, whereas at 90 micrograms decrements in motivational and performance aspects of copulation were evident. In contrast, ICV administration of the beta 1-adrenoceptor antagonists, atenolol and metoprolol, was not associated with any major modifications in copulatory behavior. We suggest that the inhibitory effects of propranolol and pindolol may involve interactions with 5-HT1A receptors in the CNS. Alternatively , it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both beta 1- and beta 2-adrenoceptors .", "source": "https://pubmed.ncbi.nlm.nih.gov/8838601/"}
+{"doc_id": "33b4a24c32bbaeaa9098849bae7fd55c", "sentence": "The combinations of irinotecan and mitomycin C or oxaliplatin have given very good results with high objective response rates and good tolerance .", "spans": [{"span_id": 0, "text": "irinotecan", "start": 20, "end": 30, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "mitomycin", "start": 35, "end": 44, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "oxaliplatin", "start": 50, "end": 61, "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": "[Irinotecan in combination for colon cancer]. As a single agent, irinotecan has demonstrated efficacy in metastatic 5FU resistant colorectal metastatic cancer. Chemotherapy with fluorouracil (5FU) plus leucovorin remains a standard in the treatment of patients with metastatic colorectal cancer. It seemed logical to test the combination of this reference treatment and the new agent. The first trials gave rather disappointing results, suggesting an inhibition of the metabolism of irinotecan into SN38 when 5FU was present in the circulation. More recent studies have given totally different results with a very good tolerance and strong efficacy of the combination of weekly folinic acid + 5FU and irinotecan or LV5FU2 (the so-called de Gramont regimen) and irinotecan. The results were so good that these new schedules are currently developed as first line regimen. Another way to combine 5FU, folinic acid and irinotecan is to alternate a cycle of 5FU, folinic acid and a cycle of irinotecan. Such an alternated schedule has given encouraging results with an objective response rate greater than 30% and a long median survival time (more than 16 months). It is also very easy to combine irinotecan with other drug which have demonstrated activity in the treatment of colorectal cancer. The combinations of irinotecan and mitomycin C or oxaliplatin have given very good results with high objective response rates and good tolerance . irinotecan plays now an important part in the treatment of metastatic colorectal cancer. This part becomes larger due to the results of the combination trials already presented which have shown strong efficacy and good tolerance.", "source": "https://pubmed.ncbi.nlm.nih.gov/9932084/"}
+{"doc_id": "b3ba634638d733010cbe6ea8555c17d1", "sentence": "The NHB of strategy A was 31.6 QALMs versus strategy C when palbociclib was included in strategy C ; similarly , strategy A had a NHB of 13.8 QALMs versus strategy C when pertuzumab was included in strategy C. Monte-Carlo simulation demonstrated that the main factor influencing NHB of strategy A over strategy C was the cost of systemic therapy .", "spans": [{"span_id": 0, "text": "palbociclib", "start": 60, "end": 71, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "pertuzumab", "start": 171, "end": 181, "token_start": 33, "token_end": 34}], "rels": [], "paragraph": "Liver Resection for Breast Cancer Liver Metastases: A Cost-utility Analysis. To estimate the cost-effectiveness of liver resection followed by adjuvant systemic therapy relative to systemic therapy alone for patients with breast cancer liver metastasis. ### background Data on cost-effectiveness of liver resection for advanced breast cancer with liver metastasis are lacking. ### methods A decision-analytic Markov model was constructed to evaluate the cost-effectiveness of liver resection followed by postoperative conventional systemic therapy (strategy A) versus conventional therapy alone (strategy B) versus newer targeted therapy alone (strategy C). The implications of using different chemotherapeutic regimens based on estrogen receptor and human epidermal growth factor receptor 2 status was also assessed. Outcomes included quality-adjusted life months (QALMs), incremental cost-effectiveness ratio, and net health benefit (NHB). ### results NHB of strategy A was 10.9 QALMs compared with strategy B when letrozole was used as systemic therapy, whereas it was only 0.3 QALMs when docetaxel\u200a+\u200atrastuzumab was used as a systemic therapy. The addition of newer biological agents (strategy C) significantly decreased the cost-effectiveness of strategy B (conventional systemic therapy alone). The NHB of strategy A was 31.6 QALMs versus strategy C when palbociclib was included in strategy C ; similarly , strategy A had a NHB of 13.8 QALMs versus strategy C when pertuzumab was included in strategy C. Monte-Carlo simulation demonstrated that the main factor influencing NHB of strategy A over strategy C was the cost of systemic therapy . ### conclusions Liver resection in patients with breast cancer liver metastasis proved to be cost-effective when compared with systemic therapy alone, particularly in estrogen receptor-positive tumors or when newer agents were used.", "source": "https://pubmed.ncbi.nlm.nih.gov/28266967/"}
+{"doc_id": "02016864b7b05842923fc562653e6d26", "sentence": "In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin , etoposide and ifosfamide .", "spans": [{"span_id": 0, "text": "carboplatin", "start": 91, "end": 102, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "etoposide", "start": 105, "end": 114, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "ifosfamide", "start": 119, "end": 129, "token_start": 18, "token_end": 19}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours. Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin , etoposide and ifosfamide . Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.", "source": "https://pubmed.ncbi.nlm.nih.gov/7692922/"}
+{"doc_id": "cbb38295f9bb8e6d792b8d943d1ea03e", "sentence": "3 . Systemic ( i.v . ) pretreatment with furosemide ( 2 - 10 mg kg-1 ) increased urine volume and dose-dependently inhibited the pressor response to i.c.v . clonidine ( 10 micrograms ) , and a long-lasting depressor response to clonidine was observed .", "spans": [{"span_id": 0, "text": "furosemide", "start": 41, "end": 51, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "clonidine", "start": 157, "end": 166, "token_start": 29, "token_end": 30}, {"span_id": 2, "text": "clonidine", "start": 228, "end": 237, "token_start": 41, "token_end": 42}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Furosemide inhibits the centrally-mediated pressor response to clonidine in conscious, normotensive rats. 1. The effect of furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injection of clonidine was investigated in freely moving, normotensive rats with chronically implanted arterial catheters. 2. When injected i.c.v., clonidine at doses of 5 and 10 micrograms produced a dose-dependent pressor response and a decrease in heart rate. No depressor response was induced by clonidine. 3 . Systemic ( i.v . ) pretreatment with furosemide ( 2 - 10 mg kg-1 ) increased urine volume and dose-dependently inhibited the pressor response to i.c.v . clonidine ( 10 micrograms ) , and a long-lasting depressor response to clonidine was observed . However, furosemide treatment did not alter the bradycardia produced in response to clonidine. 4. The systemic treatment with furosemide (10 mg kg-1, i.v.) had no effect on the pressor response to i.v. noradrenaline. 5. These results suggest that reduction of body fluid volume inhibits the centrally-mediated pressor response to clonidine and leads to the hypotensive effect. We also suggest that combined treatment with a diuretic increases the hypotensive efficacy of clonidine.", "source": "https://pubmed.ncbi.nlm.nih.gov/1797326/"}
+{"doc_id": "f76833b73a044ef61bb52a3c0dacafb8", "sentence": "Nine studies connected to the network for the PFS analysis in which necitumumab in combination with gemcitabine and cisplatin was associated with the lowest HR .", "spans": [{"span_id": 0, "text": "necitumumab", "start": 68, "end": 79, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "gemcitabine", "start": 100, "end": 111, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "cisplatin", "start": 116, "end": 125, "token_start": 18, "token_end": 19}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "First-line treatment of patients with advanced or metastatic squamous non-small cell lung cancer: systematic review and network meta-analysis. The objectives of this systematic review and meta-analysis were to compare the survival, toxicity, and quality of life of patients treated with necitumumab in combination with gemcitabine and cisplatin. These agents were investigated in published randomized controlled trials (RCTs) of patients with squamous non-small cell lung cancer (NSCLC) in the first-line setting. ### methods The systematic review was executed on January 27, 2015, and updated on August 21, 2016, using a pre-specified search strategy. Searches were conducted using PubMed, Medline, and EMBASE, with supplemental searches using the Evidence Based Medicine Reviews and ClinicalTrials.gov to identify RCTs published in English from 1995-2016 and reporting at least one of the primary outcomes [overall survival (OS), progression-free survival (PFS), toxicity, or quality of life] in patients who received first-line treatment for advanced or metastatic squamous NSCLC. Study quality and risk of bias were assessed using the Physiotherapy Evidence Database (PEDro) scale and Cochrane risk of bias tool, respectively. A Baysian network meta-analysis was performed on the primary outcomes. Hazard ratios (HRs) were evaluated for the primary analysis; secondary analyses were conducted using median OS data. Planned sensitivity analyses were conducted including reanalysis using a Frequentist approach and limiting analyses to subsets based on clinical and demographic covariates. ### results The systematic literature review resulted in identification of 4,016 unique publications; 40 publications (35 unique trials) were eligible for inclusion. Eight studies connected to a common network for the OS analysis using HR data. The majority of studies were not limited to squamous NSCLC, thus analyzable data were limited to a subset of data within the published trials. carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin were associated with lower HRs for OS versus all other comparators. Nine studies connected to the network for the PFS analysis in which necitumumab in combination with gemcitabine and cisplatin was associated with the lowest HR . Data were not available to analyze toxicity or quality of life. ### conclusions Although the results suggest that carboplatin + S-1 and necitumumab in combination with gemcitabine and cisplatin may have value in terms of OS versus other comparators, the results should be interpreted with caution due to the limited number of studies (with few focused exclusively on squamous NSCLC) and wide credible intervals.", "source": "https://pubmed.ncbi.nlm.nih.gov/30746213/"}
+{"doc_id": "aeff9357c8822f550a9039fff2c8eab1", "sentence": "To evaluate the efficacy and toxicities of gemcitabine combined with ifosfamide and anthracycline chemotherapy for recurrent platinum resistant ovarian epithelial cancer .", "spans": [{"span_id": 0, "text": "gemcitabine", "start": 43, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "ifosfamide", "start": 69, "end": 79, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "anthracycline", "start": 84, "end": 97, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": true}], "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": "cc21758921b269913859dccc84fcc675", "sentence": "Combination of erlotinib and sorafenib , synergistic in GSC11 , induced apoptosis and autophagic cell death associated with suppressed Akt and ERK signaling pathways and decreased nuclear PKM2 and \u03b2-catenin in vitro , and tended to improve survival of nude mice bearing GSC11 brain tumor .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "sorafenib", "start": 29, "end": 38, "token_start": 4, "token_end": 5}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Suppression of RAF/MEK or PI3K synergizes cytotoxicity of receptor tyrosine kinase inhibitors in glioma tumor-initiating cells. The majority of glioblastomas have aberrant receptor tyrosine kinase (RTK)/RAS/phosphoinositide 3 kinase (PI3K) signaling pathways and malignant glioma cells are thought to be addicted to these signaling pathways for their survival and proliferation. However, recent studies suggest that monotherapies or inappropriate combination therapies using the molecular targeted drugs have limited efficacy possibly because of tumor heterogeneities, signaling redundancy and crosstalk in intracellular signaling network, indicating necessity of rationale and methods for efficient personalized combination treatments. Here, we evaluated the growth of colonies obtained from glioma tumor-initiating cells (GICs) derived from glioma sphere culture (GSC) in agarose and examined the effects of combination treatments on GICs using targeted drugs that affect the signaling pathways to which most glioma cells are addicted. ### methods Human GICs were cultured in agarose and treated with inhibitors of RTKs, non-receptor kinases or transcription factors. The colony number and volume were analyzed using a colony counter, and Chou-Talalay combination indices were evaluated. Autophagy and apoptosis were also analyzed. Phosphorylation of proteins was evaluated by reverse phase protein array and immunoblotting. ### results Increases of colony number and volume in agarose correlated with the Gompertz function. GICs showed diverse drug sensitivity, but inhibitions of RTK and RAF/MEK or PI3K by combinations such as EGFR inhibitor and MEK inhibitor, sorafenib and U0126, erlotinib and BKM120, and EGFR inhibitor and sorafenib showed synergy in different subtypes of GICs. Combination of erlotinib and sorafenib , synergistic in GSC11 , induced apoptosis and autophagic cell death associated with suppressed Akt and ERK signaling pathways and decreased nuclear PKM2 and \u03b2-catenin in vitro , and tended to improve survival of nude mice bearing GSC11 brain tumor . Reverse phase protein array analysis of the synergistic treatment indicated involvement of not only MEK and PI3K signaling pathways but also others associated with glucose metabolism, fatty acid metabolism, gene transcription, histone methylation, iron transport, stress response, cell cycle, and apoptosis. ### conclusion Inhibiting RTK and RAF/MEK or PI3K could induce synergistic cytotoxicity but personalization is necessary. Examining colonies in agarose initiated by GICs from each patient may be useful for drug sensitivity testing in personalized cancer therapy.", "source": "https://pubmed.ncbi.nlm.nih.gov/26861698/"}
+{"doc_id": "285ff522dbf828beae54331363e1aa59", "sentence": "In the first trial , paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2 , respectively , for patients who had received no more than one prior chemotherapeutic regimen .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 21, "end": 31, "token_start": 5, "token_end": 6}, {"span_id": 1, "text": "doxorubicin", "start": 36, "end": 47, "token_start": 7, "token_end": 8}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to enter routine clinical practice, has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer. Given this activity, it seemed logical to attempt to combine paclitaxel with doxorubicin, the other most active single agent in metastatic breast cancer. The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination. In the first trial , paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2 , respectively , for patients who had received no more than one prior chemotherapeutic regimen . Therapy was well tolerated in this setting. At these doses, paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin. Objective responses (complete and partial responses) were seen in seven of 12 patients; two other patients had improved disease (relief of pain in bony metastases). A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination. In this phase I trial, doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion. The sequence of drug administration (D-->P or P-->D) was alternated both between and within patients, so that we might evaluate the effect of administration schedule on toxicity. Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively, of paclitaxel and doxorubicin. In addition, patients received granulocyte colony-stimulating factor 5 micrograms/kg/d. While therapy at the initial dose level was well tolerated, dose-limiting mucositis was seen at the second dose level, although only when paclitaxel preceded doxorubicin. This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and (perhaps) efficacy, a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer. Based on this study, we identified the sequence of doxorubicin (50 mg/m2) followed by paclitaxel (150 mg/m2) to be the maximum tolerated dose. This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group.", "source": "https://pubmed.ncbi.nlm.nih.gov/7939756/"}
+{"doc_id": "d94638045c3e1a5a7b55e25f7b2727bb", "sentence": "Thirty-one patients with histologically proven small cell lung cancer were treated with cyclophosphamide 1 g m-2 and etoposide ( VP16 - 213 ) 125 mg m-2 both intravenously on day 1 followed by etoposide 250 mg m-2 orally on days 2 - 3 for a maximum of six courses at 3 weekly intervals .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 88, "end": 104, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "etoposide", "start": 117, "end": 126, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "etoposide", "start": 193, "end": 202, "token_start": 33, "token_end": 34}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination cyclophosphamide and etoposide in treatment of small cell lung cancer.  Thirty-one patients with histologically proven small cell lung cancer were treated with cyclophosphamide 1 g m-2 and etoposide ( VP16 - 213 ) 125 mg m-2 both intravenously on day 1 followed by etoposide 250 mg m-2 orally on days 2 - 3 for a maximum of six courses at 3 weekly intervals . Fourteen patients had limited and 17 patients had extensive disease. Twenty-five patients were evaluable for response. Objective response was observed in 18 patients (58%) with 6 (19%) complete and 12 (39%) partial responses. Median survival of the entire group of patients was 30 weeks. There was significant survival benefit among the responders (P less than 0.005) when compared with non-responders. One patient (3.3%) developed grade 4 while 60% of patients developed grade 1-2 haematological toxicity. Other side effects were relatively mild. We conclude that combination cyclophosphamide and etoposide was active in small cell lung cancer and relatively well tolerated.", "source": "https://pubmed.ncbi.nlm.nih.gov/2160034/"}
+{"doc_id": "a4208d3dba815399d8e4010b689a8027", "sentence": "Pemetrexed plus carboplatin followed by pemetrexed , docetaxel , atezolizumab and S-1 were performed in sequence .", "spans": [{"span_id": 0, "text": "Pemetrexed", "start": 0, "end": 10, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "carboplatin", "start": 16, "end": 27, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "pemetrexed", "start": 40, "end": 50, "token_start": 5, "token_end": 6}, {"span_id": 3, "text": "docetaxel", "start": 53, "end": 62, "token_start": 7, "token_end": 8}, {"span_id": 4, "text": "atezolizumab", "start": 65, "end": 77, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4], "is_context_needed": true}], "paragraph": "Dacomitinib as a retreatment for advanced non-small cell lung cancer patient with an uncommon EGFR mutation. In non-small cell lung cancer (NSCLC), uncommon epidermal growth factor receptor (EGFR) mutations are mutations other than Ex19 deletion and Ex21 L858R, which are common mutations highly sensitive to EGFR-tyrosine kinase inhibitors. afatinib, a second-generation EGFR-tyrosine kinase inhibitor, has been shown to be effective in patients with uncommon mutations. dacomitinib, another second-generation EGFR-tyrosine kinase inhibitor, has not previously been shown to be effective in patients with uncommon mutations. Here, we report the efficacy of dacomitinib for uncommon EGFR mutations in a 71-year-old woman diagnosed with metastatic lung adenocarcinoma with uncommon EGFR mutation (Ex18 G719A). afatinib was administered as the first-line treatment, and a remarkable antitumor effect was observed. However, the tumor grew after 14\u2009months. Pemetrexed plus carboplatin followed by pemetrexed , docetaxel , atezolizumab and S-1 were performed in sequence . Although approximately four years had passed since the start of treatment, her physical condition was good. The patient started dacomitinib as the sixth-line treatment. Lesions were markedly reduced and treatment with dacomitinib was continued for 7.8 months. dacomitinib is a possible treatment option for NSCLC with uncommon mutations.", "source": "https://pubmed.ncbi.nlm.nih.gov/33651475/"}
+{"doc_id": "710177e4ab5628b7cf2962ce9a4347ee", "sentence": "The initial response ( IR ) was sustained for a mean ( s.d . ) of 309 ( 244 ) days with vildagliptin versus 270 ( 223 ) days for glimepiride ( p < 0.001 ) ( IR = nadir HbA1c where change from baseline > or = 0.5 % or HbA1c < or = 6.5 % within the first six months of treatment .", "spans": [{"span_id": 0, "text": "vildagliptin", "start": 88, "end": 100, "token_start": 22, "token_end": 23}, {"span_id": 1, "text": "glimepiride", "start": 129, "end": 140, "token_start": 30, "token_end": 31}], "rels": [], "paragraph": "Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. To show that vildagliptin added to metformin is non-inferior to glimepiride in reducing HbA1c levels from baseline over 2 years. ### methods A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. ### results In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c <7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response ( IR ) was sustained for a mean ( s.d . ) of 309 ( 244 ) days with vildagliptin versus 270 ( 223 ) days for glimepiride ( p < 0.001 ) ( IR = nadir HbA1c where change from baseline > or = 0.5 % or HbA1c < or = 6.5 % within the first six months of treatment . After IR was detected, sustained response = time between nadir and an increase of >0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. ### conclusions vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.", "source": "https://pubmed.ncbi.nlm.nih.gov/20649630/"}
+{"doc_id": "9e4a4ac0b5d6f5c60c5f0d73fcc3b766", "sentence": "The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel , combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 95, "end": 105, "token_start": 19, "token_end": 20}, {"span_id": 1, "text": "carboplatin", "start": 122, "end": 133, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer.  The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel , combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction . Twelve chemonaive patients with ovarian cancer were treated with paclitaxel followed by a 30-min infusion of carboplatin. paclitaxel dose was escalated from 150 mg m-2 to 225 mg m-2 in cohorts of three patients. carboplatin dose was based on renal function. Pharmacokinetic studies were performed in nine patients (at least two at each dose level). A total of 66 courses were evaluable for assessment. Grade 3 or 4 neutropenia was seen in 70% of the courses, however hospitalization was not required. Grade 3 or 4 thrombocytopenia occurred in 24% of the courses. Alopecia, myalgia and peripheral neuropathy were common but rarely severe. The pharmacokinetics of paclitaxel was non-linear and did not appear to be influenced by co-administration of carboplatin. The AUC of carboplatin was 7.0 +/- 1.4 mg ml-1 min, indicating that there was no pharmacokinetic interaction. The combination of carboplatin and paclitaxel may be administered as first-line treatment for advanced ovarian cancer. Although myelosuppression is the dose-limiting toxicity of the component drugs, the severity of thrombocytopenia was less than anticipated. The results of this study, with only a small number of patients, need to be confirmed in future investigations.", "source": "https://pubmed.ncbi.nlm.nih.gov/9010040/"}
+{"doc_id": "d95a9f0bb64d0b88c37b7f2b8fa950f2", "sentence": "Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain : an isobolographic analysis .", "spans": [{"span_id": 0, "text": "tramadol", "start": 12, "end": 20, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "doxepin", "start": 41, "end": 48, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "venlafaxine", "start": 52, "end": 63, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "COMB", "spans": [0, 2], "is_context_needed": true}], "paragraph": "Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain : an isobolographic analysis . Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED(50) doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination.", "source": "https://pubmed.ncbi.nlm.nih.gov/20065499/"}
+{"doc_id": "4b31d5b4682f2cb6d4de9cd5ecdc3527", "sentence": "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 .", "spans": [{"span_id": 0, "text": "mefloquine", "start": 23, "end": 33, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "artemether", "start": 39, "end": 49, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "quinine", "start": 178, "end": 185, "token_start": 25, "token_end": 26}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "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": "070556e0b7ed1a722df98cba5e44277b", "sentence": "Currently available adrenal steroidogenesis inhibitors , including ketoconazole , metyrapone , etomidate , and mitotane , have variable efficacy and significant side effects , and none are approved by the US Food and Drug Administration for CS .", "spans": [{"span_id": 0, "text": "ketoconazole", "start": 67, "end": 79, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "metyrapone", "start": 82, "end": 92, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "etomidate", "start": 95, "end": 104, "token_start": 11, "token_end": 12}, {"span_id": 3, "text": "mitotane", "start": 111, "end": 119, "token_start": 14, "token_end": 15}], "rels": [], "paragraph": "Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies. Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25\u00a0% of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. ### methods We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. ### results Currently available adrenal steroidogenesis inhibitors , including ketoconazole , metyrapone , etomidate , and mitotane , have variable efficacy and significant side effects , and none are approved by the US Food and Drug Administration for CS . Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). ### conclusions The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.", "source": "https://pubmed.ncbi.nlm.nih.gov/27600150/"}
+{"doc_id": "38e86e2ea081339e207960ade6df585f", "sentence": "The differential effects of haloperidol and methamphetamine on time estimation in the rat .", "spans": [{"span_id": 0, "text": "haloperidol", "start": 28, "end": 39, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "methamphetamine", "start": 44, "end": 59, "token_start": 6, "token_end": 7}], "rels": [], "paragraph": "The differential effects of haloperidol and methamphetamine on time estimation in the rat . Forty rats were trained to make a left lever response if a signal (white noise) was 2.5s and to make a right lever response if the signal was 6.3s. When seven intermediate signal durations, to which responses were not reinforced, were randomly interspersed the probability of a right-lever ('long') response increased as a function of signal duration. methamphetamine shifted this psychometric function leftward and decreased its slope: haloperidol also decreased the slope but shifted the function rightward. A combination of haloperidol and methamphetamine led to a function similar to the saline control function. The leftward shift probably reflects an increase in the speed of an internal clock, and the rightward shift probably reflects a decrease in its speed. Since methamphetamine releases several catecholamines, including dopamine, and haloperidol blocks dopamine receptors, it is plausible that the horizontal location of the psychometric function (the speed of the clock) is related to the effective level of dopamine.", "source": "https://pubmed.ncbi.nlm.nih.gov/6403957/"}
+{"doc_id": "e1cbaee16f90b5f5cd216566c4f3348a", "sentence": "In the present study , we evaluated the efficacy and safety of the weekly combination of etoposide , leucovorin ( LV ) and 5-fluorouracil ( 5-FU ) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer ( ACC ) , previously treated with weekly LV+5-FU .", "spans": [{"span_id": 0, "text": "etoposide", "start": 89, "end": 98, "token_start": 16, "token_end": 17}, {"span_id": 1, "text": "leucovorin", "start": 101, "end": 111, "token_start": 18, "token_end": 19}, {"span_id": 2, "text": "5-fluorouracil", "start": 123, "end": 137, "token_start": 23, "token_end": 24}], "rels": [{"class": "NEG", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer.  In the present study , we evaluated the efficacy and safety of the weekly combination of etoposide , leucovorin ( LV ) and 5-fluorouracil ( 5-FU ) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer ( ACC ) , previously treated with weekly LV+5-FU . etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.", "source": "https://pubmed.ncbi.nlm.nih.gov/12420860/"}
+{"doc_id": "e6ec9d1de8b404c19da2279ecaa39e05", "sentence": "Diazoxide , nifedipine and 2-deoxy glucose suppressed ( p < 0.05 ) glucose stimulated insulin secretion in AtT20HI-GLUT2-GK-6 cells .", "spans": [{"span_id": 0, "text": "Diazoxide", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "nifedipine", "start": 12, "end": 22, "token_start": 2, "token_end": 3}, {"span_id": 2, "text": "2-deoxy glucose", "start": 27, "end": 42, "token_start": 4, "token_end": 6}], "rels": [{"class": "COMB", "spans": [0, 1, 2], "is_context_needed": true}], "paragraph": "Cellular characterization of pituitary adenoma cell line (AtT20 cell) transfected with insulin, glucose transporter type 2 (GLUT2) and glucokinase genes: insulin secretion in response to physiological concentrations of glucose. We investigated the mechanisms of insulin secretion by transfecting into a pituitary adenoma cell line (AtT20) a combination of genes encoding human insulin (HI), glucose transporter type 2 (GLUT2) and glucokinase (GK), followed by studying the characteristics of these cells. In static incubation, a cell line transfected with insulin gene alone (AtT20HI) secreted mature human insulin but this was not in a glucose-dependent manner. Other cell lines transfected with insulin and GLUT2 genes (AtT20HI-GLUT2-3) or with insulin and GK genes (AtT20HI-GK-1) secreted insulin in response to glucose concentrations of only less than 1 mmol/l. In contrast, cell lines transfected with insulin, GLUT2 and GK genes (AtT20HI-GLUT2-GK-6, AtT20HI-GLUT2-GK-7 and AtT20HI-GLUT2-GK-10) showed a glucose-dependent insulin secretion up to 25 mmol/l glucose. Glucose utilization and oxidation were increased in AtT20HI-GLUT2-GK cell lines but not in AtT20HI, AtT20HI-GLUT2-3 and AtT20HI-GK-1 cells at physiological glucose concentrations, compared with AtT20 cells. Diazoxide , nifedipine and 2-deoxy glucose suppressed ( p < 0.05 ) glucose stimulated insulin secretion in AtT20HI-GLUT2-GK-6 cells . Glibenclamide, KCl or corticotropin releasing factor (CRF) stimulated (p < 0.05) insulin secretion both in AtT20HI and AtT20HI-GLUT2-GK-6 cells. Insulin secretion stimulated by glibenclamide, KCl or CRF was further enhanced by the addition of 25 mmol/l glucose in AtT20HI-GLUT2-GK-6 cells but not in AtT20HI cells. In perifusion experiments, a stepwise increase in glucose concentration from 5 to 25 mmol/l stimulated insulin secretion in AtT20HI-GLUT2-GK cell lines but the response lacked a clear first phase of insulin secretion. Our results suggest that both GLUT2 and glucokinase are necessary for the glucose stimulated insulin secretion in at least rodent cell lines, and that other element(s) are necessary for a biphasic insulin secretion typically observed in beta cells.", "source": "https://pubmed.ncbi.nlm.nih.gov/9867217/"}
+{"doc_id": "56767edbaaf4aa1833e32ccf779a6d71", "sentence": "Reducing the duration of medication use postoperatively may also minimize the possible side effects of ketorolac and codeine , which could develop with extended periods of use .", "spans": [{"span_id": 0, "text": "ketorolac", "start": 103, "end": 112, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "codeine", "start": 117, "end": 124, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Evaluation of ketorolac (Toradol) with varying amounts of codeine for postoperative extraction pain control. This study analyzes the combination of oral ketorolac 10 mg with varying amounts of codeine phosphate, and the postoperative pain relief that developed from these combinations. Five groups of patients were administered the codeine/ketorolac combinations. Variations of the combinations were analyzed to ascertain if an optimal analgesic ratio existed. All controllable variables involved with the surgical procedure were held constant to allow for better evaluation of postoperative pain. Results obtained from 67 patients indicated that the best pain relief was achieved with a combination of 10 mg ketorolac and 15 mg codeine phosphate. codeine alone provided adequate analgesia, but the addition of ketorolac reduced the patients' perceived side effects. The presence of codeine in the analgesic combination was also shown to reduce the number of days that the patient required the medication postoperatively. Reducing the duration of medication use postoperatively may also minimize the possible side effects of ketorolac and codeine , which could develop with extended periods of use .", "source": "https://pubmed.ncbi.nlm.nih.gov/12190134/"}
+{"doc_id": "d5f7976596eb3d6b0af16a3cf786c912", "sentence": "Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma .", "spans": [{"span_id": 0, "text": "Lenalidomide", "start": 0, "end": 12, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "dexamethasone", "start": 18, "end": 31, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.  Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma . The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. ### methods We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. ### results Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. ### conclusions In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).", "source": "https://pubmed.ncbi.nlm.nih.gov/25482145/"}
+{"doc_id": "8c077eeed55f1a34d9df0058007d72b1", "sentence": "Following definitive treatment , patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years , estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only .", "spans": [{"span_id": 0, "text": "cyclophosphamide", "start": 68, "end": 84, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "estramustine", "start": 134, "end": 146, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Adjuvant therapy for clinical localized prostate cancer treated with surgery or irradiation. Because of efficacy demonstrated with chemotherapy in patients with metastatic disease, the National Prostate Cancer Project in 1978 initiated two protocols evaluating adjuvant therapy following surgery (Protocol 900) and irradiation (Protocol 1000) for patients with localized disease at high risk for relapse. ### methods All patients underwent staging pelvic lymph node dissection. Following definitive treatment , patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years , estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only . Accession closed in 1985 and included 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable). ### results Nodal involvement was identified in 198 patients (49% of total): 29% in Protocol 900 and 63% in protocol 1000. Median progression-free survival (PFS) and survival have been greater for patients in Protocol 900 regardless of adjuvant, reflecting their lower pathologic stage. Median PFS is significantly greater for patients in Protocol 1000 receiving estramustine (52.2 months) compared to cyclophosphamide (35.0 months). Median PFS for patients with nodal involvement in Protocol 1000 receiving estramustine is increased (43.5 months) compared to no treatment (21.5 months). Patients with limited nodal involvement in Protocol 1000 have a longer median PFS (45.6 months) compared to patients with extensive disease (23.6 months). But in the latter group patients receiving estramustine experienced a significantly longer median PFS (43.5 months) compared to cyclophosphamide (29.1 months) or no adjuvant (13.5 months). Increased PFS with estramustine adjuvant was also noted in stage C patients (only Protocol 900) and in those with high-grade (grade 3) tumors (both protocols). ### conclusions With now over 10 years mean follow-up for this series of patients, we conclude that adjuvant estramustine is beneficial for prostate cancer patients receiving definitive irradiation. This benefit is particularly noted in those patients with extensive nodal involvement (N+, D-1).", "source": "https://pubmed.ncbi.nlm.nih.gov/8791049/"}
+{"doc_id": "0e3638fb7225dbfb492b6e28afaefb04", "sentence": "The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin ( r-HuEPO ) ameliorates this anemia , reducing the need for subsequent packed red blood cell ( PRBC ) transfusions .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 58, "end": 68, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "carboplatin", "start": 73, "end": 84, "token_start": 10, "token_end": 11}, {"span_id": 2, "text": "erythropoietin", "start": 193, "end": 207, "token_start": 28, "token_end": 29}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin.  The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin ( r-HuEPO ) ameliorates this anemia , reducing the need for subsequent packed red blood cell ( PRBC ) transfusions . ### methods Response to r-HuEPO was defined as reduced hemoglobin fall during preoperative chemotherapy and reduced transfusion requirements during surgery. Thirty-six patients with advanced head and neck carcinoma were evaluable after treatment with preoperative chemotherapy using paclitaxel and carboplatin. Group 1 was comprised of 14 patients who empirically received r-HuEPO at a dose of 150 U/kg 3 times per week for 3 weeks; in patients deemed nonresponders, the dose was increased to 300 U/kg and 450 U/kg in the subsequent courses. Group 2 was comprised of 22 patients who did not receive r-HuEPO. ### results During preoperative chemotherapy, the mean hemoglobin fall was 0.5 g/dL in Group 1 (P = 0.40). In Group 2 there was a statistically significant mean hemoglobin fall of 3.3 g/dL (P < 0.0001). There was also a nonstatistically significant trend toward fewer PRBC transfusions: none of 14 patients (0%) in Group 1 versus 4 of 22 patients (18%) in Group 2 (P = 0.141). ### conclusions A significant fall in hemoglobin and an increase in the need for transfusions were observed in head and neck carcinoma patients receiving carboplatin and paclitaxel chemotherapy prior to surgery. Empiric r-HuEPO therapy appeared to prevent anemia and reduced the need for PRBC transfusions.", "source": "https://pubmed.ncbi.nlm.nih.gov/9118049/"}
+{"doc_id": "31a0bb182139720ca8b79d8e68089d7e", "sentence": "Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis .", "spans": [{"span_id": 0, "text": "fluconazole", "start": 25, "end": 36, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "flucytosine", "start": 41, "end": 52, "token_start": 5, "token_end": 6}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Combination therapy with fluconazole and flucytosine in the murine model of cryptococcal meningitis . This study elucidates the role of combined fluconazole and flucytosine as therapy for cryptococcosis in the murine model of meningitis. Three strains of Cryptococcus neoformans for which the range of fluconazole MICs was wide--2 microg/ml (susceptible strain), 8 microg/ml (moderately susceptible strain), and 32 microg/ml (resistant strain)--were used for infection. One day postinfection, the mice were randomized into eight treatment groups: placebo; flucytosine (40 mg/kg of body weight/day); fluconazole at 3 mg/kg/day (low dosage), 10 mg/kg/day (moderate dosage), or 20 mg/kg/day (high dosage); and combined flucytosine and fluconazole at low, moderate, or high doses of fluconazole. Three major findings were demonstrated: (i) correlation between the MICs for the isolates and the in vivo effectiveness of fluconazole as assessed by the reduction in cryptococcal brain burden, (ii) a dose-response curve (a higher dose of fluconazole was significantly more efficacious than a lower dose [P < 0.001]), and (iii) synergism between fluconazole and flucytosine (therapy with a combination of fluconazole and flucytosine was superior to therapy with either agent alone [P < 0.01]).", "source": "https://pubmed.ncbi.nlm.nih.gov/9145879/"}
+{"doc_id": "a4eaf1e008a043a0608e1e0a1e0bf452", "sentence": "The consumption of meropenem or doripenem was calculated using the Anatomic Therapeutic Chemical classification and defined daily doses methodology .", "spans": [{"span_id": 0, "text": "meropenem", "start": 19, "end": 28, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "doripenem", "start": 32, "end": 41, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Correlation between the consumption of meropenem or doripenem and meropenem susceptibility of Pseudomonas aeruginosa in a university hospital in Japan. The appropriate use of carbapenems is essential in order to prevent resistance in Pseudomonas aeruginosa. We investigated the correlation between the consumption of meropenem or doripenem and the susceptibility of P. aeruginosa to meropenem in a Japanese university hospital from 2004 to 2009. The susceptibility data of P. aeruginosa and the annual consumption of meropenem or doripenem were analyzed. The consumption of meropenem or doripenem was calculated using the Anatomic Therapeutic Chemical classification and defined daily doses methodology . meropenem consumption decreased and doripenem consumption increased and throughout the entire investigation period, total consumption of meropenem plus doripenem was stable. Although the annual number of isolated P. aeruginosa has not changed, the annual number of isolated multidrug resistant P. aeruginosa decreased by measures against nosocomial infection. The rate of meropenem resistant P. aeruginosa decreased in a time-dependent manner. meropenem consumption was positively correlated with the meropenem resistance rate among P. aeruginosa (r = 0.9455, p<0.01). The total consumption of meropenem and doripenem was not correlated with the meropenem resistance rate (r = -0.6601, p>0.1). These results suggested that even if the total consumption of meropenem plus doripenem was not changed, meropenem susceptibility among P. aeruginosa improved by the decrease of meropenem consumption. Although meropenem and doripenem have been suggested to show cross-resistance with each other, the reduction of meropenem consumption might be effective for preventing an increase of meropenem-resistant P. aeruginosa.", "source": "https://pubmed.ncbi.nlm.nih.gov/22687536/"}
+{"doc_id": "22debd462be9d02dd7750eb8021920c8", "sentence": "After successful phase II studies , recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab , ofatumumab and obinutuzumab as a valuable treatment option for these patients .", "spans": [{"span_id": 0, "text": "chlorambucil", "start": 88, "end": 100, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "rituximab", "start": 135, "end": 144, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "ofatumumab", "start": 147, "end": 157, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "obinutuzumab", "start": 162, "end": 174, "token_start": 23, "token_end": 24}], "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": "Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia. For many decades, chlorambucil was the standard of care for chronic lymphocytic leukemia (CLL), but meanwhile has been replaced by purine analog-based chemoimmunotherapy. Monotherapy with the alkylator only retained significance in the treatment of older patients unfit for standard treatment. After successful phase II studies , recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab , ofatumumab and obinutuzumab as a valuable treatment option for these patients . Today, chlorambucil therefore should be used as a chemotherapy backbone for antibody-based chemoimmunotherapy in this patient population rather than as monotherapy. Starting from the past role of chlorambucil in CLL treatment, we here review the most recent efforts to elaborate chlorambucil-based chemoimmunotherapy in CLL and discuss clinically relevant questions that arise from this approach.", "source": "https://pubmed.ncbi.nlm.nih.gov/25219593/"}
+{"doc_id": "188b16b8466b9036888f9feac1266c4b", "sentence": "Unorthodox antibiotic combinations including ciprofloxacin against high-level gentamicin resistant enterococci .", "spans": [{"span_id": 0, "text": "ciprofloxacin", "start": 45, "end": 58, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "gentamicin", "start": 78, "end": 88, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Unorthodox antibiotic combinations including ciprofloxacin against high-level gentamicin resistant enterococci . Development of high-level gentamicin resistance among enterococci represents a serious therapeutic problem as it precludes synergy between aminoglycosides and cell-wall active agents. As part of a search for active antibiotic combinations against enterococci with high-level gentamicin resistance, we tested by the time kill curve method the efficacy of ciprofloxacin combined with ampicillin, trimethoprim-sulphamethoxazole, vancomycin or teicoplanin against ten isolates of Enterococcus faecium, three of Enterococcus casseliflavus and 13 of Enterococcus faecalis that exhibited a MIC of gentamicin > or = 2000 mg/L. Most of the E. faecium were also resistant to ampicillin and to ciprofloxacin. The combination of ciprofloxacin with ampicillin was bactericidal against five of seven E. faecium strains that exhibited a ciprofloxacin MIC < or = 4 mg/L, but was inactive against the three E. faecium that were highly resistant to ciprofloxacin. This combination was also bactericidal against the E. casseliflavus and all the E. faecalis strains. The combination of ciprofloxacin with trimethoprim-sulphamethoxazole was bactericidal against five of the seven E. faecium and seven of the nine E. faecalis strains with a ciprofloxacin MIC < or = 4 mg/L. No bactericidal activity of this combination was seen against the enterococci that were highly resistant to either ciprofloxacin or to trimethoprim-sulphamethoxazole. The combination of ciprofloxacin with glycopeptides was inactive against E. faecium and E. casseliflavus and against E. faecalis, it was either ineffective or antagonistic; in only one case it was bactericidal. Five strains of E. faecium were resistant to all antibiotic combinations tested.", "source": "https://pubmed.ncbi.nlm.nih.gov/8722538/"}
+{"doc_id": "988f81203188bfe746d002e49e6c45d7", "sentence": "Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma : CALGB 50401 ( Alliance ) .", "spans": [{"span_id": 0, "text": "Lenalidomide", "start": 20, "end": 32, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "Lenalidomide", "start": 46, "end": 58, "token_start": 6, "token_end": 7}, {"span_id": 2, "text": "Rituximab", "start": 64, "end": 73, "token_start": 8, "token_end": 9}], "rels": [{"class": "POS", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma : CALGB 50401 ( Alliance ) . lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. ### Patients And Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m(2) weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of \u2265 6 months from last dose. aspirin or heparin was recommended for patients at high thrombosis risk. ### results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). ### conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.", "source": "https://pubmed.ncbi.nlm.nih.gov/26304886/"}
+{"doc_id": "2f4875c70156aa249196fc0eaef130a8", "sentence": "Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis : implications for future clinical trials .", "spans": [{"span_id": 0, "text": "rifampin", "start": 32, "end": 40, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "isoniazid", "start": 45, "end": 54, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis : implications for future clinical trials . Standard treatment for latent tuberculosis infection (LTBI) is 9 months daily isoniazid (9INH). An alternative is 4 months daily rifampin (4RMP), associated with better completion and less toxicity; however, its efficacy remains uncertain. ### objectives To assess the cost-effectiveness of these regimens for treating LTBI in human immunodeficiency virus negative persons, using results from a recent clinical trial, plus different scenarios for 4RMP efficacy, and to estimate the costs of an adequately powered noninferiority trial and resulting savings from substitution with 4RMP. ### design A decision-analysis model tracked TB contacts and lower-risk tuberculin reactors receiving 9INH, 4RMP or no treatment. For different 4RMP efficacy scenarios, we estimated the cost-effectiveness, sample size and cost of non-inferiority trials, and potential cost savings substituting 4RMP for 9INH for 10 years in Canada. ### results With an assumed 4RMP efficacy of 60%, 9INH was more effective but slightly more expensive. Above a threshold efficacy of 69%, 4RMP was cheaper and more effective than 9INH. If the true efficacy of 4RMP is \u226575%, a trial powered to detect non-inferiority with a lower limit of 60% estimated efficacy (~20 000 subjects) may lead to cost savings within 10 years, even with the extreme assumption that Canada bears the entire cost. ### conclusion 4RMP may be a reasonable alternative to 9INH. Costs of a large-scale non-inferiority trial may be offset by subsequent savings.", "source": "https://pubmed.ncbi.nlm.nih.gov/22283892/"}
+{"doc_id": "029f80670066e918ad09b45caa1e326d", "sentence": "Treatments included once daily erlotinib , which was given alone for the first 7 days of treatments , then in combination with once daily sirolimus .", "spans": [{"span_id": 0, "text": "erlotinib", "start": 31, "end": 40, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "sirolimus", "start": 138, "end": 147, "token_start": 24, "token_end": 25}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": true}], "paragraph": "A dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas. In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib , which was given alone for the first 7 days of treatments , then in combination with once daily sirolimus . sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials.", "source": "https://pubmed.ncbi.nlm.nih.gov/22918789/"}
+{"doc_id": "0713ecdff351b72f27677723d0a8cc65", "sentence": "Cabazitaxel effectively killed PC-3R cells , and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel .", "spans": [{"span_id": 0, "text": "Cabazitaxel", "start": 0, "end": 11, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "docetaxel", "start": 107, "end": 116, "token_start": 16, "token_end": 17}, {"span_id": 2, "text": "cabazitaxel", "start": 128, "end": 139, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer. docetaxel is used as the first-line chemotherapy for castration-resistant prostate cancer (CRPC), but docetaxel resistance occurs in part owing to induction of P-glycoprotein (P-gp) encoded by multidrug resistance protein 1 (MDR1) gene. A recently developed taxane-cabazitaxel-has poor affinity for P-gp and is thereby effective in docetaxel-resistant CRPC. It has been recently demonstrated that exosomes in the body fluids could serve as a diagnostic marker because they contain proteins and RNAs specific to the cells from which they are derived. In this study, we aimed to investigate if P-gp in blood exosomes could be a marker to diagnose docetaxel resistance and select a taxoid for patients with CRPC. ### Methods And Materials Exosomes were isolated by differential centrifugation from docetaxel-resistant prostate cancer (PC-3) cells (PC-3R) and their parental PC-3 cells and from the serum of patients. Silencing of P-gp was performed by small interfering RNA transfection. Protein expression was examined by Western blot analysis. Viability of cells treated with docetaxel or cabazitaxel was determined by water soluble tetrazolium salt (WST) assay. ### results The level of P-gp was higher in exosomes as well as cell lysates from PC-3R cells than in those from PC-3 cells. Cabazitaxel effectively killed PC-3R cells , and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel . The P-gp level in blood exosomes was relatively higher in clinically docetaxel-resistant patients than in therapy-na\u00efve patients. ### conclusions Our results suggest that detection of P-gp in blood exosomes, which is involved in resistance to docetaxel but not to cabazitaxel, could be useful to diagnose docetaxel resistance and select an appropriate taxoid for patients with CRPC-docetaxel or cabazitaxel.", "source": "https://pubmed.ncbi.nlm.nih.gov/26027763/"}
+{"doc_id": "bf761dcf8faf97dba0151338f99b7f8a", "sentence": "The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril ( or another ACE inhibitor ) and high doses of loop diuretics , provided renal function is adequate .", "spans": [{"span_id": 0, "text": "spironolactone", "start": 105, "end": 119, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "captopril", "start": 136, "end": 145, "token_start": 20, "token_end": 21}, {"span_id": 2, "text": "loop diuretics", "start": 193, "end": 207, "token_start": 31, "token_end": 33}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Captopril and spironolactone therapy for refractory congestive heart failure. Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril ( or another ACE inhibitor ) and high doses of loop diuretics , provided renal function is adequate .", "source": "https://pubmed.ncbi.nlm.nih.gov/8422001/"}
+{"doc_id": "2639e095391228a032ec68c2c3f598ad", "sentence": "The MICs of erythromycin and clindamycin for most of the LAB were within the normal range of susceptibility .", "spans": [{"span_id": 0, "text": "erythromycin", "start": 12, "end": 24, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "clindamycin", "start": 29, "end": 40, "token_start": 5, "token_end": 6}], "rels": [], "paragraph": "Antibiotic resistance in lactic acid bacteria isolated from some pharmaceutical and dairy products. A total of 244 lactic acid bacteria (LAB) strains were isolated from 180 dairy and pharmaceutical products that were collected from different areas in Minia governorate, Egypt. LAB were identified phenotypically on basis of morphological, physiological and biochemical characteristics. Lactobacillus isolates were further confirmed using PCR-based assay. By combination of phenotypic with molecular identification Lactobacillus spp. were found to be the dominant genus (138, 76.7%) followed by Streptococcus spp. (65, 36.1%) and Lactococcus spp. (27, 15%). Some contaminant organisms such as (Staphylococcus spp., Escherichia coli, Salmonella spp., mould and yeast) were isolated from the collected dairy samples but pharmaceutical products were free of such contaminants. Susceptibility of LAB isolates to antibiotics representing all major classes was tested by agar dilution method. Generally, LAB were highly susceptible to Beta-lactams except penicillin. Lactobacilli were resistant to vancomycin, however lactococci and streptococci proved to be very susceptible. Most strains were susceptible to tetracycline and showed a wide range of streptomycin MICs. The MICs of erythromycin and clindamycin for most of the LAB were within the normal range of susceptibility . Sixteen Lactobacillus, 8 Lactococcus and 8 Streptococcus isolates including all tetracycline and/or erythromycin resistant strains were tested for the presence of tetracycline and/or erythromycin resistant genes [tet(M) and/or erm(B)]. PCR assays shows that some resistant strains harbor tet(M) and/or erm(B) resistance genes.", "source": "https://pubmed.ncbi.nlm.nih.gov/24948910/"}
+{"doc_id": "5ce6e216b05e1bb1b1ed43e0bc86e44d", "sentence": "Based on HRs for RFS/DFS , the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg , ipilimumab 10 mg/kg , or interferon .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 55, "end": 64, "token_start": 11, "token_end": 12}, {"span_id": 1, "text": "pembrolizumab", "start": 88, "end": 101, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "ipilimumab", "start": 125, "end": 135, "token_start": 23, "token_end": 24}, {"span_id": 3, "text": "ipilimumab", "start": 146, "end": 156, "token_start": 27, "token_end": 28}], "rels": [], "paragraph": "Comparative efficacy and safety of adjuvant nivolumab versus other treatments in adults with resected melanoma: a systematic literature review and network meta-analysis. Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA). ### methods A systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary. ### results Of 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS , the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg , ipilimumab 10 mg/kg , or interferon . Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12\u2009months, however, was lower beyond 12\u2009months (HR [95% credible interval] at 24\u2009months, 0.46 [0.27-0.78]; at 36\u2009months, 0.28 [0.14-0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10\u2009mg/kg or interferon and was similar to dabrafenib plus trametinib. ### conclusion Adjuvant therapy with nivolumab provides an effective treatment option with a promising risk-benefit profile.", "source": "https://pubmed.ncbi.nlm.nih.gov/33402121/"}
+{"doc_id": "ce0aa908b93d64279ac44dcaf232b957", "sentence": "Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment , especially in the first 6 weeks .", "spans": [{"span_id": 0, "text": "infliximab", "start": 23, "end": 33, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "methotrexate", "start": 38, "end": 50, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "methylprednisolone", "start": 138, "end": 156, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "gold", "start": 128, "end": 132, "token_start": 17, "token_end": 18}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "[Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis]. The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment , especially in the first 6 weeks .", "source": "https://pubmed.ncbi.nlm.nih.gov/12685246/"}
+{"doc_id": "73b3eae39bac7bc40153d6a660377f2b", "sentence": "Serum homocysteine , cholesterol , retinol , alpha-tocopherol , glycosylated hemoglobin and inflammatory response during therapy with bevacizumab , oxaliplatin , 5-fluorouracil and leucovorin .", "spans": [{"span_id": 0, "text": "bevacizumab", "start": 134, "end": 145, "token_start": 17, "token_end": 18}, {"span_id": 1, "text": "oxaliplatin", "start": 148, "end": 159, "token_start": 19, "token_end": 20}, {"span_id": 2, "text": "5-fluorouracil", "start": 162, "end": 176, "token_start": 21, "token_end": 22}, {"span_id": 3, "text": "leucovorin", "start": 181, "end": 191, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Serum homocysteine , cholesterol , retinol , alpha-tocopherol , glycosylated hemoglobin and inflammatory response during therapy with bevacizumab , oxaliplatin , 5-fluorouracil and leucovorin . Targeted agents present with a new spectrum of side-effects, including toxicities that negatively impact the risk of atherosclerosis. The aim of the present study was to evaluate the effect of the combination of targeted therapy and chemotherapy on serum homocysteine and other laboratory parameters of cardiovascular risk in patients with metastatic colorectal carcinoma. ### Patients And Methods Thirty-one patients with metastatic colorectal carcinoma treated with the combination of bevacizumab, oxaliplatin, 5-fluorouracil and leucovorin were studied before and during the therapy. ### results Serum homocysteine decreased significantly throughout the course of treatment. Total cholesterol and low-density lipoprotein cholesterol also decreased significantly during the first month of therapy. In contrast, serum retinol significantly increased during the second and third months of treatment. A significant increase in glycosylated hemoglobin was also observed. After an initial rise, serum C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were significantly lower compared to baseline throughout the course of treatment. Serum ferritin increased throughout most of the course of treatment. A significant correlation was observed between CRP and high-density lipoprotein cholesterol, retinol, ferritin, and CEA. CEA correlated with hemoglobin, retinol, and ferritin. Retinol correlated significantly with hemoglobin. ### conclusion Tumor control, reflected in lower CEA, resulted in suppression of the acute phase response and generally in favorable effects on laboratory parameters indicative of risk factors of atherosclerosis, including lower homocysteine concentrations, and lower total and LDL cholesterol.", "source": "https://pubmed.ncbi.nlm.nih.gov/20032440/"}
+{"doc_id": "869722511c63922c25884fec67a7e0cb", "sentence": "Reversal of drug resistance by planetary ball milled ( PBM ) nanoparticle loaded with resveratrol and docetaxel in prostate cancer .", "spans": [{"span_id": 0, "text": "resveratrol", "start": 86, "end": 97, "token_start": 14, "token_end": 15}, {"span_id": 1, "text": "docetaxel", "start": 102, "end": 111, "token_start": 16, "token_end": 17}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Reversal of drug resistance by planetary ball milled ( PBM ) nanoparticle loaded with resveratrol and docetaxel in prostate cancer . The folate receptor (FR) is a valued target that is highly expressed in various cancers, which will expedite the development of ligand-receptor binding based cancer therapeutics. In the present investigation, through tissue microarray analysis, we report higher levels of folate receptor expression in prostate cancer (PCa) tissue derived from patients, which were minimal in normal tissue. For folate-receptor based targeted therapy of PCa, we generated novel planetary ball milled (PBM) nanoparticles (NPs) encapsulated with resveratrol (RES), and in combination with docetaxel (DTX) and conjugated with folic acid (FA) on the surface. The cytotoxic effect of FA-conjugated DTX-nanoparticles was found effectual that reduced the concentration of free drug (DTX) to 28 times. Flow cytometry analysis showed a significant increase in the number of apoptotic cells by 30.92% and 65.9% in the FA-conjugated RES and in combination with DTX nanoparticle formulation respectively. However, only 8.9% apoptotic cells were found with control (empty NP). The expressions of NF-kB p65, COX-2, pro (BAX, BAK) and anti-apoptotic (BCL-2, BCL-XL) genes were significantly reduced after treatment with FA-RES\u00a0+\u00a0DTX-NP. In addition, the FA-conjugated DTX formulation exhibited additional cytotoxic effects with the down-regulation of survivin and an increased expression of Cleaved Caspase-3 in PCa cells. Further, we observed that treating DTX resistant PCa cells with FA-RES\u00a0+\u00a0DTX-NP exhibited a reversal of the ABC-transporter markers thereby limiting the multidrug resistance phenotype of the cancer cells. Our results strongly suggested that FA conjugated nanoparticle drugs acted as effective inhibitors of drug efflux that effectually enhances the intracellular concentration of the drug to exhibit their cytotoxic effect.", "source": "https://pubmed.ncbi.nlm.nih.gov/29678549/"}
+{"doc_id": "3340a0163ab0c5a4a681d3b8d9a74668", "sentence": "Records of 63 patients diagnosis of IHCC who received Gemcitabine and Carboplatin ( G-C Regimen ) chemotherapy as a first line were retrospectively reviewed .", "spans": [{"span_id": 0, "text": "Gemcitabine", "start": 54, "end": 65, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "Carboplatin", "start": 70, "end": 81, "token_start": 11, "token_end": 12}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Gemcitabine with carboplatin for advanced intrahepatic cholangiocarcinoma: A study from North India Cancer Centre. gemcitabine plus cisplatin has been established as a standard chemotherapy regimen for advanced biliary tract cancers (BTCs) based on the phase III UK ABC-02 study, which included all types of biliary cancers. There is very limited data regarding the effectiveness of known chemotherapeutic regimens especially in IHCC. ### methods Records of 63 patients diagnosis of IHCC who received Gemcitabine and Carboplatin ( G-C Regimen ) chemotherapy as a first line were retrospectively reviewed . The primary aim of this study was to assess the response rate of gemcitabine carboplatin-based chemotherapy as a first line therapy in advanced intrahepatic cholangiocarcinoma (IHCC). The secondary objectives were to assess toxicity, progression free survival and overall survival. ### results There were 38 men and 25 women in our study with a median age of 56.75 years (range 31-78 years). Of the 38+25= 63 patients, 21 patients (33.8%) progressed, 5 patients (8.06%) had complete response, 25 patients (40.3%) had partial response, 12 patients (19.3%) had stable disease. Overall response rate was 48.36% and tumor control rate was 67.6%. Progression free survival was 5.3 months and overall survival of 10.3 months was seen. The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia. Most common nonhematological toxicity was fatigue. ### conclusion gemcitabine in combination with carboplatin has activity against advanced IHCC. Our results are comparable with other gemcitabine carboplatin studies as well as gemcitabine cisplatin-based studies.", "source": "https://pubmed.ncbi.nlm.nih.gov/30693882/"}
+{"doc_id": "0bb682c2b7cf581f5630b073a89e2728", "sentence": "Drugs most commonly implicated in ADRs were amoxicillin + clavulanate ( 21.87 % ) followed by ceftriaxone ( 20.31 % ) .", "spans": [{"span_id": 0, "text": "amoxicillin", "start": 44, "end": 55, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "clavulanate", "start": 58, "end": 69, "token_start": 9, "token_end": 10}, {"span_id": 2, "text": "ceftriaxone", "start": 94, "end": 105, "token_start": 16, "token_end": 17}], "rels": [{"class": "NEG", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Adverse Drug Reactions in Hospitalized Pediatric Patients: A Prospective Observational Study. To determine the incidence, pattern, causality, preventability, severity and predictors of adverse drug reactions (ADRs) in pediatric population. ### methods It was a prospective, observational study that included patients of either sex, of any age treated in the pediatric wards of a tertiary care hospital. Study patients were followed throughout their hospital stay. Whenever an ADR was detected, all the required data was collected and analyzed. Data was analyzed for incidence, causality (by using WHO Probability scale and Naranjo's algorithm), preventability (by using Modified Shumock and Thornton scale), severity (by using Modified Hartwig and Siegel scale) and predictors of ADRs. ### results Of the 1775 children admitted in the pediatrics ward, 1082 patients met study criteria and were enrolled into the study. A total of 64 ADRs were identified from 54 patients. The incidence of ADRs was 4.99\u00a0%. Male patients experienced majority (68.52\u00a0%) of ADRs. Drugs most commonly implicated in ADRs were amoxicillin + clavulanate ( 21.87 % ) followed by ceftriaxone ( 20.31 % ) . Most (51.56\u00a0%) of the ADRs reported belonged to the system organ class, gastrointestinal system disorders. Among the ADRs reported, 82.85\u00a0% of ADRs were mild. Majority (87.5\u00a0%) of the ADRs were of 'probable' causality category and 96.9\u00a0% were not preventable. There was a significant association between occurrence of ADRs and the use of \u22654 number of medications, age (infants) and gender (male). ### conclusions Among the pediatric population, infants, male gender and those receiving \u22654 number of medications are at risk of developing ADRs. Constant monitoring is required to address the safety issue in pediatric population especially in infants and patients receiving \u22654 drugs.", "source": "https://pubmed.ncbi.nlm.nih.gov/26916890/"}
+{"doc_id": "c9b122c2f0b11e182b4ed52d9f390055", "sentence": "Dexamethasone and piroxicam provided in the diet were found to significantly inhibit lung tumors induced by 60 mg/kg vinyl carbamate at 24 weeks whereas myo-inositol also provided in the diet , did not significantly inhibit tumor formation .", "spans": [{"span_id": 0, "text": "Dexamethasone", "start": 0, "end": 13, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "piroxicam", "start": 18, "end": 27, "token_start": 2, "token_end": 3}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Chemoprevention of vinyl carbamate-induced lung tumors in strain A mice. The ability of potential chemopreventive agents to prevent vinyl carbamate-induced lung tumors was determined in 2 different experiments. Female strain A mice administered intraperitoneally either a single injection of 60 mg/kg vinyl carbamate that induced 24.0 +/- 1.72 tumors/mouse at 24 weeks or 2 injections of 16 mg/kg vinyl carbamate each (32 mg/kg total dose) that induced 43.2 +/- 3.2 tumors/mouse at 20 weeks. Lung carcinomas were found as early as 16 weeks. Dexamethasone and piroxicam provided in the diet were found to significantly inhibit lung tumors induced by 60 mg/kg vinyl carbamate at 24 weeks whereas myo-inositol also provided in the diet , did not significantly inhibit tumor formation . In animals given 6 16-mg/kg doses of vinyl carbamate, tumor multiplicity was reduced roughly 25% by alpha-difluoromethylornithine and green tea and reduced 50% by dexamethasone and piroxicam. Combinations of these agents were also tested using a total dose of 32 mg/kg of vinyl carbamate. Although alpha-difluoromethylornithine and green tea did not result in a significant inhibition of lung tumor formation if used alone, the combination of alpha-difluoromethylornithine and green tea resulted in a significant reduction of tumor multiplicity. The combinations of alpha-difluoromethylornithine or green tea with either dexamethasone or piroxicam or the combination of dexamethasone and piroxicam did not decrease tumor multiplicity greater than achieved by dexamethasone and piroxicam alone. In summary, selected chemopreventive agents previously shown to inhibit lung tumors by other chemical carcinogens also inhibited vinyl carbamate-induced lung tumors.", "source": "https://pubmed.ncbi.nlm.nih.gov/11195469/"}
+{"doc_id": "7d28ca2a855a5b496c60034074c7858a", "sentence": "We identified 938 patients with RCC who had initially been treated with sunitinib ( n = 554 ) or sorafenib ( n = 384 ) .", "spans": [{"span_id": 0, "text": "sunitinib", "start": 72, "end": 81, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "sorafenib", "start": 97, "end": 106, "token_start": 19, "token_end": 20}], "rels": [], "paragraph": "Initial patterns of care with oral targeted therapies for patients with renal cell carcinoma. To characterize the contemporary use of oral-targeted therapies (ie, sunitinib, sorafenib) among patients with renal cell carcinoma (RCC) and to assess the factors associated with short-term and sequential treatment. ### methods We used an administrative claims database of privately insured patients to evaluate oral-targeted therapy use among patients with RCC from 2006 to 2007. After identifying patients with RCC who had received sunitinib and/or sorafenib, we determined the prevalence of patients treated with short-term and/or sequential therapy. We performed bivariate and multivariate analyses to estimate the associations between the patient characteristics and receipt of short-term and/or sequential treatment regimens. ### results We identified 938 patients with RCC who had initially been treated with sunitinib ( n = 554 ) or sorafenib ( n = 384 ) . In this group, 36% and 23% of patients had received short-term or sequential therapy, respectively. Most patients (61%) who had received sequential therapy had undergone short-term treatment with \u22651 drugs, with second-line sorafenib more likely to be given as short-term therapy than sunitinib (63% vs 34%, P < .001). Short-term therapy was more common in female patients (odds ratio 1.53, 95% confidence interval 1.12-2.09) and patients in the Southern United States (odds ratio 1.71, 95% confidence interval 1.05-2.80). Sequential therapy was more common among patients receiving sorafenib first (odds ratio 2.30, 95% confidence interval 1.64-3.21). ### conclusions Short-term and sequential oral targeted therapy use was relatively prevalent among patients with RCC. For patients treated with sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the \"real-world\" clinical outcomes and economic effect associated with these treatment courses.", "source": "https://pubmed.ncbi.nlm.nih.gov/21256539/"}
+{"doc_id": "9e5fb2640e823bd9f6060982fa8daf28", "sentence": "( 3 ) Observed facilitatory effects of caerulein on the hypothalamic defensive attack were very similar to those observed with dopamine ( DA ) agonists such as methamphetamine and apomorphine and opposite to those with DA antagonists such as haloperidol and chlorpromazine .", "spans": [{"span_id": 0, "text": "methamphetamine", "start": 160, "end": 175, "token_start": 27, "token_end": 28}, {"span_id": 1, "text": "haloperidol", "start": 242, "end": 253, "token_start": 39, "token_end": 40}, {"span_id": 2, "text": "chlorpromazine", "start": 258, "end": 272, "token_start": 41, "token_end": 42}], "rels": [], "paragraph": "Facilitatory effects of caerulein on hypothalamic defensive attack in cats. Effects of intraventricularly microinjected caerulein (0.1, 1.0 and 10.0 micrograms) on the thresholds for hypothalamically elicited defensive attack and influences of haloperidol (0.5 mg/kg, i.p.) on the effects were studied in chronic cats. Directed attack and hissing were selected for threshold determination, and thresholds for these responses were measured under two situations: one with provocations by a human, and the other without such provocation. Results were as follows. (1) Caerulein lowered all thresholds in generally equal decrements and in a dose-related manner, accompanied by a general behavioral arousal. (2) Prior injection of haloperidol prevented the effects of caerulein, suggesting an antagonism-like interaction between haloperidol and caerulein. ( 3 ) Observed facilitatory effects of caerulein on the hypothalamic defensive attack were very similar to those observed with dopamine ( DA ) agonists such as methamphetamine and apomorphine and opposite to those with DA antagonists such as haloperidol and chlorpromazine . These findings suggest that caerulein exerts its facilitatory effects on the excitability of the ventromedial hypothalamic nucleus through its synergistic interaction with DA.", "source": "https://pubmed.ncbi.nlm.nih.gov/3179708/"}
+{"doc_id": "b6851a7dde2051096158e6c807455512", "sentence": "The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [ IQR 49 - 53 ] .", "spans": [{"span_id": 0, "text": "tremelimumab", "start": 63, "end": 75, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "durvalumab", "start": 90, "end": 100, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study.  The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [ IQR 49 - 53 ] . Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy. ### methods NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131. ### findings 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16\u00b75 months (95% CI 13\u00b77-19\u00b72). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22\u00b70-25\u00b70), median overall survival was 12\u00b75 months (95% CI 0\u00b70-25\u00b78), and survival at 12 months was 52\u00b79%, at 18 months was 35\u00b73%, and at 24 months was 23\u00b75%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8\u00b73 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8\u00b73 mutations per Mb and those with TMB lower than the median in the retreated cohort (41\u00b73 months vs 17\u00b74 months; p=0\u00b702). ### interpretation tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients. ### funding NIBIT Foundation, Fondazione AIRC, AstraZeneca.", "source": "https://pubmed.ncbi.nlm.nih.gov/33844995/"}
+{"doc_id": "6cfe3dd23724e0caa786ba26a68a658f", "sentence": "Sorafenib has been the standard of care for a decade , and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago .", "spans": [{"span_id": 0, "text": "Sorafenib", "start": 0, "end": 9, "token_start": 0, "token_end": 1}, {"span_id": 1, "text": "regorafenib", "start": 81, "end": 92, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "lenvatinib", "start": 114, "end": 124, "token_start": 20, "token_end": 21}], "rels": [], "paragraph": "Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges. Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade , and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago . FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.", "source": "https://pubmed.ncbi.nlm.nih.gov/30819826/"}
+{"doc_id": "0a7134a3a2612a4d409a7d631f5c6260", "sentence": "The addition of trastuzumab , pertuzumab , bevacizumab , or lapatinib to chemotherapy significantly ( P < .05 ) improved objective response rate ( ORR ) , time to failure ( TTF ) , and overall survival ( OS ) in patients with HER2-positive ( HER2(+ ) ) disease .", "spans": [{"span_id": 0, "text": "trastuzumab", "start": 16, "end": 27, "token_start": 3, "token_end": 4}, {"span_id": 1, "text": "pertuzumab", "start": 30, "end": 40, "token_start": 5, "token_end": 6}, {"span_id": 2, "text": "bevacizumab", "start": 43, "end": 54, "token_start": 7, "token_end": 8}, {"span_id": 3, "text": "lapatinib", "start": 60, "end": 69, "token_start": 10, "token_end": 11}, {"span_id": 4, "text": "chemotherapy", "start": 73, "end": 85, "token_start": 12, "token_end": 13}], "rels": [{"class": "POS", "spans": [0, 4], "is_context_needed": false}, {"class": "POS", "spans": [1, 4], "is_context_needed": false}, {"class": "POS", "spans": [2, 4], "is_context_needed": false}], "paragraph": "Effectiveness of targeted therapy in patients with previously untreated metastatic breast cancer: a systematic review and meta-analysis. Breast cancer is the most common cancer and the most frequent cause of death in women. Targeted therapies offer a possibility of effective and individualized therapy based on the molecular profile of the tumor. The aim of this systematic review was to evaluate the efficacy and safety of targeted agents added to chemotherapy or endocrine therapy in patients with previously untreated metastatic breast cancer (MBC) depending on their human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status (positive or negative). The systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library to identify randomized controlled trials (RCTs). Thirteen trials were included. The addition of trastuzumab , pertuzumab , bevacizumab , or lapatinib to chemotherapy significantly ( P < .05 ) improved objective response rate ( ORR ) , time to failure ( TTF ) , and overall survival ( OS ) in patients with HER2-positive ( HER2(+ ) ) disease . trastuzumab or lapatinib combined with endocrine therapy significantly (P < .05) improved ORR, time to progression (TTP), and progression-free survival (PFS) in patients with HER2(+) and HR(+) disease. In patients with HER2-negative (HER2(-)) cancer, bevacizumab or lapatinib added to chemotherapy significantly (P < .05), improved ORR but did not prolong PFS and OS (P > .05). In patients with HER2(-) and HR(-) disease, trastuzumab combined with chemotherapy did not significantly improve (P > .05) ORR or PFS. Targeted therapies also increased the overall risk of adverse events. So far, there is a lack of published results for everolimus and trastuzumab emtansine trials in patients with previously untreated MBC. The addition of targeted therapy to chemotherapy or endocrine therapy using HER2 and HR status significantly improved ORR, PFS, and OS in patients with previously untreated MBC.", "source": "https://pubmed.ncbi.nlm.nih.gov/25441421/"}
+{"doc_id": "ce729f6ebbcf5bb46bb08e16542fd835", "sentence": "The feasibility and efficacy of an intensified procarbazine-free consolidation regimen VECOPA ( vinblastine , etoposide , cyclophosphamide , vincristine , prednisone , doxorubicin ) were investigated .", "spans": [{"span_id": 0, "text": "vinblastine", "start": 96, "end": 107, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "etoposide", "start": 110, "end": 119, "token_start": 14, "token_end": 15}, {"span_id": 2, "text": "cyclophosphamide", "start": 122, "end": 138, "token_start": 16, "token_end": 17}, {"span_id": 3, "text": "vincristine", "start": 141, "end": 152, "token_start": 18, "token_end": 19}, {"span_id": 4, "text": "prednisone", "start": 155, "end": 165, "token_start": 20, "token_end": 21}, {"span_id": 5, "text": "doxorubicin", "start": 168, "end": 179, "token_start": 22, "token_end": 23}], "rels": [{"class": "POS", "spans": [0, 1, 2, 3, 4, 5], "is_context_needed": true}], "paragraph": "Feasibility of VECOPA, a dose-intensive chemotherapy regimen for children and adolescents with intermediate and advanced stage Hodgkin lymphoma: results of the GPOH-HD-2002/VECOPA pilot trial. The GPOH-HD (Gesellschaft f\u00fcr P\u00e4diatrische Onkologie und H\u00e4matologie-Hodgkin Disease) strategy for children and adolescents with intermediate and advanced stage Hodgkin lymphoma is based on two induction cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin) followed by COPP (cyclophosphamide, vincristine, procarbazine, prednisone) or COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine) consolidation. The feasibility and efficacy of an intensified procarbazine-free consolidation regimen VECOPA ( vinblastine , etoposide , cyclophosphamide , vincristine , prednisone , doxorubicin ) were investigated . Following two OEPA and one or two VECOPA cycles, involved field radiotherapy was applied. The main endpoint was feasibility. Secondary endpoints were toxicity, proportion of delayed cycles, granulocyte-colony stimulating factor use, and event-free and overall survival. The regimen was well tolerated with mostly hematotoxicity exceeding Common Toxicity Criteria grade 2. In most patients with advanced stage the second VECOPA cycle was delayed despite hematopoietic recovery and absence of serious adverse events. Event-free survival at 36 months was 0.86 (95% confidence interval 0.70-1). The VECOPA regimen is effective and tolerable. However, its time-intensification was not fully exploited within this trial.", "source": "https://pubmed.ncbi.nlm.nih.gov/25204374/"}
+{"doc_id": "447854f1de95488c44ec5e39824f21d7", "sentence": "The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma , with deep and sustained confirmed responses .", "spans": [{"span_id": 0, "text": "nivolumab", "start": 27, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "ipilimumab", "start": 42, "end": 52, "token_start": 6, "token_end": 7}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study. Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. ### Patients And Methods We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. ### results Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. ### conclusion The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma , with deep and sustained confirmed responses .", "source": "https://pubmed.ncbi.nlm.nih.gov/33125309/"}
+{"doc_id": "3727a540ed60fbcbe84867b9a216d7f7", "sentence": "The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase , comparing imatinib with the combination of IFN-alpha and cytarabine .", "spans": [{"span_id": 0, "text": "imatinib", "start": 197, "end": 205, "token_start": 28, "token_end": 29}, {"span_id": 1, "text": "cytarabine", "start": 244, "end": 254, "token_start": 35, "token_end": 36}, {"span_id": 2, "text": "IFN-alpha", "start": 230, "end": 239, "token_start": 33, "token_end": 34}], "rels": [{"class": "COMB", "spans": [1, 2], "is_context_needed": true}], "paragraph": "Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. ### Experimental Design The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase , comparing imatinib with the combination of IFN-alpha and cytarabine . ### results imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. ### conclusions On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.", "source": "https://pubmed.ncbi.nlm.nih.gov/12796358/"}
+{"doc_id": "cd89968df90b1bb4fb356d8c717e3738", "sentence": "A total of 164 patients with recurrent ovarian cancer were selected and randomly divided into two groups : experimental group ( n=82 , BEV + paclitaxel + carboplatin ) and control group ( n=82 , paclitaxel + carboplatin ) .", "spans": [{"span_id": 0, "text": "paclitaxel", "start": 141, "end": 151, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "carboplatin", "start": 154, "end": 165, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "paclitaxel", "start": 195, "end": 205, "token_start": 35, "token_end": 36}, {"span_id": 3, "text": "carboplatin", "start": 208, "end": 219, "token_start": 37, "token_end": 38}, {"span_id": 4, "text": "BEV", "start": 135, "end": 138, "token_start": 23, "token_end": 24}], "rels": [{"class": "POS", "spans": [0, 1, 4], "is_context_needed": true}, {"class": "COMB", "spans": [2, 3], "is_context_needed": true}], "paragraph": "Therapeutic effect of bevacizumab combined with paclitaxel and carboplatin on recurrent ovarian cancer. To observe the clinical efficacy and safety of bevacizumab (BEV) combined with paclitaxel on recurrent ovarian cancer. ### methods A total of 164 patients with recurrent ovarian cancer were selected and randomly divided into two groups : experimental group ( n=82 , BEV + paclitaxel + carboplatin ) and control group ( n=82 , paclitaxel + carboplatin ) . The clinical therapeutic effects including objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, stable disease (SD), progressive disease (PD), progression free survival (PFS) and overall survival (OS) were evaluated, together with the adverse clinical reactions and improvement of quality of life (QoL). Immunohistochemistry was used to detect the expression of phosphate and tension homology deleted on chromosome ten (PTEN). ### results The PFS, OS and ORR of patients in the experimental group were significantly higher than those in the control group (p<0.05). In addition, the incidence rates of allergy, gastrointestinal reactions and leukopenia were significantly lower in the experimental group compared with those in the control group (p<0.05). There was no significant difference in QoL score between the two groups before treatment (p>0.05). However, after treatment, the QoL score in the experimental group was increased significantly compared with the control group (p<0.05). Moreover, the expression of PTEN in PR, SD and PD patients was lower, with significant difference between the two groups (p<0.05). ### conclusion The clinical therapeutic effect of BEV combined with paclitaxel in patients with recurrent ovarian cancer was improved, suggesting it might be beneficial for the treatment of ovarian cancer.", "source": "https://pubmed.ncbi.nlm.nih.gov/31424654/"}
+{"doc_id": "bd252f7e7872efdd84ff4314959d2793", "sentence": "Successful treatment of an adult with Kasabach-Merritt syndrome using thalidomide , vincristine , and prednisone .", "spans": [{"span_id": 0, "text": "thalidomide", "start": 70, "end": 81, "token_start": 9, "token_end": 10}, {"span_id": 1, "text": "vincristine", "start": 84, "end": 95, "token_start": 11, "token_end": 12}, {"span_id": 2, "text": "prednisone", "start": 102, "end": 112, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1, 2], "is_context_needed": false}], "paragraph": "Successful treatment of an adult with Kasabach-Merritt syndrome using thalidomide , vincristine , and prednisone . Kasabach-Merritt syndrome is a rare disease that mainly occurs in infants and adolescents. It usually manifests as disseminated intravascular coagulation and severe bleeding, and is associated with high mortality. However, its low incidence and clinical rarity in adults mean that there is currently no well-verified treatment regimen for this disease. We report on an effective novel therapeutic regimen in a patient with Kasabach-Merritt syndrome. ### methods A woman with Kasabach-Merritt syndrome presented with a recurrent subcutaneous mass and disseminated intravascular coagulation, and was treated with prednisone, vincristine and thalidomide. ### results This treatment regimen successfully resolved the patient's symptoms, with tumor regression. The patient remained disease-free after 6 years of follow-up. ### conclusions prednisone combined with vincristine and thalidomide may be an effective treatment for Kasabach-Merritt syndrome, but further studies are needed to verify the use of this regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/30806107/"}
+{"doc_id": "b8ca06ae2a24839388168c966f0eaed6", "sentence": "Superiority of sirolimus ( rapamycin ) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow .", "spans": [{"span_id": 0, "text": "sirolimus", "start": 15, "end": 24, "token_start": 2, "token_end": 3}, {"span_id": 1, "text": "rapamycin", "start": 27, "end": 36, "token_start": 4, "token_end": 5}, {"span_id": 2, "text": "cyclosporine", "start": 44, "end": 56, "token_start": 7, "token_end": 8}], "rels": [], "paragraph": "Superiority of sirolimus ( rapamycin ) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow . sirolimus is a potent immunosuppressive agent with great therapeutic potential. The objective of our study was to evaluate the efficacy of sirolimus versus cyclosporine in augmenting the unresponsiveness induced by an antilymphocyte serum (ALS)/donor-specific bone marrow (BM)-based regimen across three levels of histoincompatibility: class I and II disparate (DBA/2 to B6AF1), complete mismatch (AKR to C57BL/6), and xenograft (ACI rat to B6AF1). ### methods Full-thickness skin grafts were taken from donors and placed on recipients in standard fashion. Seven groups of recipient mice (n=10-28) received various combinations of the following treatment protocols: sirolimus, 1.5 mg/kg (3.0 mg/kg for xenografts) every other day from day 0 to day 12; cyclosporine, 50 mg/kg every other day from day 10 through 22; ALS, 0.5 ml on days -1 and 2 for allografts and days -1, 2, and 4 for xenografts; and BM, 25 million donor-specific cells IV on day 7. ### results The administration of ALS or ALS/BM resulted in modest but significant prolongation of skin graft survival in all combinations tested. cyclosporine combined with ALS or ALS/BM significantly extended allograft survival compared with ALS or ALS/BM alone (P<0.05) but had no effect on xenograft survival. In contrast, the combination of sirolimus with ALS or ALS/BM resulted in a two- to threefold increase in allograft survival and over a fourfold increase in xenograft survival when compared with the comparable cyclosporine-based regimen. Additionally, lymphocytes isolated from class I and II incompatible mice with skin grafts surviving >100 days demonstrated markedly reduced interleukin 2 and interferon-gamma secretion in response to irradiated donor-specific lymphocytes in culture. ### conclusions In the regimens tested, sirolimus was superior to cyclosporine in augmenting donor BM-induced skin graft prolongation in ALS-treated mice across all levels of histoincompatibility.", "source": "https://pubmed.ncbi.nlm.nih.gov/9039923/"}
+{"doc_id": "ee9b23ccfb165468071d9c7bcef4f590", "sentence": "Profiling of drug-metabolizing enzymes/transporters in CD33 + acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine , Cytarabine and Idarubicin .", "spans": [{"span_id": 0, "text": "Fludarabine", "start": 133, "end": 144, "token_start": 15, "token_end": 16}, {"span_id": 1, "text": "Cytarabine", "start": 147, "end": 157, "token_start": 17, "token_end": 18}, {"span_id": 2, "text": "Idarubicin", "start": 162, "end": 172, "token_start": 19, "token_end": 20}, {"span_id": 3, "text": "Gemtuzumab-Ozogamicin", "start": 107, "end": 128, "token_start": 13, "token_end": 14}], "rels": [{"class": "COMB", "spans": [0, 1, 2, 3], "is_context_needed": true}], "paragraph": "Profiling of drug-metabolizing enzymes/transporters in CD33 + acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine , Cytarabine and Idarubicin . Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-ozogamicin (GO) with fludarabine-cytarabine-idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen.", "source": "https://pubmed.ncbi.nlm.nih.gov/22584460/"}
+{"doc_id": "178e161c0e0960a219110932d3746c09", "sentence": "In addition , anti-PCSK9 drugs ( evolocumab and alirocumab ) provide an effective solution for patients with familial hypercholesterolemia ( FH ) and statin intolerance at very high cardiovascular risk .", "spans": [{"span_id": 0, "text": "evolocumab", "start": 33, "end": 43, "token_start": 6, "token_end": 7}, {"span_id": 1, "text": "alirocumab", "start": 48, "end": 58, "token_start": 8, "token_end": 9}], "rels": [], "paragraph": "Treatment Strategy for Dyslipidemia in Cardiovascular Disease Prevention: Focus on Old and New Drugs. Prevention and treatment of dyslipidemia should be considered as an integral part of individual cardiovascular prevention interventions, which should be addressed primarily to those at higher risk who benefit most. To date, statins remain the first-choice therapy, as they have been shown to reduce the risk of major vascular events by lowering low-density lipoprotein cholesterol (LDL-C). However, due to adherence to statin therapy or statin resistance, many patients do not reach LDL-C target levels. ezetimibe, fibrates, and nicotinic acid represent the second-choice drugs to be used in combination with statins if lipid targets cannot be reached. In addition , anti-PCSK9 drugs ( evolocumab and alirocumab ) provide an effective solution for patients with familial hypercholesterolemia ( FH ) and statin intolerance at very high cardiovascular risk . Recently, studies demonstrated the effects of two novel lipid-lowering agents (lomitapide and mipomersen) for the management of homozygous FH by decreasing LDL-C values and reducing cardiovascular events. However, the costs for these new therapies made the cost-effectiveness debate more complicated.", "source": "https://pubmed.ncbi.nlm.nih.gov/29361723/"}
+{"doc_id": "c13dbaaf1d499d927f9739805788022f", "sentence": "Likewise , emotional , functional well-being , and QoL aspects specifically related to lung cancer were better improved in the Gefitinib group than in the Pemetrexed group ( P<0.05 ) .", "spans": [{"span_id": 0, "text": "Gefitinib", "start": 127, "end": 136, "token_start": 20, "token_end": 21}, {"span_id": 1, "text": "Pemetrexed", "start": 155, "end": 165, "token_start": 25, "token_end": 26}], "rels": [], "paragraph": "[A randomized clinical study of Gefitinib and pemetrexed as second line therapy for advanced non-squamous non-small cell lung cancer]. gefitinib and pemetrexed are drugs used as second-line therapy for advanced non-small cell lung cancer (NSCLC), although studies comparing the two drugs are limited. The aim of this study is to explore the effects, safety, and quality of life (QoL) of gefitinib and pemetrexed on patients with advanced non-squamous NSCLC. ### methods Forty-six advanced non-squamous NSCLC patients who failed to first-line therapy were randomly divided into two groups with 23 patients each, one using oral gefitinib (gefitinib group) and the other using intravenous injection pemetrexed (pemetrexed group). The effects, safety, and QoL were determined and analyzed. ### results For the pemetrexed group, objective response rate (ORR) was 13.0% (3/23), disease control rate (DCR) was 30.4% (7/23), and median progression-free survival (mPFS) was 3.1 months. In the gefitinib group, ORR was 17.3% (4/23), DCR was 39.1% (9/23), and mPFS was 4.4 months. Compared with the pemetrexed group, the ORR, DCR, and mPFS in the gefitinib group exhibited no statistical significance (P>0.05). Furthermore, the most common toxicities in the pemetrexed group were neutropenia (n=9, 39.13%) and fatigue (n=8, 34.78%), whereas those in the in gefitinib group were skin rash (n=8, 34.78%) and diarrhea (n=4, 17.39%). Compared with baseline, the QoL improved in both groups but to different degrees. Likewise , emotional , functional well-being , and QoL aspects specifically related to lung cancer were better improved in the Gefitinib group than in the Pemetrexed group ( P<0.05 ) . ### conclusions The effects of pemetrexed and gefitinib as second line therapy were similar, although with different AEs. Both drugs could improve the QoL, but gefitinib showed better overall results than pemetrexed.", "source": "https://pubmed.ncbi.nlm.nih.gov/23945243/"}
+{"doc_id": "08fdd1d12a13087c9d06f4b30fd12542", "sentence": "To determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation .", "spans": [{"span_id": 0, "text": "anakinra", "start": 80, "end": 88, "token_start": 12, "token_end": 13}, {"span_id": 1, "text": "methylprednisolone", "start": 94, "end": 112, "token_start": 14, "token_end": 15}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: an observational cohort study. Immunomodulants have been proposed to mitigate SARS-Cov-2-induced cytokine storm, which drives acute respiratory distress syndrome in COVID-19. ### objective To determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation . ### methods Secondary analysis of prospective observational cohort studies at an Italian tertiary health-care facility. COVID-19 patients consecutively hospitalized (02/25/2020 to 03/30/2020), with hyperinflammation (ferritin \u22651000ng/mL and/or C-reactive protein >10mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO ### results 120 COVID-19 patients with hyperinflammation (median age 62 years, 80.0% males, median PaO ### conclusions Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized, controlled trials including use of either agent alone are needed to confirm these results.", "source": "https://pubmed.ncbi.nlm.nih.gov/33220354/"}
+{"doc_id": "183c151df65c06b02c251456be7381a0", "sentence": "When rats were given Li for 3 days , followed by a single injection of imipramine , the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat , although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats .", "spans": [{"span_id": 0, "text": "Li", "start": 21, "end": 23, "token_start": 4, "token_end": 5}, {"span_id": 1, "text": "imipramine", "start": 71, "end": 81, "token_start": 15, "token_end": 16}, {"span_id": 2, "text": "desipramine", "start": 106, "end": 117, "token_start": 20, "token_end": 21}, {"span_id": 3, "text": "imipramine", "start": 206, "end": 216, "token_start": 37, "token_end": 38}], "rels": [{"class": "COMB", "spans": [0, 1], "is_context_needed": true}], "paragraph": "Effects of lithium on alterations of pharmacokinetics of imipramine and on the related changes of monoamines in rat brain. Rats were given chronically i.p. imipramine (20 mg/kg), LiCl (1 mg/kg) or both drugs to examine the effects of lithium (Li) on the alterations of imipramine pharmacokinetics in the whole brain and on the imipramine-related changes of norepinephrine (NE) and serotonin (5-HT) levels in the brain. When rats were given Li for 3 days , followed by a single injection of imipramine , the concentrations of desipramine in the brain and serum were higher than those in the vehicle-treated rat , although the imipramine concentrations in both tissues did not differ in Li- and in vehicle-treated rats . In rats receiving both drugs for 10 days, the steady state levels of imipramine and desipramine in the brain were the same as those in the vehicle-treated rats but the steady state level of desipramine was reached earlier with Li treatments presumably because of the enhanced demethylation of imipramine. Consequently, the desipramine-dependent alterations of NE and 3-methoxy-4-hydroxyphenylglycol levels in the brain appeared to be induced earlier and more markedly when Li was given simultaneously. As the 5-hydroxyindole acetic acid (5-HIAA) levels were elevated in the brains of Li-treated rats and reduced in brains of imipramine-treated rats as compared with the level in vehicle-treated rats, the 5-HIAA level in rats receiving both drugs was equivalent to that in vehicle-treated rats.", "source": "https://pubmed.ncbi.nlm.nih.gov/2625134/"}
+{"doc_id": "92082bec5072473e89c67b616f8a0e15", "sentence": "Using population-based data from the province of Ontario , the benefit of first-line ipilimumab was estimated by comparing outcomes of patients treated with first-line dacarbazine over the period 2007 - 2009 with patients treated over the period 2010 - 2015 with first-line ipilimumab .", "spans": [{"span_id": 0, "text": "ipilimumab", "start": 85, "end": 95, "token_start": 13, "token_end": 14}, {"span_id": 1, "text": "dacarbazine", "start": 168, "end": 179, "token_start": 24, "token_end": 25}, {"span_id": 2, "text": "ipilimumab", "start": 274, "end": 284, "token_start": 42, "token_end": 43}], "rels": [], "paragraph": "A population-based study of the treatment effect of first-line ipilimumab for metastatic or unresectable melanoma. ipilimumab is an anti-CTLA4 monoclonal antibody with demonstrated efficacy for metastatic melanoma in randomized controlled trials, including in the first-line setting. Population-based outcomes directly compared with historic chemotherapy treatment in metastatic or unresectable melanoma are lacking. Using population-based data from the province of Ontario , the benefit of first-line ipilimumab was estimated by comparing outcomes of patients treated with first-line dacarbazine over the period 2007 - 2009 with patients treated over the period 2010 - 2015 with first-line ipilimumab . Cutaneous and noncutaneous cases were included. The administrative data set utilized was high-dimensional; meaning, there was a large number of variables relative to the sample size. To adjust for important confounders among the many available variables, we utilized a double-selection method, a modified machine learning algorithm to extract the important variables that were related to both survival times and treatment usage. Time-dependent treatment modeling was utilized. Among the 2793 melanoma patients receiving palliative treatment (systemic therapy, surgery, or radiation) in Ontario (2007-2015), there were 289 patients treated with first-line ipilimumab (2010-2015) and 175 patients treated with first-line dacarbazine (2007-2009). For first-line ipilimumab, the adjusted hazard ratio compared with dacarbazine for overall survival (OS) was 0.63 (95% confidence interval: 0.47-0.84) with a 1-year survival of 46.5 versus 18.9% with dacarbazine. In subgroup analysis, ipilimumab was associated with improved OS across groups (age, sex, comorbidity, income quintile, previous interferon). First-line ipilimumab was found to have a significant OS benefit compared with historical controls in a population including those patients not routinely included in clinical trials. The treatment effect was similar to randomized controlled trials, suggesting a meaningful benefit when utilized in a population-based setting.", "source": "https://pubmed.ncbi.nlm.nih.gov/30789386/"}
+{"doc_id": "383db1cc0a36e83b809ae71e8657387a", "sentence": "In the present study the combination of tamoxifen and bromocriptine was tried for the suppression of prolactin in prolactin secreting adenomas which were resistant to suppression with bromoergocriptine alone .", "spans": [{"span_id": 0, "text": "tamoxifen", "start": 40, "end": 49, "token_start": 7, "token_end": 8}, {"span_id": 1, "text": "bromocriptine", "start": 54, "end": 67, "token_start": 9, "token_end": 10}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}], "paragraph": "[Bromocriptine and tamoxifen--a new therapeutic approach in suppression-resistant prolactin-secreting adenomas].  In the present study the combination of tamoxifen and bromocriptine was tried for the suppression of prolactin in prolactin secreting adenomas which were resistant to suppression with bromoergocriptine alone . 10 women under treatment with 2.5-10 mg of parlodel (bromocriptine) for pituitary tumours of various sizes were additionally treated with tamoxifen 10-20 mg. (nolvadex) daily. Two patients had a previous incomplete resection for chromophobe adenomas. The other patients refused operation. Two women were also studied who did not tolerate a bromoergocriptine therapy because of side effects. In 6 of the 10 women with combination treatment a satisfactory suppression of the prolactin was observed. Four women were cleared of their amenorrhoea and galactorrhoea. One woman conceived. One woman lost her frigidity. Three women, among those the two with severe side effects from bromoergocriptine, tolerated the combined treatment well. Four women showed no success with the combined treatment. The effectiveness of the combined treatment was not correlated with the size of the tumour nor the clinical or biochemical baseline. The results lead to the conclusion that tamoxifen is capable of improving the suppression of prolactin or render the adenomas suppressible in a large number of cases.", "source": "https://pubmed.ncbi.nlm.nih.gov/6924910/"}
+{"doc_id": "84d5a3309ee9e753c55c12b8ae228c9c", "sentence": "The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology .", "spans": [{"span_id": 0, "text": "thalidomide", "start": 56, "end": 67, "token_start": 8, "token_end": 9}, {"span_id": 1, "text": "dexamethasone", "start": 72, "end": 85, "token_start": 10, "token_end": 11}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": false}], "paragraph": "Refractory plasmablastic type myeloma with multiple extramedullary plasmacytomas and massive myelomatous effusion: remarkable response with a combination of thalidomide and dexamethasone. A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology .", "source": "https://pubmed.ncbi.nlm.nih.gov/19834276/"}
+{"doc_id": "975865298fd67bd4b6ff56a8d8929f5f", "sentence": "Among 788 eligible patients , the median ( SD ) age was 59 ( 22 - 74 ) years ; 263 patients were assigned to doxorubicin plus cisplatin treatment , 263 patients to docetaxel plus cisplatin treatment , and 262 patients to paclitaxel plus carboplatin treatment .", "spans": [{"span_id": 0, "text": "doxorubicin", "start": 109, "end": 120, "token_start": 25, "token_end": 26}, {"span_id": 1, "text": "cisplatin", "start": 126, "end": 135, "token_start": 27, "token_end": 28}, {"span_id": 2, "text": "docetaxel", "start": 164, "end": 173, "token_start": 33, "token_end": 34}, {"span_id": 3, "text": "cisplatin", "start": 179, "end": 188, "token_start": 35, "token_end": 36}, {"span_id": 4, "text": "paclitaxel", "start": 221, "end": 231, "token_start": 42, "token_end": 43}, {"span_id": 5, "text": "carboplatin", "start": 237, "end": 248, "token_start": 44, "token_end": 45}], "rels": [{"class": "POS", "spans": [0, 1], "is_context_needed": true}, {"class": "POS", "spans": [2, 3], "is_context_needed": true}, {"class": "POS", "spans": [4, 5], "is_context_needed": true}], "paragraph": "Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer. ### objective To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer. ### Design Setting And Participants In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017. ### interventions Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL\u2009\u00d7\u2009min) on day 1 every 3 weeks. ### Main Outcomes And Measures The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection. ### results Among 788 eligible patients , the median ( SD ) age was 59 ( 22 - 74 ) years ; 263 patients were assigned to doxorubicin plus cisplatin treatment , 263 patients to docetaxel plus cisplatin treatment , and 262 patients to paclitaxel plus carboplatin treatment . The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P\u2009=\u2009.12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P\u2009=\u2009.67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively. ### Conclusions And Relevance There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin. ### Trial Registration UMIN-CTR identifier: UMIN000000522.", "source": "https://pubmed.ncbi.nlm.nih.gov/30896757/"}