tbuckley/cabot-search huggingface dataset:
The cardiovascular safety of aromatase inhibitors and tamoxifen in post-menopausal women with breast cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: Farzin Khosrow-Khavar, Kristian B. Filion, Shatha Salem Al-Qurashi, Nazi Torabi, Nathaniel Bouganim, Samy Suissa, Laurent Azoulay
Journal: Journal of Clinical Oncology (2016)

1573 Background: The cardiovascular safety of aromatase inhibitors (AIs) in the treatment of breast cancer is controversial, with meta-analyses of randomized controlled trials (RCTs) reporting an increased risk of cardiovascular events with these drugs when compared with tamoxifen. However, it is unclear if this observed risk is real or the result of a cardioprotective effect of tamoxifen. We conducted a systematic review and meta-analysis using data from adjuvant, extended-adjuvant, and placebo-controlled breast cancer trials. Methods: We systematically searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and clinicaltrials.gov from inception to March 2015 for all RCTs comparing AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. We extracted all the cardiovascular endpoints reported in these RCTs, and study-specific relative risks were pooled using DerSimonian and Laird random-effects models with analyses stratified by trial design. Results: A total of 14 RCTs were included in the meta-analysis (n = 55,332). In the adjuvant setting, AIs were associated with an 18% (RR: 1.18, 95% CI: 1.05-1.33) increased risk of cardiovascular adverse events compared with tamoxifen. In contrast, AIs were not associated with increased risk compared with placebo in the extended-adjuvant setting (RR: 1.03, 95% CI: 0.83-1.29). In the adjuvant setting, tamoxifen was associated with a 32% (RR: 0.68, 95% CI: 0.46-1.02) decreased risk of cardiovascular adverse events compared with placebo or no-treatment. Similarly, tamoxifen was also associated with a 21% decreased risk compared with no-treatment in the extended-adjuvant setting (RR: 0.79, 95% CI: 0.63-0.98). Conclusions: The apparent increased risk of adverse cardiovascular events with AIs relative to tamoxifen is likely the result of a cardioprotective effect of the latter. This new evidence can lead to a better assessment of the risks and benefits of AIs in treatment of breast cancer in post-menopausal women.
Studies With Transplantable AK4 Mouse Leukemia. III. Effect of Spleen and Marrow Shielding on AK4 Leukemic Implants in Homologous Strains of Irradiated Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: Irene U. Boone, Betty S. Rogers, Payne S. Harris
Journal: JNCI Journal of the National Cancer Institute (1958)

Alterations in the susceptibility of homologous strains of X-irradiated mice to AK4 leukemic implants by spleen and femur shielding at the time of whole-body irradiation was determined in the A/St and C57BL strains of mice. The protective effect of spleen or femur shielding in irradiated animals that did not receive leukemia was also evaluated in these strains. The results of the experiments with irradiated animals that did not receive leukemia indicated that, although a protective effect was produced by either spleen or femur shielding in both strains, there were no significant quantitative differences afforded by the tissue shielded in either strain. Resistance to transplantable leukemia was partially protected by femur shielding in the irradiated A/St and C57BL mice and by spleen shielding in the irradiated A/St mice. However, in the irradiated C57BL animals that received leukemia, there was no significant difference between the spleen-shielded and nonshielded groups. The differences in the spleen-shielding results between the A/St and C57BL mice tend to indicate that greater protection was associated with myelopoietic tissue than with lymphoid tissue.
More on screening for mild thyroid failure
Authors: M. Helfand
Journal: JAMA (1997)

<h3>To the Editor.</h3> —In trying to replicate the results of the article on screening for mild thyroid failure by Mr Danese and colleagues,<sup>1</sup>I found a mathematical error in one of the assumptions of the cost-effectiveness model. Consequently, the analysis overestimates the effect of levothyroxine sodium on symptom relief and underestimates the costs of screening. Danese and colleagues assumed there was "symptomatic improvement in 28% of patients with mild thyroid failure." This estimate comes from 2 randomized trials of treatment for mild thyroid failure.<sup>2,3</sup>In one of these trials,<sup>2</sup>treatment with levothyroxine sodium relieved symptoms in 8 of 17 patients vs 3 of 16 patients in the placebo group. The difference of 8 of 17 (0.47) less 3 of 16 (0.19), or 0.28, is the net benefit or effect size of treatment. Its reciprocal, approximately 4, is the number needed to treat to benefit 1 patient. However,
Phase 1 study of CB-839, a small molecule inhibitor of glutaminase (GLS), alone and in combination with everolimus (E) in patients (pts) with renal cell cancer (RCC).
Authors: Funda Meric-Bernstam, Nizar M. Tannir, James Walter Mier, Angela DeMichele, Melinda L. Telli, Alice C. Fan, Pamela N. Munster, Richard D. Carvajal, Keith W. Orford, Mark K. Bennett, Othon Iliopoulos, Taofeek Kunle Owonikoko, Manish R. Patel, Rana McKay, Jeffrey R. Infante, Martin Henner Voss, James J. Harding
Journal: Journal of Clinical Oncology (2016)

4568 Background: CB-839 is a selective inhibitor of GLS, a key enzyme in the utilization of glutamine by many cancer cells. CB-839 has broad activity in preclinical models, including RCC where GLS is highly expressed. In RCC cell lines, CB-839 combines synergistically with E in vitro and in vivo, strongly inhibiting cell growth as well as glucose and glutamine metabolism. Previously reported data from this study have demonstrated that CB-839 achieved robust GLS inhibition in blood and tumors at well tolerated doses and that BID dosing with meals provided optimal PK and tolerability. Methods: CX-839-001 is an ongoing Phase 1 study evaluating the safety, PK, PD and efficacy of CB-839 in advanced/metastatic cancer patients. After completing an all-comers dose escalation of monotherapy CB-839, an RCC expansion cohort (n = 11) was opened to evaluate the efficacy of monotherapy CB-839 and was further expanded after achieving a preplanned overall response rate. In addition, the combination of CB-839 with standard E (10 mg po QD; CBE) is also being studied in RCC patients, with dose escalation ongoing (3+3 design; 400 mg BID starting dose) and two expansion cohorts for clear cell and papillary RCC planned (n = 9 each). Results: Monotherapy: Safety data from 75 pts who received 600-1000 mg BID revealed a low rate of CB-839-related Gr3/4 AEs (4/75 pts). Nineteen heavily pretreated (median of 3 prior therapies) RCC pts (10 clear cell, 6 papillary, 3 other) have been enrolled on the BID dosing regimen. One pt with RCC has achieved a confirmed Partial Response (PR) that remains ongoing after 8.3 months on therapy. Radiographic Stable Disease (SD) or PR was observed in 9 of 15 (60%) efficacy-evaluable RCC pts. Duration of clinical benefit in pts with SD or better ranged between 2.1 and 8.3+ mo (median of 4.6 mo). CBE combination: Eight pts have initiated treatment with escalating doses of CB-839 (400 – 600 mg) in combination with E to date. Conclusions: Monotherapy CB-839 has been well tolerated and demonstrated evidence of efficacy in a subset of patients, including an ongoing confirmed PR, which has resulted in further expansion of this cohort. The combination of CB-839 with E is being studied. Clinical trial information: NCT02071862.
Change in concussion measures in division i men’s lacrosse players who did not report a concussion
Authors: Theresa Miyashita, Eleni Diakogeorgiou
Journal: British Journal of Sports Medicine (2017)

Objective The purpose of our study was to investigate if a significant change in concussion baseline measurements occur in athletes who did not reportedly sustain a concussion. Design Cohort Study Setting Division I University Participants 22 Division I Men’s Lacrosse players’ data were used for the BESS test (age=19.95, ± 0.99) and 26 Division I Men’s Lacrosse players’ data were used for the CNS Vital Signs test (age=20.15, ± 1.05) Interventions calendar year; 2015 competitive lacrosse season Outcome measures Repeated-measures ANOVAs and paired samples t-tests determined the change in concussion baseline measurement scores from pre-season 2015, post-season 2015, and pre-season 2016. BESS scores and the ten tests associated with CNS Vital Signs were analysed for changes. Main results There were increases in the number of errors committed during the foam double leg stance (p=0.017) and foam tandem stance (p=0.007) from pre-season 2015 to pre-season 2016. 60% of of the tests within the CNS Vital Signs testing battery resulted in significant improvements from pre-season 2015 to pre-season 2016: psychomotor speed (p=0.031), executive function (p=0.003), cognitive flexibility (p=0.004), reaction time (p=0.004), simple reaction time (p=0.002), and shifting attention correct reaction time (p=0.016). Conclusions Concussion baseline measurements should be repeated on an annual basis to improve accuracy when implementing a return-to-play protocol following a concussion. Competing interests None
Abstract 11554: Is Metformin Treatment Hazardous in Diabetic Patients with AMI Undergoing Coronary Angiography?
Authors: Etienne Puymirat, Patrick Henry, Yves Cottin, Olivier Varenne, Wukfran Bougoin, Michel Hanssen, Vincent Bataille, Jean Ferrieres, Tabassome Simon, Nicolas Danchin
Journal: Circulation (2011)

Background: current guidelines recommend stopping metformin two days before coronary angiography or PCI. However, there is very little evidence to support this recommendation. Aim: to assess in-hos...
Sickle cells produce functional immune modulators and cytotoxics
Authors: Chiao‐Wang Sun, Li‐Chen Wu, Peter L. Knopick, David S. Bradley, Tim Townes, David S. Terman
Journal: American Journal of Hematology (2017)

Abstract Sickle erythrocytes' (SSRBCs) unique physical adaptation to hypoxic conditions renders them able to home to hypoxic tumor niches in vivo, shut down tumor blood flow and induce tumoricidal responses. SSRBCs are also useful vehicles for transport of encapsulated drugs and oncolytic virus into hypoxic tumors with enhanced anti‐tumor effects. In search of additional modes for arming sickle cells with cytotoxics, we turned to a lentiviral β‐globin vector with optimized Locus Control Region/β‐globin coding region/promoter/enhancers. We partially replaced the β‐globin coding region of this vector with genes encoding T cell cytolytics, perforin and granzyme or immune modulating superantigens SEG and SEI. These modified vectors efficiently transduced Sca + ckit ‐ Lin ‐ hematopoietic stem cells (HSCs) from humanized sickle cell knockin mice. Irradiated mice reconstituted with these HSCs displayed robust expression of transgenic RNAs and proteins in host sickle cells that was sustained for more than 10 months. SSRBCs from reconstituted mice harboring SEG/SEI transgenes induced robust proliferation and a prototypical superantigen‐induced cytokine reaction when exposed to human CD4+/CD8+ cells. The β‐globin lentiviral vector therefore produces a high level of functional, erythroid‐specific immune modulators and cytotoxics that circulate without toxicity. Coupled with their unique ability to target and occlude hypoxic tumor vessels these armed SSRBCs constitute a potentially useful tool for treatment of solid tumors.
Abstract 334: An Inotropic S100A1-derived Peptide Enhances Contractile Performance and Survival of Post-ischemic Failing Hearts
Authors: Mauro Siragusa, Kristin Spaich, Mirko Völkers, Erhe Gao, Julia Ritterhoff, Hugo A Katus, Patrick Most
Journal: Circulation Research (2015)

S100A1 gene therapy was suggested as therapeutic for cardiomyopathies since myocardial levels of S100A1 are decreased in heart failure. S100A1 increases systolic and diastolic performance of cardiomyocytes through enhanced Ca2+-induced SR Ca2+ release and augmented SR Ca2+ re-uptake. These effects are due to enhanced systolic Type 2 Ryanodine Receptor (RyR2) and diastolic Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a) activity. The S100A1 C-terminus (S100A1ct) was recently shown to be the bioactive domain of the protein. The aim of this study was therefore to characterize the effects of an S100A1ct-derived peptide on cardiomyocyte function and to test its therapeutic action in a mouse model of heart failure. An S100A1ct-derived peptide encompassing aa75-85 of the human S100A1 protein and preceded by a hydrophilic motif (DKDDPP) was named S100A1ct6/11. S100A1ct6/11 was cell permeable and accumulated in the intracellular space of intact rat ventricular cardiomyocytes in a striated pattern, similar to endogenous S100A1. S100A1ct6/11 exerted a time- and dose-dependent positive inotropic effect in electrical field stimulated rat ventricular cardiomyocytes. This effect was associated with the regulation of the SR calcium content. Peptides encompassing aa75-85 derived from S100 paralogs A4 and B did not mimic S100A1ct6/11-mediated inotropy. S100A1ct6/11 protected cardiomyocytes from pro-arrythmic store overload-induced calcium leak as well as from chronic caffeine exposure-induced apoptotic cell death. Mice intravenously injected with S100A1ct6/11 exhibited a significant enhancement of LV contractile performance under basal and βAR-stimulated conditions. Daily intraperitoneal administration of S100A1ct6/11 for two weeks to mice with post-ischemic contractile dysfunction resulted in significantly improved contractile performance and survival due to reduced myocardial apoptosis. Moreover, this treatment protected failing hearts with caffeine-induced leaky RyR2 channels from βAR-triggered lethal ventricular tachyarrhythmias. In conclusion, administration of the S100A1ct6/11 peptide may represent a novel option for the treatment of cardiomyopathies without apparent side effects.
Use of defined mutations in TNBC to enable patient selection for PLK1 inhibitor therapy.
Authors: Benjamin L Palleiko, Mark Miglarese, Michael G King, Sandra L Silberman
Journal: Journal of Clinical Oncology (2016)

e12559 Background: PLK1 inhibition has been shown preclinically to impact a number of tumor types. However, other than in AML (Döhner et al 2014), early clinical experience has yielded uniformly modest results. More recent studies indicate that PLK1 inhibition may yield greater responses in specific genetic subtypes. PLK1 has been implicated in promoting growth and survival in cooperation with MYC, PTEN-loss, the PI3K/mTOR pathway and AR signaling (Zhang et al 2014, Hou et al 2013, Liu et al 2011 and Tan et al 2013).We tested whether the selective PLK1 inhibitor P937 could differentially inhibit growth of a genetically diverse panel of TNBC PDX models, enabling selection of a potentially higher responding patient population. Methods: Ten genetically described TNBC PDX models were tested for sensitivity to P937. After implantation and establishment in SCID mice (n = 3 per group), P937 was administered over a 24-day treatment period. Body weight, tumor growth and growth delay after end of treatment were measured. Results: Nine models were evaluable and significant tumor growth inhibition (50-90%) was noted in four. Mutations in responding models have been proposed to enhance sensitivity to PLK1 inhibition in other tumor types, but not previously in TNBC. All lines with sensitivity-enhancing mutations responded while lines without did not. In the most sensitive model, P937 caused uniform, near-complete regressions that were stable for 21 days after final dosing, with minimal body weight loss. Further characterization of all models will be provided. Conclusions: This study appears to be the first report of a PLK1 inhibitor evaluation in a diverse panel of genetically-characterized models in any tumor type. Our results demonstrate that differentially sensitive molecular subtypes of TNBC can be identified and that underlying genetic profiles can be exploited to identify TNBC patients who may benefit most from PLK1 inhibitor therapy. We are continuing to refine the selection criteria as well as to explore additional predictive genetic markers of P937 sensitivity in TNBC and planning for a clinical trial in selected TNBC patients. We believe these results are also extensible into other indications that display these mutations.
Benefits and costs of bevacizumab in recurrent glioblastoma: A quality adjusted survival and cost analysis (EVALUATE).
Authors: Katrin Lisa Conen, Klazien Matter-Walstra, Sabine Schädelin, Luigi Mariani, Viviane Hess
Journal: Journal of Clinical Oncology (2017)

2032 Background: Routine clinical use of bevacizumab (Bev) in recurrent glioblastoma (rGBM) is controversial, as no large RCT has shown a survival advantage. We describe treatment algorithms, survival (OS), quality-adjusted survival (QAS) as well as costs of patients (pts) with GBM treated at an academic hospital in Switzerland, where Bev is registered and reimbursed for rGBM. Methods: Pts’ and treatment characteristics from diagnosis until death (including neurological symptoms and toxicities) of all pts over a 5-year period were retrospectively retrieved from our GBM database. For each treatment period (1 st -line, recurrence and “best supportive care”) time to next treatment (TNT), OS and QAS were calculated and modelled for prognostic factors (Cox regression). QAS was evaluated as previously described (Murray et al). In- and out-patient costs were calculated from time of diagnosis until death in respect of Bev treatment (+Bev vs. –Bev). Results: 82 newly diagnosed GBM pts with a median age of 66 years (range 39-85), median KPS of 90% (range 50-100%), who were treated with 1 (n = 75), 2 (n = 36) or 3 (n = 14) lines of therapy, respectively, lived for a median OS of 11.9 (SD 9.7) months (mos). QAS was 5.3 (SD 6.9) mos i.e. 44% of the numerical survival time. 40% of patients were treated with Bev at 1 st or 2 nd recurrence. Pts, who were selected for BEV treatment, had a longer time from diagnosis to 2 nd line treatment (median 5.2 (SD 6.3) mos) as compared to pts in the -Bev group (median 2.1 (SD 1.8) mos). Younger age and Bev treatment were associated with longer OS and QAS. QAS to OS ratio was 52% (9.4 out of 18.1 mos) for BEV treated patients and 34% (2.8 out of 8.2 mos) for the –Bev group, respectively. Bev treatment increased the overall treatment costs by 1.7x. The population adjusted incremental cost-effectiveness ratio (ICER) was CHF 75,669 per life year gained. Conclusions: QAS in patients with GBM is short (one third to half of OS). In our cohort, pts selected for Bev treatment had longer OS and longer QAS - at costs below the accepted threshold of 100,000 CHF per life year gained. Whether this gain of lifetime is a direct result of Bev treatment or a consequence of a selection bias needs to be addressed prospectively.
Nab-paclitaxel/gemcitabine first-line therapy in patients with metastatic pancreatic carcinoma and high-bilirubin levels: Data from the German QoliXane Pancreatic Cancer Registry.
Authors: Gerrit zur Hausen, Oliver Waidmann, Marcus A. Woerns, Heinz-Gert Hoeffkes, Steffen Doerfel, Mark-Oliver Zahn, Ali Aldaoud, Martina Stauch, Christoph Springfeld, Nicolai Haertel, Alexander Reichart, Claudia Pauligk, Josefine Roemmler-Zehrer, Ralf Hofheinz, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2016)

e15739 Background: Hyperbilirubinaemia is a common disease effect in patients (pts) with metastatic pancreatic cancer (mPC). As clinical trials often exclude them, data on management of these pts are rare. In the framework of a German observational multicenter study (QoliXane), quality of life and therapy data are currently being collected in pts with mPC receiving a combination of nab-paclitaxel and gemcitabine. This is an interim analysis on hyperbilirubinaemia management. Methods: Pts were included to this analysis if they entered the trial with a bilirubin level ≥ 1.5 mg/dl and completed at least 1 cycle. Bilirubin levels were documented for up to 4 cycles and methods of hyperbilirubinaemia management have been assessed. A both descriptive and explorative analysis was performed using IBM SPSS V 23. Results: 20 of 219 pts (9.1%) were included. Mean bilirubin level was 4.4 mg/dl (range 1.5-12.9) at baseline and dropped considerably by the 2nd cycle to 1.8 (range 0.35-14.1; p=0.031). Bilirubin levels decreased in 13 (65%) and increased in 2 (10%) pts upon treatment start. 14 (70%) pts started treatment with standard dosage, 6 (30%) with a reduced regime. 11 (55%) pts underwent additional intervention: either stenting (7 pts, 35%) or bile duct anastomosis (4 pts, 20%). Mean bilirubin values dropped from 5.32 to 0.48 in pts with and from 3.27 to 0.53 in pts without additional intervention. Grade 3/4 toxicity was seen in 70% of pts and most common 3/4 events were leukopenia, anemia, and fever, each observed in 20% of pts. Conclusions: Data show that bilirubin levels drop considerably after start of nab-pac/gem therapy. The treatment seems to be feasible, although considerable rates of leukopenia and fever were observed. Clinical trial information: AIO-LQ-0214.Mean bilirubin levels1. Baseline Cycle 1 Cycle 2 Cycle 3 Cycle 4 All pts (n=20) 4.40 4.70 1.80 0.70 0.50 No add. intervention (n=9) 3.27 3.81 2.62 0.7 0.53 Any add. intervention (n=11) 5.32 5.29 1.15 0.63 0.48 Add. stenting (n=7) 5.20 2.01 1.32 0.72 0.43 Add. bile duct anastomosis (n=4) 5.52 11.0 0.87 0.47 0.53 p (all pts)2 0.031 0.002 0.012 1 n's indicate # of pts at baseline 2 Wilcoxon test to baseline (related samples), level of significance p = .05