tbuckley/cabot-search huggingface dataset:
Cabozantinib (CABO) plus durvalumab (DURVA) in patients with advanced and chemotherapy-treated bladder carcinoma of urothelial and non-urothelial histology: An open-label, single-arm, phase 2 trial.
Authors: Andrea Necchi, Patrizia Giannatempo, Daniele Raggi, Andrea Anichini, Giuseppina Calareso, Flavio Crippa, Luigi Mariani
Journal: Journal of Clinical Oncology (2018)

TPS536 Background: DURVA and CABO have shown single-agent activity in patients (pts) with urothelial carcinoma (UC). Their combination may result in prolonging overall survival (OS) in pts who have failed prior platinum-based chemotherapy (CT). Additionally, DURVA+CABO may be an effective combination for treating subgroup of pts like those with bone metastases only (not having RECIST-measurable disease) or with non-UC histology. Methods: In an open-label, single-arm, multicenter, phase 2 trial, pts will assume CABO 40 mg daily, orally, and will be administered DURVA 1500 mg, intravenously, q28 days, until disease progression (PD, RECIST 1.1) or onset of unacceptable toxicity. Treatment beyond PD is not allowed. Key inclusion criteria: ECOG-PS 0-1, bladder or upper tract primary tumor, UC and non-UC histology, failure of 1 or 2 platinum-based CT for metastatic disease (2 nd -to-3 rd line only). Neoadjuvant/adjuvant CT is counted if relapse occurred ≤6 months (m) of the last CT cycle. Response is evaluated by RECIST criteria v.1.1 q2 cycles. The primary endpoint of the study is OS. The target is to detect an improvement in median OS from ≤6m (H0) to ≥9m(H1). To achieve 90% power with a one-sided non-parametric test at 5% significance, 122 pts must will be accrued over 36m and follow-up may be closed 12m after the end of accrual. PD-L1 expression will be assessed using with the Ventana SP142 assay, and categorized as high (≥25% of tumor cells [TC] or immune cells [IC]) or low/negative ( &lt; 25% TC or IC). The decision on whether or not to undertake PD-L1+ cohort expansion will be based on predictive power (PP) calculation: a PP ≥30% will be regarded as promising and necessary to continue. An interim analysis is planned after 24m (50% expected events). This analysis will be based on PP. The criterion for stopping the trial because of futility will be a PP &lt; 20%. Analyses on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). FDG-PET response in bone metastases will represent another translational endpoint (EudraCT number 2017-000580-32). Clinical trial information: 2017-000580-32.
Sports & Exercise Physiotherapy New Zealand (SEPNZ)–celebrating our new name
Authors: Hamish Ashton
Journal: British Journal of Sports Medicine (2018)

Welcome to the Sports & Exercise Physiotherapy New Zealand (SEPNZ) edition of the British Journal of Sports Medicine ( BJSM ). As many leading sports medicine groups have done, we changed our name to include physiotherapy’s focus on exercise. Although we don’t claim exercise as solely our domain, it is a huge part of what we do. Our name now proudly reflects this.

SEPNZ promotes the practical application of knowledge, and in this issue 6 of BJSM ’s 24 annual issues we highlight some terrific examples. As guest editor I have chosen a number of papers with information ‘you can use in your practice tomorrow’.

From the famous Snyder-Mackler lab in Delaware, USA, Dr Zakariya Nawasreh guides us on return to sport after ACL reconstruction ( see page 376 ). He makes a compelling case that objective criteria – not time alone – should guide return to play clearance. This extends key work from …
How to survive weekend working
Authors: Kathy Oxtoby
Journal: BMJ (2014)

Weekend working has long been a part of many doctors’ lives, and as the health service is set to provide the same services seven days a week, it is likely to affect the lives of many more. <b>Kathy Oxtoby </b>looks at the personal impact of weekend working, how doctors have learnt to deal with it, and how it might change in future
Brief Report: Attenuated Effectiveness of Tumor Necrosis Factor Inhibitors for Anti–Human T Lymphotropic Virus Type I Antibody–Positive Rheumatoid Arthritis
Authors: Takahisa Suzuki, Shoichi Fukui, Kunihiko Umekita, Junya Miyamoto, Masataka Umeda, Ayako Nishino, Akitomo Okada, Tomohiro Koga, Shin‐ya Kawashiri, Naoki Iwamoto, Kunihiro Ichinose, Mami Tamai, Keita Fujikawa, Toshiyuki Aramaki, Akinari Mizokami, Naoki Matsuoka, Yukitaka Ueki, Katsumi Eguchi, Shuntaro Sato, Toshihiko Hidaka, Tomoki Origuchi, Akihiko Okayama, Atsushi Kawakami, Hideki Nakamura
Journal: Arthritis & Rheumatology (2018)

To evaluate the effectiveness of tumor necrosis factor (TNF) inhibitors for the treatment of human T lymphotropic virus type I (HTLV-I)-positive patients with rheumatoid arthritis (RA) in an area endemic for HTLV-I infection.We conducted an observational study of 585 RA patients in whom TNF inhibitors were newly introduced as a first biologic disease-modifying antirheumatic drug in an area in southwestern Japan that is endemic for HTLV-I infection.Fifty patients (8.5%) were anti-HTLV-I antibody-positive. The ages of the patients in this group were significantly higher at entry compared with the ages of patients who were anti-HTLV-I antibody-negative (n = 535). The median Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was 5.21. Among the total group of patients, 82% were anti-citrullinated protein antibody (ACPA)-positive. The persistence rate of TNF inhibitors at 24 weeks was 89%. The median DAS28-ESR was significantly decreased at 24 weeks in each group. The European League Against Rheumatism (EULAR) response rate was significantly better in the anti-HTLV-I antibody-negative patients (P = 0.0277). Multiple regression analysis demonstrated that anti-HTLV-I antibody status was significantly associated with the EULAR response rate and change in the DAS28-ESR and was prominent especially in the ACPA-negative subjects. No patients developed adult T cell leukemia/lymphoma (ATL) or HTLV-I-associated myelopathy (HAM) during the 24-week treatment period.The efficacy of TNF inhibitors may be attenuated in anti-HTLV-I antibody-positive patients with RA. ATL and HAM did not develop when TNF inhibitors were used for 24 weeks, but the long-term risk is not known.
Evaluation of the clinical benefits of immune checkpoint inhibitors in patients with advanced melanoma.
Authors: Qiyun Ou, Yunfang Yu, Dagui Lin, Tuping Fu, Quanlong Gao, Baoming Luo
Journal: Journal of Clinical Oncology (2018)

194 Background: Immune checkpoint inhibitors selection in advanced melanoma is complicated further, with choices among anti-CTLA4 or anti-PD-1 therapeutic antibodies options. We aimed to evaluate the clinical benefits of immune checkpoint inhibitors for discussing evidence-based treatment strategies by a meta-analysis of randomized clinical trials (RCTs) data. Methods: We searched for RCTs investigating immune checkpoint inhibitors in patients with advanced melanoma until September 2017. Hazard ratios (HRs) was estimated for overall survival (OS) and progression-free survival (PFS). The quality of the evidence was evaluated with the GRADE framework. Results: Overall, 18 RCTs including a total of 8,917 patients were identified. Immune checkpoint inhibitors versus placebo or observation prolonged PFS (HR = 0.59, 95% confidence interval (CI) 0.44 to 0.78, P &lt; 0.0001) and OS (HR = 0.77, 95% CI 0.72 to 0.84, P &lt; 0.0001). The combination immunotherapy had significantly higher benefit than monotherapy for PFS (HR = 0.75, 95% CI 0.61 to 0.92, P = 0.005) and OS (HR = 0.70, 95% CI 0.61 to 0.79, P &lt; 0.0001). Treatment with anti-PD-1 monoclonal antibody was associated with improved PFS (HR = 0.61, 95% CI 0.59 to 0.69, P &lt; 0.0001) and OS (HR = 0.66, 95% CI 0.58 to 0.77, P &lt; 0.0001) compared with anti-CTLA-4 monoclonal antibody. According to BRAF status analysis, there was a PFS benefit of immune checkpoint inhibitors versus placebo or observation (mutant, HR = 0.58, 95% CI 0.35 to 0.96, P = 0.035; wild–type, HR = 0.52, 95% CI 0.43 to 0.69, P = 0.001), anti-PD-1 outperformed anti-CTLA-4 checkpoint inhibitor (mutant, PFS HR = 0.64, 95% CI 0.51 to 0.79, P &lt; 0.0001; wild–type, PFS HR = 0.58, 95% CI 0.47 to 0.71, P &lt; 0.0001); and combination compared with single-agent immunotherapy (mutant, HR = 0.38, 95% CI 0.15 to 0.98, P = 0.046; wild–type, HR = 0.40, 95% CI 0.23 to 0.69, P = 0.001). Conclusions: This analysis provides an evidence that immune checkpoint inhibitors enhanced OS and PFS in patients with advanced melanoma, as well as combination immunotherapy and anti-PD-1 monoclonal antibody appear to be clinically beneficial option preference.
Specialty training vacancies increase by 30% in a year
Authors: Tom Moberly
Journal: BMJ (2017)

The number of unfilled vacancies in specialty training after the first round of recruitment increased by 30% this year, data from Health Education England show.

In 2017, 908 of the 7487 training posts available were left unfilled after the first round of recruitment to first year specialty and core training. This is a 31% increase from 2016, when 693 of the 7366 available training posts were left unfilled at the same stage of the recruitment process.

Of the 908 unfilled posts, …
Publisher Correction: Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes
Authors: Longsen Han, Chao Ren, Ling Li, Xiaoyan Li, Juan Ge, Haichao Wang, Yi-Liang Miao, Xuejiang Guo, Kelle H. Moley, Wenjie Shu, Qiang Wang
Journal: Nature Genetics (2018)
A new deal for deaneries?
Authors: Damian Roland
Journal: BMJ (2011)

It has been a nervous time for staff in deaneries throughout England as the Health Bill seemed to signal their demise in their current form. However, during the consultation on the bill and subsequent “pause” a number of postgraduate medical training organisations, including the Academy of Medical Royal Colleges and the BMA, lobbied to retain key deanery functions. 

The government’s response to the Future Forum stated: “The post-graduate Deans and SHA [strategic health authority] staff involved in planning and developing the workforce will continue to manage and assure education and training, including the training and recruitment of junior doctors and dentists. Securing continuity for the work they do into the new arrangements will be a key part of safe transition.”1 This was an important decision, as a failure to retain well trained deanery staff, especially during busy selection periods, could have precipitated a recruitment disaster. However, it is not always wise or feasible to resist change to maintain a comfortable status quo. It is important that the opportunity is not lost for reflection on the current methods for delivering education, training, and workforce planning.

In the current deanery model the accountability in the …
Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults
Authors: Matthew Hansen, Robert H. Schmicker, Craig D. Newgard, Brian Grunau, Frank Scheuermeyer, Sheldon Cheskes, Veer Vithalani, Fuad Alnaji, Thomas Rea, Ahamed H. Idris, Heather Herren, Jamie Hutchison, Mike Austin, Debra Egan, Mohamud Daya
Journal: Circulation (2018)

Previous studies have demonstrated that earlier epinephrine administration is associated with improved survival from out-of-hospital cardiac arrest (OHCA) with shockable initial rhythms. However, the effect of epinephrine timing on patients with nonshockable initial rhythms is unclear. The objective of this study was to measure the association between time to epinephrine administration and survival in adults and children with emergency medical services (EMS)-treated OHCA with nonshockable initial rhythms.We performed a secondary analysis of OHCAs prospectively identified by the Resuscitation Outcomes Consortium network from June 4, 2011, to June 30, 2015. We included patients of all ages with an EMS-treated OHCA and an initial nonshockable rhythm. We excluded those with return of spontaneous circulation in <10 minutes. We conducted a subgroup analysis involving patients <18 years of age. The primary exposure was time (minutes) from arrival of the first EMS agency to the first dose of epinephrine. Secondary exposure was time to epinephrine dichotomized as early (<10 minutes) or late (≥10 minutes). The primary outcome was survival to hospital discharge. We adjusted for Utstein covariates and Resuscitation Outcomes Consortium study site.From 55 568 EMS-treated OHCAs, 32 101 patients with initial nonshockable rhythms were included. There were 12 238 in the early group, 14 517 in the late group, and 5346 not treated with epinephrine. After adjusting for potential confounders, each minute from EMS arrival to epinephrine administration was associated with a 4% decrease in odds of survival for adults, odds ratio=0.96 (95% confidence interval, 0.95-0.98). A subgroup analysis (n=13 290) examining neurological outcomes showed a similar association (adjusted odds ratio, 0.94 per minute; 95% confidence interval, 0.89-0.98). When epinephrine was given late in comparison with early, odds of survival were 18% lower (odds ratio, 0.82; 95% confidence interval, 0.68-0.98). In a pediatric analysis (n=595), odds of survival were 9% lower (odds ratio, 0.91; 95% confidence interval, 0.81-1.01) for each minute delay in epinephrine.Among OHCAs with nonshockable initial rhythms, the majority of patients were administered epinephrine >10 minutes after EMS arrival. Each minute delay in epinephrine administration was associated with decreased survival and unfavorable neurological outcomes. EMS agencies should consider strategies to reduce epinephrine administration times in patients with initial nonshockable rhythms.
Approaches to shared decision-making for PSA screening in primary care practice.
Authors: Cara B Litvin, Steven M. Ornstein, Lynne Nemeth
Journal: Journal of Clinical Oncology (2018)

33 Background: In April 2017, the United States Preventive Services Task Force published a draft statement recommending that clinicians inform men ages 55 to 65 about the potential benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer. The HIT-OVERUSE study is an ongoing 2 year group randomized study in 20 primary care practices to test a practice-based intervention to reduce overuse, including avoidance of routine PSA screening without shared decision making. The purpose of this report is to present qualitative findings about approaches participating practices have adopted to facilitate shared decision-making for PSA screening. Methods: Eleven practices in ten states randomized to the HIT-OVERUSE intervention group have hosted on-site visits for academic detailing and participatory planning and sent two practice representatives to a one day meeting to share ‘best practices.’ Detailed notes from site visits, follow-up emails, and the ‘best practice’ meeting were reviewed to identify strategies adopted by practices to facilitate shared decision-making for PSA screening for prostate cancer screening. Results: All practices adopted at least one strategy to promote shared-decision making for PSA screening. Four practices removed standing orders for routine PSA screening. Four practices educated their clinical staff about the test; three developed scripts for staff to use when asked by patients about the test. Six practices began using patient education handouts about PSA screening. One provider started showing a brief YouTube video with patients, while another practice developed a slide show to show in the waiting room. Most providers in nearly all practices reported modifying their conversation about PSA screening with patients to include some discussion about the benefits and the harms of screening. Conclusions: Primary care practices participating an intervention to reduce overuse have adopted varied approaches to facilitate shared-decision making for prostate cancer screening. While having face-to-face conversations is one approach, other strategies may employ staff or utilize patient education or videos to convey the benefits and harms of screening.
The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non–cell-autonomous mechanisms
Authors: Camille Balbinot, Olivier Armant, Nabila Elarouci, Laetitia Marisa, Elisabeth Martin, Etienne De Clara, Alina Onea, Jacqueline Deschamps, Felix Beck, Jean-Noël Freund, Isabelle Duluc
Journal: The Journal of Experimental Medicine (2018)

Developmental genes contribute to cancer, as reported for the homeobox gene Cdx2 playing a tumor suppressor role in the gut. In this study, we show that human colon cancers exhibiting the highest reduction in CDX2 expression belong to the serrated subtype with the worst evolution. In mice, mosaic knockout of Cdx2 in the adult intestinal epithelium induces the formation of imperfect gastric-type metaplastic lesions. The metaplastic knockout cells do not spontaneously become tumorigenic. However, they induce profound modifications of the microenvironment that facilitate the tumorigenic evolution of adjacent Cdx2-intact tumor-prone cells at the surface of the lesions through NF-κB activation, induction of inducible nitric oxide synthase, and stochastic loss of function of Apc. This study presents a novel paradigm in that metaplastic cells, generally considered as precancerous, can induce tumorigenesis from neighboring nonmetaplastic cells without themselves becoming cancerous. It unveils the novel property of non–cell-autonomous tumor suppressor gene for the Cdx2 gene in the gut.
Erosive Patches on Bilateral Nipples
Authors: Xiao-Ke Liu, Jun Li
Journal: JAMA Dermatology (2018)

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Large meta-analysis ends doubts about efficacy of antidepressants
Authors: Abi Rimmer
Journal: BMJ (2018)

Antidepressants are more effective than placebo for short term treatment of acute depression in adults, a large meta-analysis has found.1

Carmine Pariante, consultant perinatal psychiatrist and a spokesman for the Royal College of Psychiatrists, said that the research would finally put to bed the controversy about antidepressants, as it clearly showed that these drugs work in lifting mood and helping most people with depression.

“Importantly, the paper analyses unpublished data held by pharmaceutical companies and shows that the funding of studies by these companies does not influence the result, thus confirming that the clinical usefulness of these drugs is not affected by pharma sponsored spin,” he said.

Patients with moderate to severe depression—the group covered by the study—are …
Detection of copy number aberrations in cholangiocarcinoma using shallow whole genome sequencing of plasma DNA.
Authors: Maria Farooq, Jan B. Egan, Bradon McDonald, Havell Markus, Tania Contente-Cuomo, Martin Fernandez-Zapico, George Vasmatzis, Esteban Braggio, Mitesh J. Borad, Muhammed Murtaza
Journal: Journal of Clinical Oncology (2018)

293 Background: Cholangiocarcinoma (CCA) is a deadly cancer with ~20% five year survival. Obtaining tissue to confirm diagnosis of CCA is often challenging. This also limits the use of tumor genotyping that could guide potential molecularly targeted treatment (such as FGFR inhibitors for a subset of cases). We investigated whether circulating tumor DNA (ctDNA) analysis in plasma is feasible for noninvasive tumor genotyping in patients with advanced CCA. Methods: We collected and processed plasma samples for ctDNA analysis from 17 patients with CCA at presentation and from 11 healthy volunteers. Following cell-free DNA extraction and quality assessment using digital PCR, we performed low-pass, shallow whole genome sequencing (sWGS). We analyzed sequencing data to identify copy number aberrations and quantify tumor fraction in plasma using recently published computational approaches. Results: Median total cfDNA concentration in patients with CCA was 7,003 genome equivalents (GEs)/mL plasma (range: 1,512- 107,707 GEs/mL) and significantly higher than healthy volunteers (two tailed t-test p &lt; 0.04, median: 1,658 GEs/mL, range: 661-4,938 GEs/mL). We successfully sequenced all tumor libraries, generating a median of 173 million paired-end reads. ctDNA was detectable in 10/17 samples using sWGS. In these 10 samples, median tumor fraction in plasma DNA was 7.1% (range: 3.9%-44.6%). We found recurrent copy number aberrations expected in CCA including 1q gain in 80%, 7p gain in 50%, 1p loss in 70% and 3p loss in 50% of cases. Conclusions: ctDNA analysis for noninvasive tumor genotyping is feasible in patients with advanced cholangiocarcinoma. On-going work is focused on expanding these results using targeted and whole-exome sequencing.
Corrigendum to “Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic” [Biomaterials 54 (2015) 72−86]
Authors: Weiguo Xu, Jianxun Ding, Chunsheng Xiao, Lingyu Li, Xiuli Zhuang, Xuesi Chen
Journal: Biomaterials (2018)