tbuckley/cabot-search huggingface dataset:
Midterm Safety and Performance of a Leadless Cardiac Pacemaker
Authors: Fleur V.Y. Tjong, Reinoud E. Knops, Petr Neuzil, Jan Petru, Lucie Sediva, Arthur A.M. Wilde, Johannes Sperzel, Vivek Y. Reddy
Journal: Circulation (2018)

Leadless cardiac pacemakers (LCPs) have been introduced to decrease lead- and pocket-related complications. Initial studies have shown short-term complication rates of 4% to 6.7% and adequate electric performance in up to 12 months of follow-up.1–3 However, to fully appreciate the clinical impact and the robustness of this novel technology, additional follow-up is required to determine the long-term safety and performance. In this study, we report the longest clinical follow-up to date: the 3-year results of the LEADLESS trial (Nanostim Safety and Performance Trial for a Leadless Cardiac Pacemaker System).4

Patients implanted with an LCP (Nanostim, St. Jude Medical/Abbott) were retrospectively assessed to evaluate the safety and performance of this device with a minimum of 3 years of follow-up. No patients were lost to follow-up. Medical records were analyzed from June 2014 until May 2016 and evaluated for (1) serious adverse device effects (SADEs) and (2) electric performance of the LCP. The primary outcome was freedom from SADEs (Kaplan-Meier estimate) at 40 months of follow-up. Categorical variables are presented as frequencies and continuous variables as means (±SD). Permission of the local institutional review boards was obtained for this retrospective analysis, and all participants gave written informed consent.

Thirty-three patients (age 77±8 years, 67% male) were enrolled and were followed for a median duration of 38 months (range, 21–41 months). Two patients were …
FIRST-IN-MAN CORRELATION BETWEEN PREOPERATIVE CORONARY PHYSIOLOGY AND THE ACUTE PERFUSION RESPONSE TO CORONARY ARTERY BYPASS GRAFTING: THE PERSEUS PILOT STUDY
Authors: Ashesh N. Buch, Hazaim Alwair, Jimmy Efird, Christopher Cook, Ricardo Petraco Da Cunha, Arjun Chagarlamudi, Christopher Gregory, Justin Davies, T. Ferguson
Journal: Journal of the American College of Cardiology (2018)
Endovascular treatment for acute ischaemic stroke in routine clinical practice: prospective, observational cohort study (MR CLEAN Registry)
Authors: Ivo G H Jansen, Maxim J H L Mulder, Robert-Jan B Goldhoorn
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To determine outcomes and safety of endovascular treatment for acute ischaemic stroke, due to proximal intracranial vessel occlusion in the anterior circulation, in routine clinical practice. <h3>Design</h3> Ongoing, prospective, observational cohort study. <h3>Setting</h3> 16 centres that perform endovascular treatment in the Netherlands. <h3>Participants</h3> 1488 patients included in the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry who had received endovascular treatment, including stent retriever thrombectomy, aspiration, and all alternative methods for acute ischaemic stroke within 6.5 hours from onset of symptoms between March 2014 and June 2016. <h3>Main outcome measures</h3> The primary outcome was the modified Rankin Scale (mRS) score, ranging from 0 (no symptoms) to 6 (death) at 90 days after the onset of symptoms. Secondary outcomes were excellent functional outcome (mRS score 0-1), good functional outcome (mRS score 0-2), and favourable functional outcome (mRS score 0-3) at 90 days; score on the extended thrombolysis in cerebral infarction scale at the end of the intervention procedure; National Institutes of Health Stroke Scale score 24-48 hours after intervention; and complications that occurred during intervention, hospital admission, or three months’ follow up period. Outcomes and safety variables in the MR CLEAN Registry were compared with the MR CLEAN trial intervention and control arms. <h3>Results</h3> A statistically significant shift was observed towards better functional outcome in patients in the MR CLEAN Registry compared with the MR CLEAN trial intervention arm (adjusted common odds ratio 1.30, 95% confidence interval 1.02 to 1.67) and the MR CLEAN trial control arm (1.85, 1.46 to 2.34). The reperfusion rate, with successful reperfusion defined as a score of 2B-3 on the extended thrombolysis in cerebral infarction score, was 58.7%, the same as for patients in the MR CLEAN trial. Duration from onset of stroke to start of endovascular treatment and from onset of stroke to successful reperfusion or last contrast bolus was one hour shorter for patients in the MR CLEAN Registry. Symptomatic intracranial haemorrhage occurred in 5.8% of patients in the MR CLEAN Registry compared with 7.7% in the MR CLEAN trial intervention arm and 6.4% in the MR CLEAN trial control arm. <h3>Conclusion</h3> In routine clinical practice, endovascular treatment for patients with acute ischaemic stroke is at least as effective and safe as in the setting of a randomised controlled trial.
Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial
Authors: Jorge E. Cortes, Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D. le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane F. Apperley, H. Jean Khoury, Moshe Talpaz, Daniel J. DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M. Rivera, Frank G. Haluska, François Guilhot, Michael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, Neil P. Shah, Hagop M. Kantarjian
Journal: Blood (2018)
Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma.
Authors: Reinhard Dummer, Ana María Arance Fernández, Johan Hansson, James M. G. Larkin, Georgina V. Long, Eduard Gasal, Mathilde Kaper, Allison Upalawanna, Bijoyesh Mookerjee, Victoria Atkinson
Journal: Journal of Clinical Oncology (2018)

189 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT &gt; 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in &gt; 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in &gt; 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.
A Critical Need for Better Cancer Immunotherapy Models: Are Organotypic Tumor Spheroid Cultures the Answer?
Authors: Justin M. Balko, Jeffrey A. Sosman
Journal: Cancer Discovery (2018)

Abstract Summary: Immunotherapy has transformed the therapeutic landscape of cancer, but the preclinical evaluation of combination approaches that will deepen and broaden its clinical benefit has lagged far behind due to the lack of expedient and easily accessible ex vivo human systems. In this issue, Jenkins and colleagues and Deng and colleagues report the use of organotypic cultures of tumors derived from mice and humans containing both tumor cells and cells from their local immune microenvironment to recapitulate the in vivo use of immune checkpoint inhibitors and extend the application of this system to therapeutic combinations of immune checkpoint blockade and molecularly targeted agents. Cancer Discov; 8(2); 143–5. ©2018 AACR. See related article by Jenkins et al., p. 196. See related article by Deng et al., p. 216.
Concurrent deletion of <i>BRCA2</i> and <i>RB1</i> and aggressive prostate cancer.
Authors: Goutam Chakraborty, Joshua Armenia, Ying Zhang Mazzu, Gouri Nanjangud, Kalyani Chadalavada, Mohammad Omar Atiq, Kazumasa Komura, Yuki Yoshikawa, Nabeela Khan, Shin-Yi Du, Gwo-Shu Mary Lee, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2018)

241 Background: Pathogenic variants of BRCA2 have been observed in a substantial subset of men with metastatic castration resistance prostate cancer (mCRPC). Prostate cancer (PC) patients with germline mutations of BRCA2 experience more rapid progression of their localized PC to mCRPC. This stands in contrast to other cancers where BRCA2 alterations do not appear to be associated with a worse prognosis. We identified homozygous and hemizygous deletions of BRCA2 in a subset of primary PC, which had been previously unrecognized. BRCA2 deletion in PC more frequently co-exists with RB1 deletion rather than alone. BRCA2-RB1 co-deletion in primary PC (TCGA and Taylor cohort) is associated with a shorter disease free survival and increased genomic instability in patients, indicating that BRCA2-RB1 null tumors are likely very aggressive in nature. Methods: To determine the underlying molecular and genomic consequences of BRCA2- RB1 loss, we CRISPR/shRNA-out these genes from human PC cell lines and subjected them to various in vitro assays, RNA-seq and kinase arrays. We applied a 3-color FISH assay to identify the deletion of BRCA2 and RB1 in PC. Results: BRCA2-RB1 null LNCaP cells exhibit androgen independence as evidenced by relative resistance to enzalutamide, and increased growth in absence of androgen but show enhanced sensitivity towards PARPi or platinum. Moreover, the null cell induces an aggressive EMT like phenotype, which is associated with enhanced migration and invasion. RNA-seq and array results show significant activation of EMT related signaling pathways including an unexpected activation of WNK1 upon co-deletion of BRCA2-RB1. FISH assay revealed significant co-deletion of BRCA2-RB1 in ADT resistant aggressive PC tumor cells. More importantly these cells also show greater sensitivity towards PARPi or platinum. Conclusions: Our finding suggests that concurrent deletion of BRCA2-RB1 is most likely is a driver of therapy resistant aggressive PC rather than the consequence of exposure to therapy. We propose that screening for BRCA2-RB1 deletion early could be implemented to identify those at highest risk of aggressive PC and provide an opportunity for early intervention and alternative treatments.
I am about to start a staff grade job in genitourinary medicine—any suggestions as to which books I should read or which courses I should attend? Do I have to have MRCOG or MRCP to get a certificate of completion of specialist training (CCST) in genitourinary medicine?
Authors: Alison Bigrigg
Journal: BMJ (2004)

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.
Esthetic evaluation and patient‐centered outcomes in single‐tooth implant rehabilitation in the esthetic area
Authors: Martina Stefanini, Pietro Felice, Claudio Mazzotti, Ilham Mounssif, Matteo Marzadori, Giovanni Zucchelli
Journal: Periodontology 2000 (2018)

Abstract Criteria for successful implants, in the rehabilitation of a single missing tooth in the esthetic area, should be determined by composite outcomes, including functional and esthetic aspects of soft tissues and the reconstruction, as well as patient‐reported outcomes. This paper focuses on current methods in esthetic assessment and patient‐centered/reported outcomes in single‐tooth implant rehabilitation in the esthetic area. The relationship between subjective, patient‐based esthetic evaluations and objective, professional‐based esthetic evaluations is reviewed. In spite of increasing interest in the assessment of ‘success’ in implant dentistry, it is not yet possible to provide evidence‐based conclusions because of the lack of consensus on a universal implant‐supported crown esthetic index. There is also a need to standardize reporting of patient‐centered outcomes in partially edentulous patients treated with implants.
Classic or simplified LV5FU2 regimen: Multivariate analysis from a phase III study in metastatic colorectal cancer in elderly patients.
Authors: Jean-Louis Legoux, Thomas Aparicio, Emilie Maillard, Jean Marc Phelip, Jean-Louis Jouve, Christophe Locher, Pierre Michel, Thierry Lecomte, Olivier Bouche, Laurent Bedenne
Journal: Journal of Clinical Oncology (2017)

3550 Background: In the early 2000s, classic LV5FU2 (C) (folinic acid, 5FU bolus, then 5FU infusion on D1 and D2) was replaced with simplified LV5FU2 (S) (folinic acid and 5FU bolus on D1 only), considered as effective and less toxic. No trial proved this assertion. The LV5FU2 companion in the FOLFIRI or FOLFOX regimen was C or S. The FFCD 2001-02 study compared in a 2 x 2 factorial design, in not-pretreated elderly patients (75+) with metastatic colorectal cancer, C or S, with or without irinotecan. No significant differences in PFS and OS were observed in the comparison with or without irinotecan. The median OS was 15.2 months in C versus 11.4 months in S, HR = 0.71 (0.55–0.92) and objective response rate was 37.1% in C vs S 25.6% in S, p = 0.004. The aim of this study was to present the factors associated with these differences. Methods: Prognostic factors associated with OS were studied using a Cox model. The multivariate analysis used the significantly different items from the univariate analysis and the differences observed at the inclusion. For each of these items, a subgroup analysis was performed. The second- and third-line treatments were analysed. Results: The 282 patients from the intent-to-treat study were included in the model. In OS, the prognostic factors were C versus S, number of metastatic sites, alkaline phosphatases (AP) and CEA. The interaction test in each subgroup for OS was not significant but C was significantly better in the following subgroup: age &gt; 80 years, male, Karnofsky 100%, 1-2 Charlson index, AP ≤ 2N, leucocyte count &gt; 11,000, CEA &gt; 2N, CA 19-9 ≤2N. No differences were observed in the NCI toxicities but 130 serious adverse events in S versus 102 in C. A second-line was used for 55% patients in C, 46% in S, 81% of them with oxaliplatin or irinotecan in C, 76% after S. The third-line administration (20%) and targeted therapy (15%) were similar in C and S. Conclusions: C-LV5FU2 was superior both in subgroups with better and lower prognostics and this difference cannot be explained by an imbalance between the populations. The toxicity was not higher and a second-line was more often possible after C. The switch from C to S without scientific proof was perhaps a mistake in our practices. Clinical trial information: NCT00303771.
ECG-DERIVED VENTRICULAR GADIENT OUTPERFORMS ECHO IN THE EARLY DETECTION OF PULMONARY HYPERTENSION IN PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: Fleur Meijer, P. Kies, Monique Jongbloed, Cees Swenne, Suzanne van Wijngaarden, Jeska de Vries, Hubert Vliegen
Journal: Journal of the American College of Cardiology (2018)
Abstract PL2: Advances in the understanding and the applications of mutational signatures in human cells
Authors: S Nik-Zainal
Journal: Cancer Research (2018)

Abstract A cancer genome is an historical account of the mutagenic activity that has occurred throughout the development of the tumour. Indeed, every mutation matters. While driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically informative. We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers. Recently, the intellectual framework of mutational signatures was extended to include six novel rearrangement signatures. Exploring this in &amp;gt;2,500 whole genome sequenced tumours of multiple tumour types, reveals how our early (and rather simplistic) thinking of mutational signatures, requires critical re-evaluation. There are more nuances than previously appreciated. Diving into the detail of individual mutational signatures, we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the landscape of cancer genomes. In some instances, our findings invite more thoughtful consideration of that relatively binary distinction between drivers and passengers. Furthermore, we demonstrate why our whole genome profiling methods could assist in taking things to a clinical level, with mutational signatures forming an additional weapon in the arsenal of cancer diagnostics and therapeutic stratification, in the modern war against cancer. Finally, we validate cancer mutational signatures using cell-based model systems and arrive at new realisations (unpublished). This powerful approach (humbles the analyst and) emphasises how biological exploration of big data still relies indispensably on experimental work to truly advance understanding. Citation Format: Nik-Zainal S. Advances in the understanding and the applications of mutational signatures in human cells [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 PL2.
Neuroanatomy operative approaches (part I)
Authors: Andrew Alalade
Journal: BMJ (2012)

This course deals with the commoner neurosurgical cranial approaches and the associated anatomy.

The course is aimed primarily at ST3 to ST5 trainees in neurosurgery. It is of great benefit to anyone performing cranial procedures and serves as a good update session in neuroanatomy. Part I of the course takes place in September and part II in February each year.

The course is run by the Department of Neurosurgery at the General Infirmary in Leeds. It is usually held in the Worsley Building of the University of Leeds.

I did this course to improve my surgical technique …
Nadir testosterone (T) following in-situ polymer delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).
Authors: Przemyslaw Twardowski, John A. McLane, Stuart Atkinson, Debbie Boldt-Houle, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2018)

204 Background: Achieving and maintaining T suppression to castration level is the cornerstone of androgen deprivation therapy (ADT) for advanced PCa. Modern assay methodology found median T level after surgical castration to be 15ng/dL; the 2016 European Association of Urology guidelines define castration as T &lt; 20ng/dL. Additionally, reaching nadir T &lt; 20ng/dL is correlated with improved duration of response to ADT, time to progression or disease-specific survival (Klotz 2015), and prognosis for overall survival (Kamada 2015). To examine the effectiveness of in-situ polymer-delivered, subcutaneously-administered leuprolide acetate (SC-LA) on T suppression, nadir T was evaluated in 4 pivotal trials. Methods: Eugonadal patients with advanced PCa were treated with either 7.5 (6 doses), 22.5, 30, or 45mg (2 doses each) SC-LA lasting 1, 3, 4, or 6 months, respectively in 4 open-label, fixed-dose, pivotal trials. Serum T levels were evaluated byradioimmunoassay. T was measured 2-4 times on day 0 and once on days 1, 3, 7, and every week until the next dose, and repeated until end of study. The 45mg group had an additional measurement on day 2. LA was measured on days 0, 4, 7, 14, 21, 28, 35, 42, 49, and 56 post-injection. Nadir T was the lowest value obtained in the entire trial. Results: Across the SC-LA formulations, median LA levels were consistently between 0.1-1ng/mL from week 2 until the end of study. When pooled, 90-96% of patients achieved T≤20ng/dL by week 6 and 90-97% maintained T≤20ng/dL from weeks 6-24. Pooled analysis (n = 437) showed 99%, 97%, 91%, and 80% of patients reached nadir T≤20ng/dL, ≤10ng/dL, ≤5ng/dL, and ≤3ng/dL respectively with a median nadir T≤3 ng/dL. When comparing across all doses, &gt; 88% of patients reached nadir T≤5ng/dL. Conclusions: Across all doses, SC-LA achieves consistent and prolonged serum LA drug delivery above 0.1ng/mL and provides favorable T suppression &lt; 20ng/dL, which may be attributed to the in-situ forming polymeric delivery system. Multiple T measurements throughout the study confirmed that 91% of PCa patients achieved low nadir T≤5ng/dL, which may have implications for extending progression-free survival and duration of response to ADT.
Government rebuffs BMA’s offer of dispute resolution over junior doctor contract
Authors: Abi Rimmer
Journal: BMJ (2015)

The government has rebuffed the BMA’s offer of dispute resolution to resolve the dispute over the junior doctors’ contract in England, saying that such resolution should happen only after further negotiation. 

On Thursday 19 November the BMA announced that 98% of junior doctors had voted in favour of strike action over plans to change their contract in England.1 The association said that it …
Two thirds of public support junior doctors in contract dispute, poll finds
Authors: Abi Rimmer
Journal: BMJ (2016)

Two thirds (66%) of the public support the junior doctors’ strike on Wednesday 10 February, a survey by Ipsos MORI and the Health Service Journal has found.

The survey of 847 adults in England also found that support for the planned strike was at the same level as it was when junior doctors last took action on Tuesday 12 January, while the proportion strongly supporting junior doctors rose by …