tbuckley/cabot-search huggingface dataset:
Abstract P3-05-12: VISTA expression on tumor-infiltrating lymphocytes in breast cancer: Clinical correlates and association with PD-1
Authors: S Burugu, D Gao, TO Nielsen
Journal: Cancer Research (2018)

Abstract Background: The V-domain containing Ig Suppressor of T Cell Activation (VISTA) is a recently discovered immune checkpoint receptor with homology to PD-1. VISTA expression on tumor-infiltrating lymphocytes (TILs) blocks their proliferation and effector functions. Recent pre-clinical data in cancer mouse models treated with anti-VISTA and anti-PD-L1 combinations showed promising results and non-redundant functions of VISTA and PD-L1 blockade. However, the expression and prognostic value of VISTA+ TILs in primary breast tumors has not been investigated in detail. Here we assess expression, prognostic value, and associations of VISTA+TILs with other immune checkpoint markers (PD-1/PD-L1, LAG-3, and IDO-1) and with H&amp;E TIL counts. Methods: A tissue microarray consisting of breast carcinoma primary excision specimens (n=330) from the University of British Columbia hospital, linked to detailed clinicopathological data and outcomes, was used in this study. Patients from this cohort did not receive neoadjuvant treatment. A VISTA antibody (Clone D1L2G) was applied on a 4μm section of the tissue microarray by immunohistochemistry using a Ventana automated stainer. VISTA+TILs in direct contact with tumor nest were scored and reported as absolute count per 0.6mm core. Positive cases were defined as cases with VISTA+TILs≥1. All descriptive and survival analyses were conducted using SPSS software. Results: VISTA+TILs were present in 30% of cases and were significantly (p&amp;lt;0.05) associated with younger age (&amp;lt;50 years old), larger tumors (&amp;gt;2cm), hormone receptor negativity (ER/PR) and high Ki67proliferation index (≥13.25%). Almost half (48%) of basal-like breast cancers were positive for VISTA expressing TILs. No significant prognostic associations were observed in this cohort. Among the immune checkpoint receptors analyzed, VISTA+TILs were highly associated with PD-1+ TILs: 79% of cases positive for PD-1+TILs were also infiltrated by VISTA+TILs. Interestingly, we found that VISTA+TILs and PD-1+TILs were enriched in cases with otherwise low levels (&amp;lt;10%) of H&amp;E TILs. Conclusions: Our study identifies the presence of VISTA+TILs in breast cancer patients and its strong association with PD-1+TILs. These results suggest that VISTA blockade could be a good candidate for combination therapy with other immune checkpoint inhibitors, a concept being tested in early phase clinical trials. Validation of these findings in a larger independent cohort powered for multivariate analysis is currently ongoing. Citation Format: Burugu S, Gao D, Nielsen TO. VISTA expression on tumor-infiltrating lymphocytes in breast cancer: Clinical correlates and association with PD-1 [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 P3-05-12.
The global Optima HIV allocative efficiency model: targeting resources in efforts to end AIDS
Authors: Sherrie L Kelly, Rowan Martin-Hughes, Robyn M Stuart, Xiao F Yap, David J Kedziora, Kelsey L Grantham, S Azfar Hussain, Iyanoosh Reporter, Andrew J Shattock, Laura Grobicki, Hassan Haghparast-Bidgoli, Jolene Skordis-Worrall, Zofia Baranczuk, Olivia Keiser, Janne Estill, Janka Petravic, Richard T Gray, Clemens J Benedikt, Nicole Fraser, Marelize Gorgens, David Wilson, Cliff C Kerr, David P Wilson
Journal: The Lancet HIV (2018)
Major depression prevalence among Syrian migrants seeking asylum in Greece: a cross-sectional survey
Authors: Danielle Poole, Bethany Hedt-Gauthier, Nathaniel Raymond, Till Bärnighausen
Journal: The Lancet Global Health (2018)

BackgroundSince the start of the Syrian war in 2011, 250 000 Syrians have sought asylum in Greece, and more than 1 million people have attempted to reach other countries in the European Union by travel through Greece. Migrants face a myriad of poor mental health outcomes, including major depression requiring treatment. However, the prevalence of major depression among Syrians undergoing the asylum process—a potential window for intervention—has not been reported. This study quantified the prevalence of major depression among Syrian migrants in a refugee camp setting.MethodsWe did a cross-sectional survey via face-to-face interviews in a Syrian refugee camp in Greece from January 16–31, 2017. Individuals aged 18 years or older, residing in the refugee camp, and with verbal Arabic or English language skills were eligible to participate. The Patient Health Questionnaire-8 (PHQ-8) was used to evaluate depression. Sociodemographic and displacement data were collected using a standardised instrument. The study was approved by the Harvard T H Chan School of Public Health (Protocol IRB16-2015) and all participants provided oral informed consent.Findings135 surveys were completed, with a response rate of 97%, representing 38% of the adult population in the refugee camp. The mean age of participants was 31·4 years (range 18–61 years); 40·7% of the sample was female; 74·4% of the participants had ever married; and 67·2% had children. 33·4% of participants had not attended secondary school, including 11·4% who had never attended school. The median time spent in the asylum process in Greece was 10 months (<1–49 months). Major depression was detected in 43·7% (95% CI 37·2–50·4) of participants. 20·7% of participants reported no symptoms of depression, and 35·6% were found to have mild depression.InterpretationSyrian migrants face an extraordinarily high burden of major depression as they seek asylum. The high prevalence of major depression may be explained by the particular plight of fleeing the Syrian war, the social and physical conditions in the refugee camp, as well as the protracted asylum process—a period extending beyond 1 year in Greece since the adoption of the EU–Turkey Statement. The incorporation of screening and treatment into service provision within refugee camps is urgently needed, particularly in the context of delayed asylum procedures.FundingInternational Data Responsibility Group.
Inconsistent regulation threatens patient safety, researchers warn
Authors: Abi Rimmer
Journal: BMJ (2014)

A lack of consistency in the way doctors are regulated across Europe could have “significant implications” for the safety of patients, researchers have warned.

A study published in the International Journal for Quality in Health Care assessed how medical regulators managed professional issues involving quality and patient safety in the UK, Austria, Belgium, Estonia, Germany, Hungary, the Netherlands, Slovenia, and Spain. …
Junior doctors spend £17 114 on postgraduate training
Authors: Helen Jaques
Journal: BMJ (2011)

Junior doctors are spending on average £17 114, mostly of their own funds, on royal college, exam, and professional fees over the course of their postgraduate training, an analysis from the BMA shows.

Anaesthetics was the most expensive specialty, costing juniors £24 912 to train to certificate of completion of training (CCT) level, and general practice the cheapest, at £6825. Postgraduate training in acute medicine and gastroenterology was also particularly expensive, both at more than £20 000 in total.

When the figures were broken down into cost per year of training, anaesthetics was still the most expensive specialty, costing more than £3500 a year, followed closely by acute medicine and gastroenterology. Training as a GP cost more than …
Co-delivery nanoparticle to overcome metastasis promoted by insufficient chemotherapy
Authors: Qing Zhou, Yihui Li, Yanhong Zhu, Chan Yu, Haibo Jia, Binghao Bao, Hang Hu, Chen Xiao, Jianqi Zhang, Xiaofan Zeng, Ying Wan, Huibi Xu, Zifu Li, Xiangliang Yang
Journal: Journal of Controlled Release (2018)
Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum
Authors: Emanual Maverakis, Chelsea Ma, Kanade Shinkai, David Fiorentino, Jeffrey P. Callen, Uwe Wollina, Angelo Valerio Marzano, Daniel Wallach, Kyoungmi Kim, Courtney Schadt, Anthony Ormerod, Maxwell A. Fung, Andrea Steel, Forum Patel, Rosie Qin, Fiona Craig, Hywel C. Williams, Frank Powell, Alexander Merleev, Michelle Y. Cheng
Journal: JAMA Dermatology (2018)

Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a "diagnosis of exclusion," a definition not compatible with clinical decision making or inclusion for clinical trials.To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum.Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation.Delphi exercise yielded 1 major criterion-biopsy of ulcer edge demonstrating neutrophilic infiltrate-and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or "wrinkled paper" scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively.This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.
CHOLESTEROL CRYSTAL IS ASSOCIATED WITH 12-MONTH CARDIOVASCULAR EVENTS: AN OPTICAL COHERENCE TOMOGRAPHY STUDY
Authors: Kazuhiro Fujiyoshi, Yoshiyasu Minami, Kohki Ishida, Yusuke Muramatsu, Toshimitsu Sato, Ryota Kakizaki, Teruyoshi Nemoto, Takuya Hashimoto, Kentaro Meguro, Takao Shimohama, Taiki Tojo, Junya Ako
Journal: Journal of the American College of Cardiology (2018)
3.2% OF YOUNG SUBJECTS UNDER 45 YEARS WITH ACUTE MYOCARDIAL INFARCTION HAVE GENETICALLY VERIFIED FAMILIAL HYPERCHOLESTEROLEMIA
Authors: Kirsten Holven, Linn K.L. Øyri, Sigrun Halvorsen, Dan Atar, Trond Leren, Martin Bogsrud
Journal: Journal of the American College of Cardiology (2018)
TEMPORAL TRENDS IN THE UTILIZATION OF MECHANICAL CARDIAC SUPPORT (MCS) IN TRANSCATHETER AORTIC VALVE REPLACEMENT (TAVR): A NATIONWIDE INPATIENT SAMPLE ANALYSIS
Authors: Nikhil Nalluri, Varunsiri Atti, Varun Kumar, Nileshkumar Patel, Deepak Asti, Sushruth Edla, Sainath Gaddam, Samer Saouma, Emad Barsoum, Boutros Karam, Jonathan Spagnola, Mohammad Zgheib, Roman Royzman, Gregory Maniatis, Frank Tamburrino, Ruben Kandov, James Lafferty, Chad Kliger
Journal: Journal of the American College of Cardiology (2018)
Retrospective analysis of fatigue in men with metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Srikala S. Sridhar, Alan D. Smith, Nazanin Fallah-Rad, Aaron Richard Hansen
Journal: Journal of Clinical Oncology (2018)

374 Background: Enzalutamide (E) improves survival in men with metastatic castration-resistant prostate cancer (mCRPC). Fatigue (F) while taking E is poorly understood and may limit the use of this life-prolonging drug. Methods: All men treated with E for mCRPC at Princess Margaret Cancer Centre from August 2010 and July 2016 were included. Relevant factors collected, include age, ECOG, Charleston Comorbidity Index, disease characteristics, prior therapies, concomitant medications, and details regarding E treatment and response. Univariate (UVA) and multivariate (MVA) analysis were performed using logistic regression. Results: 415 men started E for mCRPC during this period. Median age at diagnosis was 66 years (range 42-94) and median time to castration-resistance (TTCR) was 113 days. Prior therapies included docetaxel (21%) and abiraterone (26%). Bone was the most common site of metastasis (76%) followed by lymph nodes (45%) and visceral (20%). Concurrent corticosteroid use was 18% and PSA response (≥50%) rate was 55%. Median duration on E was 224 days. F on E occurred in 178 patients (43%) and 56 (13%) men required a dose-reduction due to F. 26 men (6%) stopped E due to F (Table). Conclusions: F is an important and common side effect of E in men with mCRPC. Duration of exposure to androgen deprivation, markers of systemic inflammation (such as increased NLR and platelets) and advanced age appear to be associated with E-related F and difficulty administering drug. There was no association between corticosteroid use and E-related F and difficulty administering drug. [Table: see text]
Foundation programme will have unfilled places in 2017
Authors: Abi Rimmer
Journal: BMJ (2017)

The foundation training programme will be undersubscribed in 2017 and 63 posts will be cut in England, the UK Foundation Programme Office (UKFPO) has said.

The UKFPO said that when applications for the 2017 programme closed on Friday 14 October 2016, it had received 98 more applications than the number of places available. Using data on withdrawals from previous years, it predicted that the foundation training programme would be undersubscribed by 444 applicants at the point of allocation in March 2017.1

Before 2017, …
Anti-retroviral drugs: current state and development in the next decade
Authors: Xingquan Zhang
Journal: Acta Pharmaceutica Sinica B (2018)

The pace of discovery of new antiretroviral (ARV) drugs has slowed, although the efficacy and safety of once-daily fixed dose combinations have been extensively investigated. Several traditional ARV drugs remain in phase III clinical trials. This review summarizes current information on ARV drugs in phase III clinical trials and focuses on the development of ARV drugs in the next decade.
Effect of Plaque Burden and Morphology on Myocardial Blood Flow and Fractional Flow Reserve
Authors: Roel S. Driessen, Wijnand J. Stuijfzand, Pieter G. Raijmakers, Ibrahim Danad, James K. Min, Jonathon A. Leipsic, Amir Ahmadi, Jagat Narula, Peter M. van de Ven, Marc C. Huisman, Adriaan A. Lammertsma, Albert C. van Rossum, Niels van Royen, Paul Knaapen
Journal: Journal of the American College of Cardiology (2018)
Jury finds trainee GP not guilty of sexually assaulting five patients
Authors: Clare Dyer
Journal: BMJ (2018)

A trainee GP who was charged with sexually assaulting five female patients in 10 days while working at a practice in Dudley, West Midlands, has been acquitted on all counts.

Amirul Haque, 33, was found not guilty of five charges by a jury at Wolverhampton Crown Court after an 11 day trial.

All five women had accused him of pressing his groin against them during physical examinations for complaints that included earache, eye problems, and swollen ankles, said Philip Bradley QC, prosecuting. One patient complained that he had asked her to move her …
Phase I adoptive cellular therapy trial with ex-vivo stimulated autologous CD8+ T-cells against multiple targets (ACTolog IMA101) in patients with relapsed and/or refractory solid cancers.
Authors: Apostolia Maria Tsimberidou, Chad Stewart, Carsten Reinhardt, Hong Ma, Steffen Walter, Toni Weinschenk, Amir A. Jazaeri, Borje Andersson, Patrick Hwu, Cassian Yee, Harpreet Singh
Journal: Journal of Clinical Oncology (2018)

TPS77 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g. only one target is addressed), or iii) off-target toxicities (e.g. expression of targets on normal tissues). The ACTolog concept, utilizing antigen specific T cells (IMA101) against targets identified by the Immatics’ proprietary XPRESIDENT technology, is intended to overcome these limitations by addressing multiple novel relevant tumor antigens per patient. ACTolog is a personalized, multi-targeted ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Methods: This study is an open-label first-in-human phase I trial in patients with relapsed or refractory solid tumors expressing at least one target from a warehouse of 8 cancer targets. Key eligibility criteria include: HLA-A*02:01 phenotype, qPCR expression of warehouse target(s), prior established lines of therapy, RECIST v1.1 measurable lesions, and ECOG performance status 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells for manufacturing of IMA101 cells. Patients will receive their last line of established therapy during the production phase of IMA101. IMA101 will be infused after a pre-conditioning regimen (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and tolerability of IMA101. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objective is to assess the in vivo persistence and ex vivo functionality of transferred T cells in addition to evaluation of target expression in tumors. Enrollment to the study is currently ongoing. Clinical trial information: NCT02876510 .
Long-term results of organ preservation rate and progression risk in high-risk non-muscle-invasive bladder cancer (NMIBC) patients treated with radiofrequency-induced thermochemotherapy effect (RITE) with the Synergo system.
Authors: Jill-Isabel Kilb, Arne Hauptmann, Florian Wagenlehner, Gerson Luedecke
Journal: Journal of Clinical Oncology (2018)

456 Background: High risk NMIBC is a dangerous BC with a challenging treatment by BCG or early cystectomy to cure. The first has bad treatment tolerance and a remission of about 35%, whereas the last offer a curing perspective of 84% with extremely bad living conditions. RITE checked prospectively the therapy in respect to organ preservation, curing rate and risk of progression over 10 years in a single institution experience. Methods: All patients were EORTC high risk NMIBC. Treatment with induction phase: 8 treatments weekly with 2x40 mg Mitomycin C, 42°C intravesically induced by RITE. Followed by a re-resection of the bladder at week 11 to ensure complete remission and maintenance with treatments every 6 weeks with 2x20 mg Mitomycin C for 6 times. Cystoscopy controls were performed first 2 years every 3 month and following in 6 month until now. Study started in 2006 ongoing until today. Results: We enrolled 67 patients (4 female, 63 male), 65.7% Cis positive rate. 85% of the patients were treated alternatively to BCG with primary RITE whereas 15% were BCG failure patients treated alternatively to indicated cystectomy. Tumor persistence at week 11 after induction therapy proven by TURB was (10/67) 14.9% resulting in early cystectomy (4/10). Mean recurrence free time 3.5 years. In case of recurrence 10.4% progressed to MIBC including 6% metastatic tumors, high risk NMIBC was observed in 6% resulting in cystectomy and low risk NMIBC recurrence was 1.5% with organ preservation. BC death rate was 1 out of 67. Incomplete treatments induced by SAE of RITE was 9%. Bladder preservation rate was 80.6% with a long-lasting effectiveness ( &gt; 5 years) of 14/26 (53.8%). Conclusions: The RITE method is in short- and long-term manner a powerful procedure to cure and maintain a recurrence free BC status in high risk NMIBC with a very low risk for cystectomy and a minimal risk for systemic progression resulting in BC death. The organ preservation rate was achieved in 80.6% lasting for up to 11 years longest. RITE is an alternative to BCG and preferable to early cystectomy in high risk NMIBC.
From genetics to response to injury: vascular smooth muscle cells in aneurysms and dissections of the ascending aorta
Authors: Jean-Baptiste Michel, Guillaume Jondeau, Dianna M Milewicz
Journal: Cardiovascular Research (2018)

Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.