tbuckley/cabot-search huggingface dataset:
Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.
Authors: D R Budman, L N Igwemezie, S Kaul, J Behr, S Lichtman, P Schulman, V Vinciguerra, S L Allen, J Kolitz, K Hock
Journal: Journal of Clinical Oncology (1994)

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count &gt; or = 4,000/microL, and platelet count &gt; or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.
MPs criticise Hunt for unclear plans on seven day NHS and “attacks” on NHS staff, but others praise him
Authors: Adrian O’Dowd
Journal: BMJ (2015)

MPs have voiced serious doubts about the approach of England’s health secretary, Jeremy Hunt, in dealing with the medical profession over the government’s aim for a seven day a week NHS.

During a two and a half hour debate in Westminster Hall at parliament on 14 September, critics said that he had thrown a “grenade” into his dealings with doctors, while supporters described him as being honourable and deeply passionate about the safety of patients.

Hunt did not join the debate, which was prompted by an online petition (https://petition.parliament.uk/petitions/104334) calling for him to be subject to a vote of no confidence by MPs. So far more than 220 500 people have signed the petition, which says, “Jeremy Hunt has alienated the entire workforce of the NHS by threatening to impose a harsh contract and conditions on first consultants and soon the rest of the NHS staff.” The petition was sparked after Hunt gave a speech on 16 July in which he spoke of his intention to force the NHS to change to provide a truly seven days a week service and for a seven day rota for hospital consultants.1

Opening the debate, Helen Jones, chair of the House of Commons petitions committee and Labour MP for Warrington North, said that the topic for debate had been amended to focus on contracts and conditions in the NHS, because the committee did not have the power to call for a vote of no confidence.

Jones emphasised how stretched the NHS and its staff were at present, saying, “It is a long time since I last saw dedicated doctors, nurses, and ancillary staff so demoralised and, sometimes, despairing.

“NHS staff have …
Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer
Authors: F Amicarella, M G Muraro, C Hirt, E Cremonesi, E Padovan, V Mele, V Governa, J Han, X Huber, R A Droeser, M Zuber, M Adamina, M Bolli, R Rosso, A Lugli, I Zlobec, L Terracciano, L Tornillo, P Zajac, S Eppenberger-Castori, F Trapani, D Oertli, G Iezzi
Journal: Gut (2015)

The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated.To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells.IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments.IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival.Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.
Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC).
Authors: Miriam Koopman, Lieke Simkens, Anne May, Linda Mol, Harm van Tinteren, Cornelis J. A. Punt
Journal: Journal of Clinical Oncology (2014)

LBA388 Background: The optimal duration of chemotherapy and bevacizumab (bev) in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine (cap) + bev versus observation in mCRC patients (pts) not progressing during induction treatment with cap, oxaliplatin, and bev (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after six cycles of CAPOX-B were randomized between observation (arm A) or maintenance treatment with cap 625 mg/m2 bid daily continuously + bev 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were to be treated with CAPOX-B until 2nd progression (PFS2, primary endpoint). Secondary endpoints were overall survival (OS) and time to 2nd progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1, and quality of life. Preplanned subsetanalyses were performed. Results: A total of 558 pts were randomized. Median follow-up is 48 months. Upon PFS1, CAPOX-B was reintroduced in 61% of pts in arm A and 48% in arm B. Multivariable analyses for survival, with treatment adjusted for a series of pre-specified potentially confounding factors at baseline showed significant interactions for treatment (observation vs. maintenance) with resection of the primary tumor (yes vs. no) and synchronous or metachronous metastases at baseline (p values for interaction &lt;0.0001). Especially pts with synchronous metastases with resected primary tumor (n=180) appear to benefit from maintenance treatment; median OS 18.0 months (observation arm) vs. 25.0 months (maintenance arm) (log-rank p value: &lt;0.0001). Conclusions: Multivariable analysis showed significant interaction of treatment with some baseline covariates which were not equally distributed among both arms. The positive effect on survival for maintenance treatment with cap + bev is most obvious in pts with synchronous disease in whom the primary tumor was resected. Further details and final results on survival will be presented at the meeting. Clinical trial information: NCT00442637.
Abstract 274: Polarization of Macrophage Confers Regenerative Capacity of Using Adipose Derived Regenerative Cells
Authors: Satoshi Shintani, Yuuki Shimizu, Changning Hao, Kazuhisa Kondo, Ryo Hayashida, Toyoaki Murohara
Journal: Circulation Research (2013)

Background: Recent studies indicate that macrophages (Mφ) have conflicting characteristics, pro-inflammatory or anti-inflammatory phenotypes. We previously demonstrated that implantation of adipose derived regenerative cells (ADRCs) augmented angiogenesis and lymph angiogenesis by modulating Mφ phenotype in animal models. We thus examine whether Mφ polarization to M2 type is important for neovascularization in various models. Methods and Results: Culture medium of ADRCs accelerated not only migration of human umbilical vein endothelial cells (HUVECs) but also polarization of M2 type Mφ. Cultured ADRCs released SDF-1, VEGF-C, and prostaglandin E2 (PGE2). PGE2 plays a key role for the polarization of M2 type Mφ via EP2/4 receptors. Matrigel tube formation assay conformed that ADRCs were incorporated into HUVEC network. In vivo, implanted ADRCs participated in the formation of capillary networks in ischemic tissue. In a mice model of tail lymphedema, the number of bone marrow derived Mφ was significantly higher in the ADRCs treated group than in the un-treated group. Most of Mφ differentiated into lymphatic endothelial cell in the edematous tissue and were polarized to M2 phenotype. Moreover, in a mice model of hind limb ischemia, implantation of ADRCs facilitated the polarization of Mφ into M2 type Mφ and up regulated IL-10 expression to suppress inflammation at ischemic tissue. Conclusion: Polarization into anti-inflammatory phenotype of Mφ plays an important role for regenerative action of ADRCs.
Tracheobronchial fungal infections and their bronchoscopic features
Authors: Ruichao Niu, Chengping Hu
Journal: European Respiratory Journal (2014)

Purpose:  Tracheobronchial fungal infection (TBFI) is a life-threatening complication in immunocompromised hosts, but is rarely reported. Early diagnosis of TBFI before microbiologic and pathologic analysis has not been established. This study seeks to analyze the bronchoscopic features of TBFI and their roles in the diagnosis of TBFI.   Methods:  The demographic, clinical, and bronchoscopy data of 53 patients diagnosed with TBFI were retrospectively analyzed.   Results:  Lung cancer and tuberculosis are the primary diseases associated with TBFI. The most common characteristics of  Aspergillosis  were bronchial stenosis, mucosal edema, yellowish-white necrotic material-plaques, suppurative secretions, edematous irregular mucosa, ulcerative appearance or uneven surface, white-colored nodules, grayish-white mucous plaque, grayish-black pigmentation, and granulation tissue. The mainly bronchoscopic characteristics of  Mucormycosis  included bronchial stenosis, mucosal edema, ulcerative appearance or uneven surface, yellowish-white necrotic material-plaques, and white necrosis. The bronchoscopic characteristics of  Cryptococcosis  included stenosis, swelling, uneven of mucus, purulent discharge overflow, and viscous secretions.   Conclusion:  The bronchoscopic features of  Aspergillosis ,  Mucormycosis,  and  Cryptococcosis  may be helpful for the early diagnosis of tracheobronchial fungal infection.
Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.
Authors: F J Panettiere, P J Goodman, J J Costanzi, A B Cruz, V K Vaitkevicius, J D McCracken, R W Brownlee, L Laufman, R L Stephens, J Bonnet
Journal: Journal of Clinical Oncology (1988)

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.
Letter by Mansencal et al Regarding Article, “Sudden Cardiac Arrest During Sports Activity in Middle Age”
Authors: Nicolas Mansencal, Bernard Montalvan, Olivier Dubourg
Journal: Circulation (2015)

We read with great interest the article by Marijon et al 1 that was published recently in Circulation.They nicely demonstrated that sports-associated sudden cardiac arrest (SCA) in middle age represents a relatively small proportion of the overall SCA burden during a large period of inclusion (2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013).We totally agree with this idea of high-benefit, low-risk nature of sports activity in elderly population.Several previous studies have demonstrated that sports improve quality of life and life expectancy. 2However, physical activity may be a trigger of myocardial infarction and SCA. 3 It is well-known that sports have different static and dynamic components, 4 suggesting that some sports with high static and dynamic components could be of high-risk of SCA, as compared to sports with low static and dynamic components.In the present study, jogging, basketball, and cycling were the 3 main sports related to SCA (58% versus 6% for volleyball and tennis).In a previous study of Marijon et al, 5 cycling, jogging, and soccer represented 65% of SCA, versus 2.5% for volleyball and tennis.These 2 studies found similar results concerning the relation between SCA and sports.However, in the recent study of Marijon et al, 1 the authors focused their study in patients ≥35 years, but it could be of interest to know the number of sports-associated SCA in patients <35 years during this period of inclusion and the category of sports related to SCA.These additional data could help us to improve the knowledge of this rare but dramatic clinical setting.
Abstract 13903: When an Octopus Acts Like a Chameleon: a Case of Takotsubo’s Cardiomyopathy with Concurrent Severe Coronary Disease
Authors: Troy Leo, Julie Damp, Lisa Mendes
Journal: Circulation (2014)

Introduction: Takotsubo’s cardiomyopathy, or stress induced cardiomyopathy, is characterized by transient wall-motion abnormalities involving the left ventricular apex and mid-ventricle in the absence of obstructive epicardial coronary disease. It is seen more commonly in post-menopausal women and is usually preceded by an acute medical illness or intense emotional or physical stress. While the Mayo Criteria for the classification of Takotsubo’s cardiomyopathy involves the absence of epicardial coronary disease, up to 10% of patients have been found to have concurrent significant coronary artery disease. Conclusions: We present a case of a patient who presented with seizures and was found to have ST elevations, elevated cardiac enzymes and a new cardiomyopathy. While it was discovered that she had severe coronary disease of her LAD and RCA, the true nature of her cardiomyopathy and presentation was a stress-induced cardiomyopathy in the setting of seizure. The accuracy of this diagnosis affected the prognosis and treatment options for our patient. Cardiac MRI, and specifically the presence or absence of late gadolinium enhancement, helped differentiate the etiology of her cardiomyopathy. With the increasing prevalence of coronary disease, we will likely see more cases such as these in the future and should continue to evolve our definition and tools for the diagnosis of an increasing and interesting phenomenon.
Multicenter phase II study of a cremophor-free polymeric micelle-formulated paclitaxel in patients (pts) with metastatic breast cancer (MBC)
Authors: K. S. Lee, H. C. Chung, S. A. Im, Y. H. Park, S. B. Kim, C. S. Kim, J. Ro
Journal: Journal of Clinical Oncology (2006)

10520 Background: The results of a phase I trial of a novel taxane, a cremophor-free polymeric micelle-formulated paclitaxel (Genexol-PM), were previously reported (Clin Cancer Res 10:3708, 2004). The dose limiting toxicities were neuropathy, myalgia, and neutropenia. Notably, acute hypersensitivity reaction was not observed. Methods: This was a single arm phase II study performed at 6 major hospitals in Korea to evaluate the efficacy and safety of Genexol-PM as a 1st- or 2nd-line therapy for MBC. Genexol-PM with no premedication was given at 300 mg/m 2 i.v. over 3 hr on day 1 every 3 weeks until disease progression or intolerability. Two-stage group sequential design was used. If more than 14 responses were attained in the first 30 pts, early termination was possible. Results: Forty-three pts with MBC were enrolled from 7/2004 to 12/2004. Median follow-up duration was 7.0 mo. Thirty-seven of 41 pts excluding 2 pts who did not receive Genexol-PM received Genexol-PM as a first-line therapy. Nineteen pts received prior anthracycline containing regimen in adjuvant (15) and in metastatic (4) settings. No pts were anthracycline-resistant. Median age was 48 years (range; 30 to 69 years) with ECOG PS 0 or 1. A total of 331 cycles were administered, with median of 8 per patient (range; 1 to 16). Of 39 pts evaluable for efficacy, there were 5 CRs /19 PRs with response rate of 61.5%, 13 SDs and 2 PDs. Median response duration was not reached (range; 1.9+ to 10.0+ mo). Median TTP and OS were 9.8 and 11.2 mo, respectively. G3 non-hematologic toxicities included peripheral sensory neuropathy (51.2%) and myalgia (2.4%). Hematologic toxicities were G3/G4 neutropenia (51.2%, 17.1%, respectively) and G1/2 thrombocytopenia (22.0%). Seventeen pts (41.5%) required dose reductions due to G3 neuropathy. No febrile neutropenia was observed. Eight pts developed hypersensitivity reactions with G3 in 2 pts. Mean dose intensity (DI) was 87.4 mg/m 2 /wk (range; 27.7 to 116.7) at 87.4% of planned DI. Conclusions: Genexol-PM at 300 mg/m 2 appears a promising agent with high response rate for anthracycline sensitive MBC. Further trials at a different dose schedule or duration of delivery, or in combination with other drugs are warranted. Supported by Samyang Co, Korea. No significant financial relationships to disclose.
Front-Line Antibiotic Therapy in Early-Stage H. Pylori-Positive Gastric Diffuse Large B-Cell Lymphomas with or Without Malt Features
Authors: L.-T. Chen, S.-H. Kuo, K.-H. Yeh, M.-S. Wu, C.-W. Lin, P.-N. Hsu, H.-P. Wang, A.-L. Cheng
Journal: Annals of Oncology (2012)
Psychodynamics of suicide, with particular reference to the young
Authors: H Hendin
Journal: American Journal of Psychiatry (1991)

The article reviews the literature on the psychodynamics of suicide, focusing on factors that will help in evaluating and treating the young suicidal patient. Articles published in refereed journals and books and book chapters based on such articles are the source of most of the material. Articles that first brought a new finding to notice are given preference. Methodological limitations and contradictions with the data of other studies are pointed out.The psychodynamic meaning of suicide for a patient derives from both affective and cognitive components. Rage, hopelessness, despair, and guilt are important affective states in which young patients commit suicide. The meanings of suicide can be usefully organized around the conscious (cognitive) and unconscious meanings given to death by the suicidal patient: death as reunion, death as rebirth, death as retaliatory abandonment, death as revenge, and death as self-punishment or atonement.Knowledge of the psychodynamics helps to distinguish which patients with any given diagnosis are at risk for suicide. Such knowledge is essential to the psychotherapeutic treatment of the young suicidal patient. Topics for future research include the role of anxiety in suicide; the capacity to bear hopelessness, rage, and other unpleasant affects without regression; the use of particular defense mechanisms in distinguishing the risk of either suicidal or violent behavior; and the relation of specific psychodynamic conflicts seen in suicidal patients to particular psychiatric diagnoses.
Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect
Authors: Cesar G Victora, Rajiv Bahl, Aluísio J D Barros, Giovanny V A França, Susan Horton, Julia Krasevec, Simon Murch, Mari Jeeva Sankar, Neff Walker, Nigel C Rollins
Journal: The Lancet (2016)
Titration of dosage of the protective effect of zoledronic acid in patients submitted to androgen-deprivation therapy due to CaP
Authors: P. Rodrigues, F. Hering, P. Bruna, A. E. Meler
Journal: Journal of Clinical Oncology (2007)

15561 Background: Androgen-deprivation therapy is gold-standard treatment for advanced CaP. Zoledronic acid has become a new adjuvant drug for osteoporosis prevention and pain control in patients submitted to androgen-deprivation therapy but regimen of administration is not consensual. Many off-label regimens are used on different occasions. Methods: 64 patients (mean age: 71.7 y-o) after being diagnosed with non-intended to cure therapy were initiated with androgen-deprivation with LHRH agonists at the same time they initiated no treatment (control-16 cases) or monthly (12), bi- monhtly (10), tri-monthly (14) or semestral (12) zoledronic acid infusions for 24 months. Lumbar BMD were evaluated periodically with dual- energy X-ray absorptiometry with densitometry in L2-L4 at 6-month intervals. Tuckey-Kramer and Scheffe`s tests were used for statistical significance of 0.05. Results: Control patients revealed a subgroup showing progressive diminishing BMD along the studied period while another sub-group remained stable. Patients receiving treatment with zoledronic acid showed increasing BMD at the lumbar area (p &lt;0.05) for the 4 treated groups. The protective effects of lumbar BMD were remarkable starting at 18 months in the 4 treated groups with progressive increase of BMD with no clear advantage to any particular regimen (p &gt;0.05). Bone protection could be achieved in the 4 treated groups with no differences for the monthly, bimestral, trimestral or semestral infusions. Conclusions: Zoledronic acid is effective in decreasing bone loss after androgen-deprivation therapy compared to no treatment for osteoporosis. Titration of the dosage regimen of the infusions showed no statistical advantage for any temporal regimen. Reasons for that can only be speculative at this time. [Table: see text] No significant financial relationships to disclose.