tbuckley/cabot-search huggingface dataset:
Comparison of tumor mutational burden (TMB) in <i>PBRM1/BAP1</i>-based subsets of advanced renal cell carcinoma (aRCC).
Authors: Sumanta K. Pal, Russell Madison, Jon Chung, Neeraj Agarwal, Paulo Gustavo Bergerot, Dominick Bosse, Ethan Sokol, Ryan James Hartmaier, Vincent A. Miller, Jeffrey S. Ross, Toni K. Choueiri, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2018)

634 Background: Using IHC, Joseph et al (J Urol 2016) propose that 40.1%, 48.6%, 8.7% and 1.8% of patients (pts) can be characterized as PBRM1+BAP1+, PRBM1-BAP1+, PBRM1+BAP1- and PBRM1-BAP1-, respectively. We sought to confirm consistency of the frequency of genomic alterations (GAs) and IHC data and to compare TMB across subsets. Methods: DNA was extracted from 40 microns of FFPE sections from pts with aRCC. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. TMB was determined on 1.2 million Mb of sequenced DNA; results are reported in subsets segregated by presence or absence of PBRM1 and BAP1 alteration. Results: 648 consecutive pts (459:189 M:F) with clear cell RCC (ccRCC) were assessed with a median age of 58, and 368 consecutive pts (254:114 M:F) with non-clear cell RCC (nccRCC) were assessed with a median age of 57. Mutations in BAP1 and PBRM1 were found more frequently in ccRCC vs nccRCC (P &lt; 0.05 for both). In pts with ccRCC, average TMB was highest in pts with co-occurring PBRM1 and BAP1 GAs (4.87 muts/Mb), and lowest in pts lacking both GAs (2.77 muts/Mb) (P &lt; 0.05). TMB was similar across PBRM1/BAP1-based subsets amongst pts with nccRCC. Conclusions: As anticipated, the frequency of PBRM1/BAP1-mutated subsets by CGP is inversely related to the frequency of subsets with PBRM1/BAP1 loss by IHC from previous reports. In addition to these confirmatory findings, this large series identifies that pts with dual PBRM1/ BAP1 GAs (associated with the worst prognosis) had the highest TMB. [Table: see text]
Vote on legalising assisted dying in Guernsey is due in months
Authors: Adrian O’Dowd
Journal: BMJ (2018)

Politicians in Guernsey look set to vote on the controversial issue of taking steps towards legalising assisted dying, which would be the first such regime in the British Isles.

Several members of the island’s parliament have put forward a “requete”1—the closest equivalent to a private member’s bill in Westminster—on the issue of assisted dying, with a debate and vote due to take place sometime in May.

Passing it would mean agreement, in principle, to the development of a suitable legal regime to permit assisted dying in Guernsey for people who are terminally ill and mentally competent, and would lead to an …
Response by Asrress et al to Letter Regarding Article, “Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise”
Authors: Kaleab N. Asrress, Rupert Williams, Timothy Lockie, Muhammed Z. Khawaja, Tiffany Patterson, Satpal Arri, Kalpa De Silva, Divaka Perera, Michael S. Marber, Simon R. Redwood
Journal: Circulation (2018)
Outcomes in patients (Pts) with advanced prostate cancer and inactivating germline mutations in BRCA2 or ATM.
Authors: Steven Yip, Daniel Khalaf, Werner J. Struss, Katherine Sunderland, Gillian Vandekerkhove, Evan W Warner, Matti Annala, Alexander William Wyatt, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

242 Background: Germline mutations in homologous recombination repair (HRR) genes, including BRCA2, are present in 6-12% of pts with metastatic castration-resistant prostate cancer (mCRPC). BRCA2 germline mutations are associated with high-grade and poor-prognosis localized disease, while outcomes in pts with advanced prostate cancer continue to be defined. Methods: Germline DNA from 536 consecutive mCRPC pts in our liquid biopsy program were screened for BRCA2 and ATM gene mutations using targeted sequencing. Kaplan-Meier curves were used to estimate the median time from androgen deprivation therapy (ADT) initiation to mCRPC, progression free survival (PFS) on first-line androgen receptor (AR) targeted therapy, and overall survival (OS). Outcomes in BRCA2 or ATM germline mutation carriers and a subset of the total sample of HRR wild-type (WT) pts, who had clinical data available (n = 113), were compared using the log-rank test. Results: 26/536 (4.9%) of pts had germline BRCA2 (n = 22) or ATM mutations (n = 4). After ADT initiation, HRR mutated pts progressed to mCRPC with a median time of 13.4 mo compared to 19.0 mo in WT pts (HR = 1.6, [95% CI 1.0-2.5], p = 0.03). HRR mutated pts had a median PFS on first-line AR-targeted therapy in the mCRPC setting of 3.3 mo versus 7.9 mo in WT pts (HR = 2.2, [95% CI 1.3-3.5], p = 0.002). OS for HRR mutated pts from the time of ADT was 57.7 mo in contrast to 104.9 mo in WT pts (HR = 1.8, [95% CI 1.0-3.4], p = 0.07). OS from time of CRPC was 29.7 mo in HRR mutated pts versus 50.3 mo in WT pts (1.6, [95% CI 0.8-2.9], p = 0.16). Conclusions: Germline HRR mutated pts perform poorly with shorter PFS on first-line AR-targeted therapy and time to mCRPC, in contrast to WT pts. These findings support the hypothesis that BRCA2 and ATM gene mutated pts have poor outcomes with current AR-targeted treatments and should be evaluated for alternate regimens.
Translational Challenges in Atrial Fibrillation
Authors: Jordi Heijman, Jean-Baptiste Guichard, Dobromir Dobrev, Stanley Nattel
Journal: Circulation Research (2018)

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is associated with substantial morbidity and mortality. Current treatment options for AF have significant limitations. Basic research has provided information on mechanisms relevant to the management of AF and promises to contribute significantly to future advances, yet many important translational challenges remain. Here, we analyze the therapeutic limitations for which improvement is needed, consider the translational opportunities presented by recent scientific and technological developments, and attempt to look into the future of where these may lead. We first review the limitations of current AF management, with a focus on rhythm control therapy. These include arrhythmia complications, progression to advanced treatment-resistant forms, insufficient effectiveness of available therapeutic options, adverse consequences of therapy, and difficulties in new therapeutic development. The translational challenges in addressing these shortcomings are then addressed, including (1) defining actionable patient-specific arrhythmia mechanisms to enable personalized therapy; (2) identifying and treating key dynamic modulators controlling AF initiation and progression; (3) achieving atrial-restricted targeting of specific molecular arrhythmia mechanisms; and (4) clarifying the response of the substrate to interventions. For each of these, we describe the translational goal and the opportunities created by recent advances in cardiac imaging, computational modeling, rhythm monitoring, ablation technology, and preclinical studies in human samples and animal models. Finally, we consider the prospects for future solutions that might appreciably improve our ability to understand and manage the arrhythmia over the years to come.
Human Gut Microbiota and Gastrointestinal Cancer
Authors: Changting Meng, Chunmei Bai, Thomas D. Brown, Leroy E. Hood, Qiang Tian
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract Human gut microbiota play an essential role in both healthy and diseased states of humans. In the past decade, the interactions between microorganisms and tumors have attracted much attention in the efforts to understand various features of the complex microbial communities, as well as the possible mechanisms through which the microbiota are involved in cancer prevention, carcinogenesis, and anti-cancer therapy. A large number of studies have indicated that microbial dysbiosis contributes to cancer susceptibility via multiple pathways. Further studies have suggested that the microbiota and their associated metabolites are not only closely related to carcinogenesis by inducing inflammation and immune dysregulation, which lead to genetic instability, but also interfere with the pharmacodynamics of anticancer agents. In this article, we mainly reviewed the influence of gut microbiota on cancers in the gastrointestinal (GI) tract (including esophageal, gastric, colorectal, liver, and pancreatic cancers) and the regulation of microbiota by diet, prebiotics, probiotics, synbiotics, antibiotics, or the Traditional Chinese Medicine. We also proposed some new strategies in the prevention and treatment of GI cancers that could be explored in the future. We hope that this review could provide a comprehensive overview of the studies on the interactions between the gut microbiota and GI cancers, which are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, diagnosis, and treatment.
Effect of a Collaborative Care Intervention vs Usual Care on Health Status of Patients With Chronic Heart Failure
Authors: David B. Bekelman, Larry A. Allen, Connor F. McBryde, Brack Hattler, Diane L. Fairclough, Edward P. Havranek, Carolyn Turvey, Paula M. Meek
Journal: JAMA Internal Medicine (2018)

Many patients with chronic heart failure experience reduced health status despite receiving conventional therapy.To determine whether a symptom and psychosocial collaborative care intervention improves heart failure-specific health status, depression, and symptom burden in patients with heart failure.A single-blind, 2-arm, multisite randomized clinical trial was conducted at Veterans Affairs, academic, and safety-net health systems in Colorado among outpatients with symptomatic heart failure and reduced health status recruited between August 2012 and April 2015. Data from all participants were included regardless of level of participation, using an intent-to-treat approach.Patients were randomized 1:1 to receive the Collaborative Care to Alleviate Symptoms and Adjust to Illness (CASA) intervention or usual care. The CASA intervention included collaborative symptom care provided by a nurse and psychosocial care provided by a social worker, both of whom worked with the patients' primary care clinicians and were supervised by a study primary care clinician, cardiologist, and palliative care physician.The primary outcome was patient-reported heart failure-specific health status, measured by difference in change scores on the Kansas City Cardiomyopathy Questionnaire (range, 0-100) at 6 months. Secondary outcomes included depression (measured by the 9-item Patient Health Questionnaire), anxiety (measured by the 7-item Generalized Anxiety Disorder Questionnaire), overall symptom distress (measured by the General Symptom Distress Scale), specific symptoms (pain, fatigue, and shortness of breath), number of hospitalizations, and mortality.Of 314 patients randomized (157 to intervention arm and 157 to control arm), there were 67 women and 247 men, mean (SD) age was 65.5 (11.4) years, and 178 (56.7%) had reduced ejection fraction. At 6 months, the mean Kansas City Cardiomyopathy Questionnaire score improved 5.5 points in the intervention arm and 2.9 points in the control arm (difference, 2.6; 95% CI, -1.3 to 6.6; P = .19). Among secondary outcomes, depressive symptoms and fatigue improved at 6 months with CASA (effect size of -0.29 [95% CI, -0.53 to -0.04] for depressive symptoms and -0.30 [95% CI, -0.55 to -0.06] for fatigue; P = .02 for both). There were no significant changes in overall symptom distress, pain, shortness of breath, or number of hospitalizations. Mortality at 12 months was similar in both arms (10 patients died receiving CASA, and 13 patients died receiving usual care; P = .52).This multisite randomized clinical trial of the CASA intervention did not demonstrate improved heart failure-specific health status. Secondary outcomes of depression and fatigue, both difficult symptoms to treat in heart failure, improved.clinicaltrials.gov Identifier: NCT01739686.
Please advise me how to apply for GP vocational training, and what are the criteria?
Authors: Sian Howell
Journal: BMJ (2004)

<i>Got 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 (www.bmjcareers.com/advicezone) 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.</i>
High-dose chemotherapy (HDC) and stem-cell rescue as salvage treatment for germ cell testicular tumors in second- and third-line, and outside clinical trials.
Authors: Fernanda Carneiro Ronchi, Daniel Vilarim Araujo, Ana Claudia Machado Urvanegia, José Augusto Rinck
Journal: Journal of Clinical Oncology (2018)

557 Background: Germ-cells testicular tumors are the most common cancer in young males, usually curable in early stages. Therefore, only 25% of relapsed patients are long-term survivors. Previous non-randomized studies showed promising results with HDC, however, the only randomized trial did not support this approach. Here we report our experience in a Brazilian academic center Methods: We conducted a retrospective review of all consecutive patients treated with salvage HDC followed by Stem-Cell transplantation at our service (1996 – 2016). Survival curves were estimated by Kaplan-Maier method. Prognostic factors were determined by Cox regression model. Results: We found 36 eligible patients. The cohort median follow-up was 56 months (m). At 2 years 50.4% of the patients were alive, and 46.7% were disease-free. The median overall survival (OS) was not-reached and the median progression-free survival (PFS) was 21.8 m. The overall response-rate was 61.2% (22% had complete response and 39% had partial response). All patients who achieved complete response were alive at the last follow-up, and only one had progressive disease. Out of the patients who achieved partial response, one third were rescued with surgery (46% teratoma, 23% fibrosis, and 31% residual disease). Approximately 80% were alive in 2 years vs 20% not operated. Complete response (vs. others) and HDC as second line treatment (vs. 3 rd and 4 th ) were good prognostic factors, (HR N/A; p 0,03, HR 0.19; CI: 0.04-0.88, p = 0.01 respectively). In 2 years, the OS in patients treated in 2 nd line was approximately 80%, 50% for 3 rd line, and 0% of those treated in 4 th line. 89% of the patients experienced grade 3 toxicity, and 25% grade 4. The most common were neutropenic fever (69%), mucositis (36%) and diarrhea (25%). There were 3 deaths related to the treatment. Conclusions: Patients with complete response have sustained long-term survival, and represent the subgroup with evident benefit of the treatment. Surgery, when feasible, can rescue 80% of the patients with partial response. According to our data, we do not recommend this modality of treatment in 4 th line.
A Protein-Truncating<i>HSD17B13</i>Variant and Protection from Chronic Liver Disease
Authors: Noura S. Abul-Husn, Xiping Cheng, Alexander H. Li, Yurong Xin, Claudia Schurmann, Panayiotis Stevis, Yashu Liu, Julia Kozlitina, Stefan Stender, G. Craig Wood, Ann N. Stepanchick, Matthew D. Still, Shane McCarthy, Colm O’Dushlaine, Jonathan S. Packer, Suganthi Balasubramanian, Nehal Gosalia, David Esopi, Sun Y. Kim, Semanti Mukherjee, Alexander E. Lopez, Erin D. Fuller, John Penn, Xin Chu, Jonathan Z. Luo, Uyenlinh L. Mirshahi, David J. Carey, Christopher D. Still, Michael D. Feldman, Aeron Small, Scott M. Damrauer, Daniel J. Rader, Brian Zambrowicz, William Olson, Andrew J. Murphy, Ingrid B. Borecki, Alan R. Shuldiner, Jeffrey G. Reid, John D. Overton, George D. Yancopoulos, Helen H. Hobbs, Jonathan C. Cohen, Omri Gottesman, Tanya M. Teslovich, Aris Baras, Tooraj Mirshahi, Jesper Gromada, Frederick E. Dewey
Journal: New England Journal of Medicine (2018)

Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets.
Abstract P6-06-04: Targeting replication stress in triple negative breast cancer treatment regimen: An emerging approach
Authors: S Rajamanickam, JH Park, K Bates, S Timilsina, VK Eedunuri, B Onyeagucha, P Subbarayalu, N Abdelfattah, KH Jung, E Favours, TA Mohammad, H-IH Chen, RK Vadlamudi, Y Chen, BA Kaipparettu, JL Arbiser, MK Rao
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancers (TNBCs) represent aggressive heterogeneous subtype of breast cancer with poor clinical outcome. TNBCs have been reported to have high levels of replication stress due to i) various oncogene activations (C-myc or EGFR) ii) germline BRCA mutations iii) “BRCAness” in the absence of BRCA mutations in sporadic TNBCs. Replication stress is known to cause genomic instability, promote tumorigenesis and plays a critical role in therapy resistance in TNBCs. Therefore, targeting replication stress has emerged as an effective approach for better TNBC treatment through further downregulation of the remaining checkpoints to induce catastrophic failure of TNBC cells proliferation. Herein, we evaluated the anticancer efficacy of Carbazole Blue (CB), a synthetic analogue of Carbazole, on TNBC cells growth and progression. Our results demonstrated that CB inhibits short and long term viability of TNBC (MDA-MB-231, MDA-MB-468 and BT549) cells in a dose dependent manner without affecting normal mammary epithelial (MCF-10A) cells. In addition, CB treatment significantly reduced proliferation of TNBC cells, as evidenced by the BrdU proliferation assay. Consistent with this, our results further demonstrated that CB treatment induced G1/S cell cycle arrest and apoptosis in TNBCs. Importantly, systemic delivery of CB using nanoparticle-based delivery approach suppressed breast cancer growth without inducing toxicity, in preclinical orthotopic xenograft and PDX mouse models of TNBC. Furthermore, our gene microarray analysis revealed that CB treatment modulates the expression and activity of several genes known to be involved in DNA replication (CDC6, CDT1, MCMs, Claspin, POLE and PCNA) and associated DNA repair machinery such as (XRCC3, Exo1 and RAD51), which play pivotal roles in replication stress. Our results for the first time highlight the potential use of CB as a novel and potent therapeutic agent for treating TNBCs. As exploiting replication stress to treat cancer is gaining major interest, compound/s that may induce replication stress and inhibit DNA repair ability of cancer cells, has immense translational potential. Citation Format: Rajamanickam S, Park JH, Bates K, Timilsina S, Eedunuri VK, Onyeagucha B, Subbarayalu P, Abdelfattah N, Jung KH, Favours E, Mohammad TA, Chen H-IH, Vadlamudi RK, Chen Y, Kaipparettu BA, Arbiser JL, Rao MK. Targeting replication stress in triple negative breast cancer treatment regimen: An emerging approach [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 P6-06-04.
Japan multicenter prospective study: FDG PET/CT in the assessment of advanced renal cell carcinoma treated with sorafenib.
Authors: Noboru Nakaigawa, Ukihide Tateishi, Takuma Kato, Tomohiro Kaneta, Keiichi Kondo, Mikio Sugimoto, Masahiro Yao, Tomio Inoue, Yoshiyuki Kakehi, Yoshinobu Kubota
Journal: Journal of Clinical Oncology (2018)

605 Background: We previously reported that the early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma (aRCC) treated with tyrosine kinase inhibitors (TKIs) predicted the disease course. In this study, we investigated prospectively the relationship of the clinical outcome of patients with aRCC treated with sorafenib and radiological parameters obtained with FDG-PET/CT at baseline and 4 weeks (4W). Methods: The patients with TKI-naïve aRCC planning to be treated by sorafenib were enrolled and assessed by FDG-PET/CT at baseline and at 4W. The relationship between radiological parameters, (1) max SUVmax at baseline, (2) change in max SUVmax at 4week, and (3) response criteria defined by Ueno D et al. ( The prognosis of aRCC which max SUVmax decreased more or 20% at 4W demonstrated good prognosis. BMC Cancer 2012) and progression-free survival (PFS) and overall survival (OS) was exploratory evaluated. This study is multicenter-study using PET/CT systems which quality is ensured by previous phantom study. Results: Total 34 patients were enrolled. The median PFS were 9.7 months and mean OS were 35.8 months (survival curve did not reach 0.5). The median of max SUVmax (the highest standardized uptake value in each patients) at baseline was 5.1. The median PFS of patients with baseline max SUVmax ≤ 5.1 showed longer PFS and OS compared that with max SUVmax &gt; 5.1 (median PFS 11.9months vs. 9.2 month P= 0.0354, median OS --- vs. 15.3 months P= 0.027 ). The median change ratio in max SUVmax at 4W was -9.5%. The change ratio did not affect the PFS and OS, analyzing the total patients. When the patients with max SUVmax &gt; 4.0 at baseline were focused, the PFS of patients which max SUVmax decreased more or 20% at 4W demonstrated tendency to be longer than that of other patients (median PFS 15.6 months vs 9.2 months, P= 0.0727) Conclusions: In this study, we demonstrated that the pretreatment max SUVmax predicted the PFS and OS of aRCC treated by sorafenib, but change of max SUV max at 4W did not. The change ratio could have potency as a predict marker for the PFS in the cases with high max SUVmax at baseline. It was speculated that the accurate assessment of change ratio in the cases with low max SUVmax at baseline was difficult. Clinical trial information: 000009812.
Editor’s Choice: Feeding curiosity
Authors: Tom Moberly
Journal: BMJ (2016)

“The most exciting phrase to hear in science, the one that heralds new discoveries,” said Isaac Asimov, the science fiction author and biochemistry professor, “is not ‘Eureka’ but ‘That’s funny . . .’”

In BMJ Careers this week Thuvaraka Ware makes a case for a “that’s funny” response being the fuel …
I am from Greece, and I have worked as a senior house officer in paediatrics for two years. I have a PhD in allergiology and I would like to study allergiology in England.
Authors: Elitham Turya
Journal: BMJ (2004)

<i>Got 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 (www.bmjcareers.com/advicezone) 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.</i>
Mentoring schemes for new consultants are too rigid, researchers say
Authors: Abi Rimmer
Journal: BMJ (2014)

Mentoring schemes for new consultants are often hampered by overly rigid structural frameworks, researchers have said.

A group of researchers led by Reema Harrison, of Sydney Medical School in Australia, interviewed 31 doctors working across nine UK hospitals in the Yorkshire and Humber region about their experiences of mentoring. They looked specifically at the benefits that mentoring could offer to newly …