tbuckley/cabot-search huggingface dataset:
Trauma courses with cadaver dissections
Authors: Surjit Lidder
Journal: BMJ (2009)

Many junior surgical trainees find it difficult to gain sufficient experience in operative techniques because of the restructuring of working days following the introduction of the European Working Time Directive. Often orthopaedic courses offer dry bone teaching, and only a few cadaveric courses allow the surgeon to appreciate both soft tissue handling and planes of dissection. The trauma courses with cadaver dissections, run by the AO Foundation, offer a great opportunity for trainees. 

The series of courses on cadaveric approaches and osteosynthesis are held in Graz, Austria, in English during September. Although the courses are primarily for trauma and orthopaedic surgeons, the hand course is also valuable for plastic and hand surgeons.

The principles in operative fracture treatment course is an introductory workshop …
Augmented Th17 Differentiation Leads to Cutaneous and Synovio‐Entheseal Inflammation in a Novel Model of Psoriatic Arthritis
Authors: Lu Yang, Melania H. Fanok, Aranzazu Mediero‐Munoz, Laura K. Fogli, Carmen Corciulo, Shahla Abdollahi, Bruce N. Cronstein, Jose U. Scher, Sergei B. Koralov
Journal: Arthritis & Rheumatology (2018)

Objective To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3C stopfl/fl CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. Methods We characterized a novel murine model of Th17‐driven cutaneous and synovio‐entheseal disease directed by T cell–specific expression of a hyperactive Stat3 allele. By crossing R26Stat3C stopfl/fl CD4Cre mice onto an interleukin‐22 (IL‐22)–knockout background or treating the mice with a neutralizing antibody against IL‐17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. Results R26Stat3C stopfl/fl CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell–specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL‐producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL‐17 or IL‐22 improved both the skin and bone phenotype in R26Stat3C stopfl/fl CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. Conclusion Perturbation of the IL‐23/Th17 axis instigates Th17‐mediated inflammation in R26Stat3C stopfl/fl CD4Cre mice, leading to cutaneous and synovio‐entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL‐17A and IL‐22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA.
Safety and antitumor activity of ramucirumab plus pembrolizumab in treatment naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: Preliminary results from a multi-disease phase I study (JVDF).
Authors: Ian Chau, Nicolas Penel, Hendrik-Tobias Arkenau, Rafael Santana-Davila, Emiliano Calvo, Andres O. Soriano, Gu Mi, Jin Jin, David Ferry, Roy S. Herbst, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2018)

101 Background: Preclinical evidence suggests simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) and programed cell death 1 protein (PD-1) induces synergistic antitumor effects. We assessed safety and preliminary efficacy of ramucirumab (anti-VEGFR-2) plus pembrolizumab (anti-PD-1) in patients (pts) with treatment naïve advanced G/GEJ adenocarcinoma. Methods: This ongoing, multi-cohort, phase 1a/b trial enrolled ECOG PS 0-1 pts with treatment naïve advanced G/GEJ adenocarcinoma with measurable disease and baseline tumor tissue. PD-L1 status was assessed by DAKO PD-L1 22C3 IHC pharmDx assay using the combined positive score with ≥1% being positive. Ramucirumab was administered at 8 mg/kg on Days 1 &amp; 8 with pembrolizumab 200 mg on Day 1 q3W. Primary objective was safety and tolerability of study treatment; preliminary efficacy was examined. Results: As of 31-July-2017, 28 treatment naïve G/GEJ adenocarcinoma pts were treated. Median age was 63 y, 75% male, 57% had ECOG PS of 0, and 68% were PD-L1 positive. At data cutoff, 8 (28%) pts continued to receive study treatment. Median duration of follow-up was 8.1 mo (IQR 6-10). Median treatment duration was 4.3 mo (IQR 2-7). All grades treatment-related adverse events (TRAEs) occurred in 27 (96%) of patients; TRAEs in ≥15% of pts were fatigue (36%), hypertension (25%) and headache (18%). Seventeen (61%) pts experience grade 3 TRAEs, most commonly hypertension (14%), diarrhea (11%), and elevated alanine (7%) or aspartate (7%) aminotransferase. No grade 4-5 TRAEs occurred. An objective response was achieved by 7 (25%) pts, 6 positive and 1 negative for PD-L1. Disease control rate was 68%. Median time to response was 2.7 mo (95% CI 1.3-2.8) and median duration of response was 10 mo (95% CI 9.7-10.3). Median progression-free survival was 5.3 mo (95% CI 3.2-11). Median overall survival has not been reached. Conclusions: Ramucirumab plus pembrolizumab demonstrated encouraging antitumor activity in treatment naïve advanced G/GEJ adenocarcinoma with no grade 4 TRAE observed. Clinical trial information: NCT02443324.
Mortality Reduction in EMPA-REG OUTCOME Trial: Beyond the Antidiabetes Effect
Authors: Samy Suissa
Journal: Diabetes Care (2018)

Two recent large-scale cardiovascular outcome trials, a now common tool in assessing the safety of pharmacological treatments for type 2 diabetes, reported significant reductions in all-cause mortality. In EMPA-REG OUTCOME [BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients], patients who received the SGLT2 inhibitor empagliflozin had a notable reduction of 9.2 deaths per 1,000 per year, while LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation) found that the patients receiving the GLP-1 receptor agonist liraglutide had a reduction of 3.7 deaths per 1,000 per year. The hypotheses to explain the sizable mortality reduction in EMPA-REG OUTCOME have mainly focused on the potential cardiovascular mechanisms of empagliflozin, but none considered its expected antidiabetes effects. I estimated the portion of the reduction in mortality observed in EMPA-REG OUTCOME expected to be a result of its antidiabetes effects, as measured by glycemic control and the need for additional antidiabetes medication, and contrasted it with LEADER. With use of the mean 0.45% reduction in HbA1c with empagliflozin compared with placebo in EMPA-REG OUTCOME, the rate reduction of 9.2 deaths per 1,000 per year would be expected to be at most 4.5 deaths per 1,000 per year, leaving 4.7 deaths per 1,000 per year otherwise explained. On the other hand, LEADER’s rate reduction of 3.7 deaths per 1,000 per year with liraglutide would be expected to be 3.5 by virtue of its effect on HbA1c, leaving 0.2 deaths per 1,000 per year explained otherwise. Similar results were found using the need for additional antidiabetes treatment during follow-up to measure the antidiabetes impact. In conclusion, the expected antidiabetes effects of empagliflozin and liraglutide on the reduction in mortality are important. However, empagliflozin appears to have significant additional effects on survival, possibly due to specific cardiovascular mechanisms, which merit further investigation.
Epigenetic modifiers as new immunomodulatory therapies in solid tumours
Authors: S. Aspeslagh, D. Morel, J.-C. Soria, S. Postel-Vinay
Journal: Annals of Oncology (2018)

BackgroundImmune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest.Material and methodsWe reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents. Experimental approaches, clinical applicability and corresponding ongoing clinical trials are described.ResultsSeveral epigenetic modifiers, such as histone deacetylase inhibitors, DNA methyl transferase inhibitors, bromodomain inhibitors, lysine-specific histone demethylase 1 inhibitors and enhancer of zeste homolog 2 inhibitors, display intrinsic immunomodulatory properties. The latter can be achieved through the action of these drugs either on cancer cells (e.g. presentation and generation of neoantigens, induction of immunogenic cell death, modulation of cytokine secretion), on immune cells (e.g. linage, differentiation, activation status and antitumor capability), or on components of the microenvironment (e.g. regulatory T cells and macrophages). Several promising combinations, notably with immune checkpoint blockers or adoptive T-cell therapy, can be envisioned. Dedicated clinically relevant approaches for patient selection and trial design will be required to optimally develop such combinations.ConclusionIn an era where immune therapies are becoming a treatment backbone in many tumour types, epigenetic modifiers could play a crucial role in modulating tumours' immunogenicity and sensitivity to immune agents. Optimal trial design, including window of opportunity trials, will be key in the success of this approach, and clinical evaluation is ongoing.
IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer
Authors: Weizhi He, Jinghua Wu, Juanjuan Shi, Yan-Miao Huo, Wentao Dai, Jing Geng, Ping Lu, Min-Wei Yang, Yuan Fang, Wei Wang, Zhi-Gang Zhang, Aida Habtezion, Yong-Wei Sun, Jing Xue
Journal: Cancer Research (2018)

Abstract Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell–related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1. Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293–305. ©2018 AACR.
Turkish National Colon Cancer Registry.
Authors: Mustafa Benekli, Esra Dumanli, Saadettin Kilickap, Dogan Uncu, Mehmet Aliustaoglu, Irfan Cicin, Mahmut Gumus, Metin Ozkan, Murat Kocer, Aziz Karaoglu, Faysal Dane, Abdurrahman Isikdogan, Tamer Elkiran, Bulent Yalcin, Mukremin Uysal, Berna Oksuzoglu, Melih Cem Boruban, Arife Ulas, Huseyin Abali, Suleyman Buyukberber
Journal: Journal of Clinical Oncology (2015)

e12646 Background: Colorectal cancers (CRC) have become the 3rd most common cancer in Turkey with increasing incidence over the years. Studies investigating the clinical and biologic features of CRC Turkey are small retrospective case series providing limited information. We initiated a Turkish National CRC Registry program in October 2012 to define clinical and pathological variables of CRC. Methods: Pts presenting to medical oncology clinics were prospectively registered in 28 centers nationwide. Pt demographics and clinicopathological characteristics were recorded. Results: 6143 pts (mean age 58.2±12.3) were analyzed (57% males). Mean ages of males were higher (59 vs 57 yrs, p = 0.001). Adenocarcinoma was the most common histology (97.8%). Initial stages at diagnosis: I (5.4%), II (29.6%), III (33.8%) and IV (20.2%), unknown (9.8%). Pts from Eastern Turkey were younger (56 vs 59, p < 0.001) with a more advanced stage (metastatic pts, 26.5% vs 18.4%). T stage was unknown in 22%, and T3 (46%) and T4 (20%) tumors were most commonly observed. Median number of examined and involved lymph nodes were 14 (1-148) and 1, respectively. Lymphovascular and perineural invasion were present in 27.7% and 21.2%. Most common tumor sites were rectum (35%), and sigmoid (24%). Surgery was done in 85.4%: hemi/partial colectomy (35%), LAR (34%), APR (4.6%), total colectomy (3.6%). Metastasectomy was done in 16.9% with R0 resection in 15.9%. Adjuvant chemo was given to 66.3% of nonmetastatic patients with fluoropyrimidines and oxaliplatin-based regimens. 10.8% pts received neoadjuvant chemoradiotherapy. 33% pts had metastasis (at diagnosis or recurrent disease): liver (62%), lung (26%) and others. Metastatic pts received chemo in combination with bevacizumab in 53.5%. KRAS was available in 41% and BRAF in 3% of metastatic pts. Of these, 61% were KRAS wild-type and 20% BRAF mutant. Cetuximab in first-line was rare (3.7% total, 16% of KRAS wild-type). Conclusions: This study is the first comprehensive CRC registry in Turkey. Pt demographics were similar to Western countries including molecular studies. However, molecular testing was not readily available in most of the metastatic cases. A low rate of biologicals use in combination therapies in metastatic pts may result in inferior pt outcome overall.
A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study.
Authors: Eileen Mary O'Reilly, Do-Youn Oh, Neesha Dhani, Daniel John Renouf, Myung Ah Lee, Weijing Sun, George A. Fisher, Aram F. Hezel, Shao-Chun Chang, Gordana Vlahovic, Osamu Takahashi, Yin Yang, Philip Agop Philip
Journal: Journal of Clinical Oncology (2018)

217 Background: Durvalumab (D) and tremelimumab (T), monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, have shown efficacy as monotherapy/combination therapy in multiple cancer types. Herein, we report a randomized phase 2 study to evaluate efficacy and safety of D monotherapy with or without T (D+T) in previously treated mPDAC. Methods: Part A was a lead-in safety and signal-seeking study with plans to expand to Part B as a nonrandomized or randomized controlled study pending efficacy signal. Eligible pts had progressive disease (PD) following front-line 5-FU- or gemcitabine-based therapy. In Part A, pts were randomized to D (1.5 g IV Q4W) or D+T (D 1.5 g IV + T 75 mg IV Q4W × 4 doses → D 1.5 g IV Q4W) for up to 12 months (mo) or until confirmed PD or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate per RECIST 1.1. Results: In Part A, 65 pts were randomized to D (n = 33) or D+T (n = 32). Due to a pretreatment death, 64 pts received therapy. Eleven pts (34.4%) in D+T and 10 (31.3%) in D had treatment-related adverse events (trAEs); 7 (22%) in D+T and 2 (6%) in D had grade ≥3 trAEs. Common trAEs: fatigue (12.5%), diarrhea (12.5%), and hypothyroidism (9.4%) in D+T; fatigue (9.4%), diarrhea (6.3%), and pruritus (6.3%) in D. Grade ≥3 trAEs were diarrhea (9.4%), fatigue (6.3%) in D+T and ascites (3.1%), hepatitis (3.1%), and increased lipase (3.1%) in D. In D+T, 3 (9.4%) pts and 1 (3.1%) in D discontinued therapy due to trAEs. No trAEs resulted in death. In D+T, 1 (3.1%) pt had a durable confirmed partial response (PR) &gt; 12 mo and disease control rate (DCR) was 9.4%. In D, 2 (6.1%) pts had unconfirmed PRs, and the DCR was 6.1%. Median PFS in both arms was 1.5 mo, and median OS was 3.1 mo in D+T and 3.6 mo in D. Biomarker analyses (tumor mutation burden, PD-L1 and microsatellite status) are currently being evaluated. Conclusions: Typical safety profiles were observed for D or D+T in mPDAC. Part B was not enrolled as the threshold for efficacy was not met in Part A. D and D+T had modest activity in second-line non-selected mPDAC, underpinning the need for multimodal immune-based combinations to overcome intrinsic resistance in this disease. Clinical trial information: NCT02558894.
HUMAN EPIDIDYMIS PROTEIN 4 IS A NOVEL FIBROSIS MARKER TO PREDICT PATHOLOGICAL CARDIAC REMODELING AND ADVERSE OUTCOMES IN PATIENTS WITH DILATED CARDIOMYOPATHY
Authors: Masahiro Yamamoto, Shinsuke Hanatani, Ishida Toshifumi, Yamamura Satoru, Hirakawa Kyoko, Seiji Takashio, Yasuhiro Izumiya, Kenichi Tsujita
Journal: Journal of the American College of Cardiology (2018)
BMA to explain junior doctor contract details through June road shows
Authors: Tom Moberly
Journal: BMJ (2016)

Details of the new contract deal will be explained to junior doctors in a series of road shows that the BMA will be holding across England in early June.

The full terms and conditions of the new contract will be published on 31 May, alongside an equality impact assessment of the revised agreement. Junior doctors will be balloted on whether to accept the new contract between 17 June and 1 July.

The BMA will be seeking to persuade junior doctors to vote to accept the deal agreed with the government …
Review of Jonathan Ives, Michael Dunn, and Alan Cribb, eds.,<i>Empirical Bioethics: Theoretical and Practical Perspectives</i><sup>1</sup>
Authors: Silvia Camporesi
Journal: The American Journal of Bioethics (2018)

Edited by Jonathan Ives (University of Bristol), Michael Dunn (University of Oxford), and Alan Cribb (King's College London), Empirical Bioethics is the first book systematically tackling the epist...
Placenta‐on‐a‐Chip: Placental Drug Transport‐on‐a‐Chip: A Microengineered In Vitro Model of Transporter‐Mediated Drug Efflux in the Human Placental Barrier (Adv. Healthcare Mater. 2/2018)
Authors: Cassidy Blundell, Yoon‐Suk Yi, Lin Ma, Emily R. Tess, Megan J. Farrell, Andrei Georgescu, Lauren M. Aleksunes, Dongeun Huh
Journal: Advanced Healthcare Materials (2018)

In article number 1700786, Dongeun Huh and co-workers present a micro-engineered model of the human placental barrier for investigation of maternal–fetal drug transfer in pregnancy. The placenta-on-a-chip system reconstitutes efflux transporter-mediated transport of a test compound, demonstrating proof-of-principle for use as a screening platform for prediction of drug transport in pregnancy.
Phase II study of eribulin mesylate as first- or second-line therapy for metastatic HER2-negative breast cancer.
Authors: Mitsuhiko Iwamoto, Nayuko Sato, Risa Terasawa, Hiroya Fujioka, Yuko Takahashi, Kosei Kimura, Satoru Tanaka, Kazuhisa Uchiyama
Journal: Journal of Clinical Oncology (2013)

TPS1140 Background: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor that is approved in patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens (including an anthracycline and a taxane) for metastatic breast cancer. In a previous phase III study, eribulin mesylate demonstrated to significant improvement in overall survival in patients with heavily pretreated, locally recurrent or metastatic breast cancer when compared to treatment of physician’s choice. The majority of patients were HER2-negative and all had previously failed 2 or more regimens. Overall, the tolerability and positive phase III findings in this patient population suggest eribulin mesylate may provide a treatment advantage when given earlier in the course of therapy for HER2-negative, metastatic breast cancer. Methods: This study is phase II, multicenter, open-label, single-arm in patients with HER2-negative metastatic breast cancer who have been treated with chemotherapeutic regimens including an antheracycline and a taxane. Eribulin mesylate (1.4mg/m 2 ) will be given on days 1 and 8 of each 21-day cycle. The primary endpoint is objective response rate, and secondary endpoints include duration of response, progression-free survival, overall survival, the safety of the treatment, and quality of life. Eligibility Criteria: Patients must have confirmed HER2-negative metastatic breast cancer with at least 4 weeks since prior neoadjuvant or adjuvant chemotherapy, and have not received over 2 chemotherapeutic regimens for metastatic disease. Additional eligibility criteria include adequate performance status (ECOG PS:0-2) and end organ/marrow function, and ejection fraction &gt; 50%. Accrual: This study began in December 2012. The expected end of accrual of 35 patients will be the last quarter 2015.
GLOBAL RANK ENDPOINT USING NT-PROBNP VERSUS 6 MINUTE WALK DISTANCE IN HF PATIENTS: ANALYSIS FROM THE CAT-HF TRIAL
Authors: JoAnn Lindenfeld, Olaf Oldenburg, David Whellan, Mona Fiuzat, Naresh Punjabi, Dalane Kitzman, Amy Blase, Adam Benjafield
Journal: Journal of the American College of Cardiology (2018)
Risk and Prognosis of Cancer After Lower Limb Arterial Thrombosis
Authors: Jens Sundbøll, Katalin Veres, Erzsébet Horváth-Puhó, Kasper Adelborg, Henrik Toft Sørensen
Journal: Circulation (2018)

Venous thromboembolism can be a presenting symptom of cancer, but the association between lower limb arterial thrombosis and cancer is unknown. We therefore examined cancer risk and prognosis of cancer in patients with lower limb arterial thrombosis.Using nationwide population-based Danish medical registries, we identified all patients diagnosed with first-time lower limb arterial thrombosis (1994-2013) and followed them until the occurrence of any subsequent cancer diagnosis, emigration, death, or November 30, 2013, whichever came first. We computed standardized incidence ratios with 95% confidence intervals as the observed number of cancers relative to the expected number based on national incidence rates by sex, age, and calendar year. To examine the prognostic impact of lower limb arterial thrombosis on all-cause mortality after cancer, we constructed a matched comparison cohort of patients who had cancer without lower limb arterial thrombosis.Among 6600 patients with lower limb arterial thrombosis, we observed 772 subsequent cancers. The risk of any cancer was 2.5% after 6 months of follow-up, increasing to 17.9% after 20 years. During the first 6 months of follow-up, the standardized incidence ratio of any cancer was 3.28 (95% confidence interval, 2.79-3.82). The standardized incidence ratio remained elevated during 7 to 12 months (1.42; 95% confidence interval, 1.09-1.83) and beyond 12 months (1.14; 95% confidence interval, 1.05-1.24). The strongest associations were found for lung cancer and other smoking-related cancers. Lower limb arterial thrombosis also was associated with increased all-cause mortality after colon, lung, urinary bladder, and breast cancer, but not after prostate cancer.Lower limb arterial thrombosis was a marker of occult cancer, especially lung cancer, and was an adverse prognostic factor for mortality in common cancers.
A third of psychiatry core training posts are vacant after round one of specialty recruitment
Authors: Helen Jaques
Journal: BMJ (2011)

Only 61% of core training posts in psychiatry for 2011 have been filled by the first round of specialty recruitment, despite the Royal College of Psychiatrists extending the application window by almost a month.

Fill rates around the country vary considerably, with some regions such as the north west having a rate as low as 39% of psychiatry posts filled.

At the close of the first round on 20 December 2010 there were only 0.7 applicants for every core training position in psychiatry, although this rose to 1.2 after the Royal College of Psychiatrists extended the application window to 14 January. 

The overall competition ratio for …