tbuckley/cabot-search huggingface dataset:
Dexamethasone in pretreated men with metastatic castration-resistant prostate cancer (mCRPC): A prospective study.
Authors: Giulia Baciarello, Zineb Hamilou, Ralph Chebib, Laurence Albiges, Alina Fuerea, Yohann Loriot, Christophe Massard, Emeline Colomba, Mario Di Palma, Bernard Escudier, Karim Fizazi
Journal: Journal of Clinical Oncology (2018)

239 Background: Corticosteroids have demonstrated activity in men with mCRPC. Previous data suggested that dexamethasone (D) can induce PSA responses when introduced after progression in mCRPC men receiving AR axis targeted drugs and/or prednisone (P). Methods: We prospectively tested P to D switch or D addition at PSA progression in 43 men with mCRPC with PSA progression and stable clinical disease. Baseline characteristics of the patients, time to castration resistance (TTCRPC), response to previous treatment, PSA response during D 0.5 mg/day and biochemical progression-free-survival (bPFS) after D initiation were recorded. Results were assessed using the Fisher’s exact test to compare variables. Results: Data from 43 patients were prospectively collected: 29 (67%) had been treated with abiraterone (AA) + P, 11 (26%) with enzalutamide (ENZ) and 3 (7%) with other treatments. At progression, 27 patients (63%) switched from P to D while continuing AA, 9 (21%) stopped their treatment and began D alone and 7 (21%) received D added to ENZ. Median age was 75 (70-79.5) and median bPFS with previous treatment was 17 months (6.75-22.25). After D initiation, 28% of patients had a PSA decrease ≥ 30% and the median bPFS was 4 months (2-6). The median bPFS was non-statistically different in patients with previous response to AR axis targeted drugs ≥ 6 months (4 [2-6] vs 1 [1-2] months; p-value = 1) and in those with TTCRPC ≥12 months (4 months [2-7.5] vs. 2 [1.5-2]; p-value = 0.3). Eleven patients (26%) had a bPFS ≥ 6 months and 5 (12%) had a bPFS ≥ 12 months. All long D responders (bPFS ≥ 6 months) had a TTCRPC ≥ 12 months, 10/11 patients had a previous PFS ≥ 6 months on AA or ENZ. None of the 2 patients (4.6%) with primary resistance to AA, responded to switch from P to D. Conclusions: D alone or in combination with previous AR axis targeted agents has activity in mCRPC men, with long responders observed amongst those with previous long response to ADT or to next generation AR axis targeting.
THE EFFICACY AND SAFETY OF APIXABAN VERSUS WARFARIN ARE PRESERVED IN PATIENTS WITH ATRIAL FIBRILLATION AND EXTREMELY HIGH BODY WEIGHT: INSIGHTS FROM THE ARISTOTLE STUDY
Authors: Marat Fudim, Renato Lopes, John Alexander, Daniel Wojdyla, Justin Ezekowitz, Michael Hanna, Dan Atar, Ziad Hijazi, Maria Bahit, Jose Lopez-Sendon, Lars Wallentin, Christopher Granger, Stefan Hohnloser
Journal: Journal of the American College of Cardiology (2018)
Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non–Small Cell Lung Cancer Patients
Authors: Zhe Yang, Nong Yang, Qiuxiang Ou, Yi Xiang, Tao Jiang, Xue Wu, Hua Bao, Xiaoling Tong, Xiaonan Wang, Yang W. Shao, Yunpeng Liu, Yan Wang, Caicun Zhou
Journal: Clinical Cancer Research (2018)

Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified.Results:EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC50) of osimertinib in vitro, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS, and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations.Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo, and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097-107. ©2018 AACR.
Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer
Authors: Alessandra Metelli, Mohammad Salem, Caroline H. Wallace, Bill X. Wu, Anqi Li, Xue Li, Zihai Li
Journal: Journal of Hematology & Oncology (2018)

GARP (glycoprotein-A repetitions predominant) is a type I transmembrane cell surface docking receptor for latent transforming growth factor-β (TGF-β) that is abundantly expressed on regulatory T lymphocytes and platelets. GARP regulates the availability of membrane-bound latent TGF-β and modulates its activation. For this reason, GARP expression on immune and non-immune cells is involved in maintaining peripheral tolerance. It plays an important role in preventing inflammatory diseases such as allergy and graft versus host disease (GvHD). GARP is also frequently hijacked by cancer cells to promote oncogenesis. This review summarizes the most important features of GARP biology described to date including gene regulation, protein expression and mechanism in activating latent TGF-β, and the function of GARP in regulatory T cell biology and peripheral tolerance, as well as GARP's increasingly recognized roles in platelet-mediated cancer immune evasion. The promise for GARP-targeted strategy as a novel immunotherapy of cancer is also highlighted.
Driving Under the Influence of Cannabis
Authors: Johannes G. Ramaekers
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract P1-09-01: A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC)
Authors: HS Rugo, P Kabos, MN Dickler, WJ John, I Smith, Y Lu, S Young, SM Tolaney
Journal: Cancer Research (2018)

Abstract Background: Abemaciclib is a selective and potent small molecule inhibitor of CDK4 and 6, with evidence of single-agent antitumor activity, and a safety profile that enables dosing on a continuous schedule. Abemaciclib demonstrated anti-tumor activity as a single agent with a 19.7% objective response rate for women with previously treated HR+, HER2- MBC1. In the phase 1b study JPBH, abemaciclib demonstrated a tolerable safety profile when combined with endocrine or HER2 targeted agents for MBC2. Abemaciclib given BID in combination with pembrolizumab also demonstrated a tolerable safety profile in phase 1b study of stage IV NSCLC3. Methods: JPCE is a multicenter, nonrandomized, open-label, phase 1b study of abemaciclib plus pembrolizumab for patients with HR+, HER2- MBC or NSCLC (ClinicalTrials.gov NCT02779751). The study has 3 disease-specific cohorts, each with approximately 25 patients (N=75); the HR+, HER2- MBC cohort (part C) will be presented here. The primary objective was to characterize safety of the abemaciclib and pembrolizumab combination. Secondary objectives included efficacy endpoints (objective response rate, disease control rate, duration of response, progression-free survival, and overall survival), pharmacokinetics of abemaciclib plus pembrolizumab, and changes in patient-reported pain and disease-related symptoms. Patients received 150 mg of abemaciclib orally Q12H plus pembrolizumab 200 mg as a 30-minute IV infusion on Day 1 every 21 days. Eligible patients included women with confirmed HR+, HER2- MBC who have previously received at least 1 but no more than 2 prior chemotherapy regimens for MBC; are able to provide tumor tissue at baseline and at cycle 3, day 1; have measurable disease (RECIST v.1.1), adequate organ function, ECOG PS ≤1, are able to swallow oral medications; and have not received treatment with CDK4 &amp; 6 or PD-1/ PD-L1 inhibitors. Results: At the time of abstract submission, study JPCE part C cohort (HR+, HER2- MBC) was fully enrolled at 25 patients. Data to be presented include patient demographics, baseline disease characteristics, adverse events by frequency and by grade, and preliminary efficacy of the abemaciclib plus pembrolizumab combination in HR+, HER2- MBC. References: 1. Dickler et al, Clin Cancer Res. 2017 2. Goetz et al. poster presented at SABCS, 2015 3. Goldman et al. poster presented at IASLC 2016 Citation Format: Rugo HS, Kabos P, Dickler MN, John WJ, Smith I, Lu Y, Young S, Tolaney SM. A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-01.
Abstract 19192: In Vivo Multiphoton Microscopy Following Myocardial Infarction Reveals Vascular Disarrangement
Authors: David M Small, Jason S Jones, Irwin I Tendler, Nozomi Nishimura
Journal: Circulation (2016)

Introduction:  Perturbed cardiomyocyte contractility and vascularization post-injury contribute to disease progression.  In vivo  multiphoton microscopy (MPM) allows for three-dimensional visualization of cell motion within a cardiac cycle. Revascularization is considered important for tissue repair after injury, however structural abnormalities suggest inefficient vessel function. The aim of this project was to study vascular alterations following myocardial infarction using  in vivo  MPM.   Methods:  C57Bl6 mice underwent transmural ventricular cryoinfarction (CI) with a liquid-N 2 -cooled copper probe. Imaging was performed in healthy controls and at 7-days post-injury. A region of the heart surface is stabilized by attaching a cover glass held by a 3D-printed titanium probe. Intravenous Texas-Red dextran is administered to label blood plasma. Imaging is conducted using a custom-built microscope equipped with high-speed image acquisition (30 frames/sec). Post-processing of images is used to align image frames according to ECG cycle. Histology for endothelial cells (PECAM-1), myofibroblasts (αSMA), and collagens (H&E, Masson’s) was performed post-imaging.   Results:  In vivo  MPM of the beating heart demonstrated vessel tortuosity, orientation changes and red blood cell motion. 7-days post-CI, vessel anisotropy increased within a 3D volume (Control: 8.9±1.1, CI: 17.4±1.7, p   Conclusions:  We have demonstrated the presence of vascular disarrangement following myocardial infarction using the novel technique of  in vivo  MPM. This technology allows for  in vivo  monitoring during active phases of cardiac repair following injury.
Government must take action on industry to improve public health
Authors: Natalie J Savona
Journal: BMJ (2018)

The argument in The BMJ between action or more research on behaviour in public health is a false dichotomy—both are indispensable.1 We need to act across all levels of any given issue to truly effect change, and public health has much to learn.2 But we must not forget that companies with vested interests have already …
Exenatide has a pronounced effect on energy intake but not energy expenditure in non-diabetic subjects with obesity: A randomized, double-blind, placebo-controlled trial
Authors: Alessio Basolo, Joshua Burkholder, Kristy Osgood, Alexis Graham, Sarah Bundrick, Joseph Frankl, Paolo Piaggi, Marie S. Thearle, Jonathan Krakoff
Journal: Metabolism (2018)
DIRECT ORAL ANTICOAGULANTS VERSUS WARFARIN FOR ATRIAL FIBRILLATION IN FRAIL AND NON-FRAIL PATIENTS
Authors: Masatomo Ozaki, Hiroshi Tasaka, Reo Hata, Mituru Yoshino, Noriyuki Ohashi, Kazushige Kadota
Journal: Journal of the American College of Cardiology (2018)
Global, regional, and subregional trends in unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian hierarchical model
Authors: Jonathan Bearak, Anna Popinchalk, Leontine Alkema, Gilda Sedgh
Journal: The Lancet Global Health (2018)

Estimates of pregnancy incidence by intention status and outcome indicate how effectively women and couples are able to fulfil their childbearing aspirations, and can be used to monitor the impact of family-planning programmes. We estimate global, regional, and subregional pregnancy rates by intention status and outcome for 1990-2014.We developed a Bayesian hierarchical time series model whereby the unintended pregnancy rate is a function of the distribution of women across subgroups defined by marital status and contraceptive need and use, and of the risk of unintended pregnancy in each subgroup. Data included numbers of births and of women estimated by the UN Population Division, recently published abortion incidence estimates, and findings from surveys of women on the percentage of births or pregnancies that were unintended. Some 298 datapoints on the intention status of births or pregnancies were obtained for 105 countries.Worldwide, an estimated 44% (90% uncertainty interval [UI] 42-48) of pregnancies were unintended in 2010-14. The unintended pregnancy rate declined by 30% (90% UI 21-39) in developed regions, from 64 (59-81) per 1000 women aged 15-44 years in 1990-94 to 45 (42-56) in 2010-14. In developing regions, the unintended pregnancy rate fell 16% (90% UI 5-24), from 77 (74-88) per 1000 women aged 15-44 years to 65 (62-76). Whereas the decline in the unintended pregnancy rate in developed regions coincided with a declining abortion rate, the decline in developing regions coincided with a declining unintended birth rate. In 2010-14, 59% (90% UI 54-65) of unintended pregnancies ended in abortion in developed regions, as did 55% (52-60) of unintended pregnancies in developing regions.The unintended pregnancy rate remains substantially higher in developing regions than in developed regions. Sexual and reproductive health services are needed to help women avoid unintended pregnancies, and to ensure healthy outcomes for those who do experience such pregnancies.Dutch Ministry of Foreign Affairs and UK Aid from the UK Government.
Everolimus (E) plus bevacizumab (B) is effective first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) with papillary features (PF): Results from a phase II trial.
Authors: Darren R. Feldman, Chung-Han Lee, Ana M. Molina, Andrea Knezevic, Yingbei Chen, Joshua Chaim, Devyn Taylor Coskey, Yasser Ged, Satish Tickoo, Victor E. Reuter, Sujata Patil, Han Xiao, Jahan Aghalar, Arlyn J. Apollo, Maria Isabel Carlo, Robert J. Motzer, Martin Henner Voss
Journal: Journal of Clinical Oncology (2018)

627 Background: We previously reported on a phase II trial of E+B across various non-clear cell RCC histologies and observed significant activity among pts with papillary or unclassified RCC ( uRCC ) with PF (objective response rate [ORR] 39%, median progression-free survival [PFS] 12.9 months [m]; Voss, JCO, 2016). An expansion cohort limited to these two histologies was conducted to confirm the efficacy of E+B. Methods: E + B was administered at standard doses until progressive disease (PD) or intolerance to therapy. The current analysis included 19 pts with pRCC or uRCC with PF in the initial cohort and 20 pts in the expansion cohort (total n=39). The primary endpoint was 6 month PFS with secondary endpoints of ORR, median PFS, and overall survival (OS). Correlative analyses included next generation sequencing (NGS) from tumor and germline across &gt;341 genes of interest. Results: Of 39 pts, 24 had uRCC with PF, 14 had papillary RCC, and 1 had translocation RCC with PF. Among 37 evaluable pts, the ORR was 35%; 43% for uRCC with PF and 23% for papillary RCC. Six-month PFS for all 39 pts was 78%; 82% for uRCC with PF and 68% for papillary RCC. Median PFS was 13.7m; 13.7m for uRCC with PF and 8.4m for papillary RCC (Table). With median followup of 17.6m, median OS is 33.9m. Toxicity with E+B was similar to previous reports. 33 of 39 pts had NGS performed and partial responses were observed across a wide spectrum of genomic alterations, including several recurrently seen in papillary RCC variants such as mutations in FH, MET, NF2, and ARID1a. Conclusions: The expansion cohort confirms the activity of E+B for pts with advanced papillary RCC or uRCC with PF with superior ORR, PFS, and OS compared to historical results with sunitinib for these histologies. E+B represents a new standard first-line treatment option for these pts. Clinical trial information: NCT01399918. [Table: see text]
Junior contract could undermine recruitment, warns former Tory health minister
Authors: Abi Rimmer
Journal: BMJ (2016)

A former Conservative health minister has expressed concern over the impact a new junior doctor contract could have on recruitment and retention of female trainees.

Speaking on BBC Radio 4’s Woman’s Hour on Tuesday 5 April, former Conservative health minister Dan Poulter discussed the new contract for junior doctors in England.1

“Certainly I have concerns over the impact that this will have on the potential recruitment and retention of particularly female trainees,” he said. “We know that 15% of GPs are part time for family reasons, and I think there is …
I have a career gap of over two years, spent doing the PLAB exam after I relocated. How do I put this on my curriculum vitae?
Authors: Eric Chemla
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
Modern techniques in total knee arthroplasty
Authors: James Gillespie
Journal: BMJ (2012)

Total knee arthroplasty or replacement is a common elective orthopaedic operation. It is usually performed for osteoarthritis and uses metal to replace the articular surfaces of the tibia and femur. 

When a senior orthopaedic trainee demonstrates a good understanding of the principles behind this procedure, he or she is gradually allowed to perform this surgery under supervision. This course reassures trainees, and their consultants, that they have understood why the surgery is performed as well as how it is performed. 

The course is run by the medical education department of Depuy, a Johnson and Johnson company. The topics discussed are generic and are not specific to any particular type of implant.

This two day course is for trainees in orthopaedic surgery and would suit any trainee who is getting exposure to elective knee arthroplasty clinics and theatre. 

There were 40 people on the course I attended. Although it is aimed at specialty doctors and specialty trainees in their third year and above, there were some core trainees present. 

This two day course …
GPs should be subject to “friends and family” test of patient and staff satisfaction
Authors: Zosia Kmietowicz
Journal: BMJ (2013)

The prime minister has called for all GPs in England to undergo the “friends and family” test as a way to root out services that offer unacceptable standards of care.

Last May the government announced that hospitals in England would be subject to the test from this April, after a recommendation from the Nursing Quality Care Forum, which was set up last January after a number of high profile cases of poor care in the NHS.1 …
Specialty training competition stabilises as applications and posts rise
Authors: Helen Jaques
Journal: BMJ (2012)

Competition ratios for specialty training have largely dropped or levelled off after round one of recruitment across the United Kingdom this year, although the number of applications per trainee and the number of posts available have risen since 2011.

In 2012 a total of 16 635 applications were submitted for 7499 specialty training year 1 posts across the UK, producing an overall competition ratio of 2.2 applications per post. In 2011 15 203 applications were received for 6871 posts, again resulting in an overall competition ratio of 2.2:1. 

The reduction in the ratio in most specialties, largely because they have moved towards nationally coordinated recruitment, has resulted in major cost and time savings for the …
COMPARISON BETWEEN THREE-DIMENSIONAL ECHOCARDIOGRAPHY AND COMPUTED TOMOGRAPHY FOR TRICUSPID ANNULUS SIZING: IMPLICATIONS FOR THE GRADING OF TRICUSPID REGURGITATION USING THE QUANTITATIVE DOPPLER METHOD
Authors: Fabien Praz, Omar Khalique, Leon Dos Reis Macedo, Jennifer Jantz, Codner Pablo, Amisha Patel, Juan Terre, Torsten Vahl, Vinayak Bapat, Isaac George, Tamim Nazif, Susheel K. Kodali, Martin B. Leon, Rebecca T. Hahn
Journal: Journal of the American College of Cardiology (2018)