tbuckley/cabot-search huggingface dataset:
Development and validation of the mastocytosis activity score
Authors: F. Siebenhaar, B. Sander, L. H. T. Ho, A. Ellrich, M. Maurer, K. Weller
Journal: Allergy (2018)

Abstract Background Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific and validated instrument to measure and monitor signs and symptoms in patients with mastocytosis. Objective To develop and validate a disease‐specific tool to measure and monitor the activity of signs and symptoms in patients with mastocytosis, the Mastocytosis Activity Score (MAS). Methods Nineteen potential MAS items were developed in a combined approach consisting of semi‐structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients followed by a review for face validity. The resulting MAS was tested for validity, reliability and influence factors. In parallel, a US American English version of the MAS was developed. Results A total of 68 mastocytosis patients took part in the MAS validation study. The final 9‐item MAS was found to have a three‐domain structure (“skin,” “gastrointestinal tract” and “other”), a valid total score and an excellent test‐retest reliability. Multiple regression analysis revealed that disease duration, age or gender is not a significant determinant of the MAS results. Conclusions The MAS is a disease‐specific, valid and reliable patient‐reported outcome measure for adult patients with cutaneous and indolent systemic mastocytosis. It may serve as a valuable tool to measure and monitor mastocytosis activity, both, in clinical trials and in routine care.
Corrigendum to “Intervention studies to foster resilience — A systematic review and proposal for a resilience framework in future intervention studies” [Clinical Psychology Review 59 (2018) 78–100]
Authors: A. Chmitorz, A. Kunzler, I. Helmreich, O. Tüscher, R. Kalisch, T. Kubiak, M. Wessa, K. Lieb
Journal: Clinical Psychology Review (2018)
Government sets out plan to move GMC registration to point of graduation
Authors: Abi Rimmer
Journal: BMJ (2014)

Plans to move full registration with the General Medical Council from the end of the first year of foundation training to the point of graduation from medical school have been set out by the government.

The plans are laid out in the Health Education England (HEE) mandate for April 2014 to March.1 The mandate outlines the priority areas that the government has identified for HEE to take forward over the coming year. …
Phase II trial of pexa-vec (<i>pexastimogene devacirepvec</i>; JX-594), an oncolytic and immunotherapeutic vaccinia virus, in patients with metastatic, refractory renal cell carcinoma (RCC).
Authors: Seong-Geun Kim, Hong Koo Ha, Sung-nam Lim, Naomi S. De Silva, Adina Pelusio, Jae Hee Mun, Richard H. Patt, Caroline J. Breitbach, James M. Burke
Journal: Journal of Clinical Oncology (2018)

671 Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating anti-tumor immunity, direct oncolysis, and tumor vascular disruption. ( Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration ( Lancet Oncol 2008; Nature 2011). Methods: RCC patients failing at least 1 prior VEGF/R-targeted therapy received five weekly IV Pexa-Vec infusions. Starting at Week 6, patients with disease control or otherwise clinically benefitting from treatment could continue to receive IV infusions every 3 weeks. The primary study objective was radiographic response based on modified Response Evaluation Criteria (RECIST) 1.0. Secondary objectives included disease control rate, progression free survival and safety. Results: All seventeen patients enrolled received the initial 5 weekly Pexa-Vec infusions. Twelve patients received at least one additional infusion (median Pexa-Vec infusions = 8; range 5-12). The treatment regimen was well-tolerated. Transient influenza-like illness (100%), asthenia (47%), anemia (29%) and nausea (29%) were the most common adverse events. All patients were evaluable radiographically at Week 6. The RECIST disease control rate was 76% at Week 6 including 1 complete response. Conclusions: Pexa-Vec was well-tolerated and associated with one complete RECIST response and 76% disease control at Week 6 in patients with advanced RCC. Further trials of Pexa-Vec in RCC patients are warranted.
TEMPORAL TREND IN THE TREATMENT AND OUTCOMES OF ACUTE CORONARY SYNDROME PATIENTS IN RELATION TO THE 2017 AHA/ACC MYOCARDIAL INFARCTION CLINICAL PERFORMANCE AND QUALITY MEASURES, 2008-2017
Authors: Mitsuaki Sawano, Shun Kohsaka, Ikuko Ueda, Keiichi Fukuda
Journal: Journal of the American College of Cardiology (2018)
Tumor-infiltrating lymphocytes to predict survival to anthracycline/taxane-based adjuvant chemotherapy in triple negative breast cancer.
Authors: Qiyun Ou, Yunfang Yu, Xiaoyun Xiao, Baoming Luo
Journal: Journal of Clinical Oncology (2018)

1 Background: Previous clinical data suggested that the tumour-infiltrating lymphocytes (TILs) were predictive in breast cancer treated with adjuvant chemotherapy; however, clinical relevance has yet to be established. We hypothesized that TILs would be associated with overall survival (OS) and disease-free survival (DFS) after anthracycline/taxane-based adjuvant chemotherapy in breast cancer subtypes. Methods: PubMed and EMBASE were searched until March 2017 for studies that investigated the association of TILs with survival for anthracycline/taxane-based adjuvant chemotherapy in breast cancer. OS and DFS were combined using random-effects meta-analysis and calculated as combined hazard ratio (HR) with 95% credible intervals (CIs). The PROSPERO registry number is CRD42017072133. Results: Twelve studies comprising 9,023 patients were eligible for analysis. Six were prospective adjuvant trials (n = 7686) and six were retrospective studies (n = 1337). Pooled analysis indicated that high TILs have no significant predictive association in overall population (DFS, HR = 0.87, 95% CI, 0.70 – 1.08; OS, HR = 0.98, 95% CI, 0.89 – 1.07), Luminal A/B (DFS, HR = 0.99, 95% CI, 0.94 – 1.04; OS, HR = 1.01, 95% CI, 0.92 – 1.12), and HER2–positive patients (DFS, HR = 0.84, 95% CI, 0.71 – 1.00; OS, HR = 0.89, 95% CI, 0.77 – 1.02), but were related to improved DFS (HR, 0.81; 95% CI, 0.73 – 0.89) and OS (HR, 0.74; 95% CI, 0.66 – 0.84) in triple negative breast cancer (TNBC) patients. Additionally, increasing TILs were not significantly associated with reduced risk of relapse in HER2-positive patient through adjuvant trastuzumab (HR, 0.97; 95% CI, 0.93 – 1.01). Conclusions: This meta-analysis provides an evidence that TILs predicts survival to anthracycline/taxane-based adjuvant chemotherapy in TNBC patients and suggests that predictive benefit seemed to be influenced by breast cancer subtypes as well.
Inhaler technique among adults with uncontrolled asthma from low-income Philadelphia neighborhoods
Authors: Patrick K. Gleeson, Luzmercy Perez, Russell Localio, Knashawn Morales, Xiaoyan Han, Maryori Canales, Nadirah Lampkin, Tyra Bryant-Stephens, Andrea J. Apter
Journal: Journal of Allergy and Clinical Immunology (2018)
Phase I trial evaluating genetically modified autologous T cells (ACTengine IMA201) expressing a T-cell receptor recognizing a cancer/germline antigen in patients with squamous NSCLC or HNSCC.
Authors: George R. Blumenschein, Agathe Bourgogne, Carsten Reinhardt, Hong Ma, Steffen Walter, Toni Weinschenk, Partow Kebriaei, Patrick Hwu, Harpreet Singh
Journal: Journal of Clinical Oncology (2018)

TPS78 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy. T-cell receptor (TCR) engineered ACT approach has contributed to success in solid tumors. ACTengine IMA201 is a product based on autologous T cells engineered to express a naturally occurring TCR specific to a cancer-germline peptide. The target peptide has been characterized in depth by Immatics’ proprietary antigen discovery platform, XPRESIDENT showing exceptional specificity, copy number and expression homogeneity. XPRESIDENT has applied two independent methodologies to confirm the selectivity of tumor target: i) ultra-sensitive quantitative immunopeptidome analyses by mass spectrometry and ii) quantitative mRNA expression analyses by RNASeq. Immatics´ TCR discovery platform is optimized to identify TCRs with low micromolar affinity, specific recognition of tumor cell lines and lack of recognition of healthy normal cells. Methods: This study is an open-label first-in-human dose-escalating phase I trial investigating safety, tolerability and clinical activity in end-stage solid tumor patients. Key eligibility criteria include: recurrent or refractory squamous non-small cell lung cancer or head and neck squamous cell cancer, HLA-A*02:01 phenotype, qPCR biomarker positive from a tumor biopsy, prior established lines of therapy, RECIST v1.1 measurable lesions and ECOG score 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells (PBMC). The activated PBMC will be transduced with a lentiviral vector for manufacturing of IMA201. IMA201 is infused after a pre-conditioning (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objectives include: i) the persistence and functionality of IMA201 in vivo, ii) correlative biomarkers for clinical success, and iii) target expression levels in the tumor. Enrollment to the study is currently ongoing. Clinical trial information: NCT03247309 .
Regulatory T Cells Subvert Mycobacterial Containment in Patients Failing Extensively Drug-Resistant Tuberculosis Treatment
Authors: Malika Davids, Anil S. Pooran, Elize Pietersen, Helen C. Wainwright, Anke Binder, Robin Warren, Keertan Dheda
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: The advent of extensively drug-resistant (XDR) tuberculosis (TB) and totally drug-resistant TB, with limited or no treatment options, has facilitated renewed interest in host-directed immunotherapy, particularly for therapeutically destitute patients. However, the selection and utility of such approaches depend on understanding the host immune response in XDR-TB, which hitherto remains unexplored.Objectives: To determine the host immunological profile in patients with XDR-TB, compared with drug-sensitive TB (DS-TB), using peripheral blood and explanted lung tissue.Methods: Blood and explanted lung tissue were obtained from patients with XDR-TB (n = 31), DS-TB (n = 20), and presumed latent TB infection (n = 20). T-cell phenotype (T-helper cell type 1 [Th1]/Th2/Th17/regulatory T cells [Tregs]) was evaluated in all patient groups, and Treg function assessed in XDR-TB nonresponders by coculturing PPD-preprimed effector T cells with H37Rv-infected monocyte-derived macrophages, with or without autologous Tregs. Mycobacterial containment was evaluated by counting colony-forming units.Measurements and Main Results: Patients failing XDR-TB treatment had an altered immunophenotype characterized by a substantial increase in the frequency (median; interquartile range) of CD4+CD25+FoxP3+ Tregs (11.5%; 5.9–15.2%) compared with DS-TB (3.4%; 1.6–5.73%; P < 0.001) and presumed latent TB infection (1.8%; 1.2–2.3%; P < 0.001), which was unrelated to disease duration. Tregs isolated from patients with XDR-TB suppressed T-cell proliferation (up to 90%) and subverted containment of H37Rv-infected monocyte-derived macrophages (by 30%; P = 0.03) by impairing effector T-cell function through a mechanism independent of direct cell-to-cell contact, IL-10, TGF (transforming growth factor)-β, and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4).Conclusions: Collectively, these data suggest that Tregs may be contributing to immune dysfunction, and bacterial persistence, in patients with XDR-TB. The relevant cellular pathways may serve as potential targets for immunotherapeutic intervention.
Government puts more emphasis on trainees’ views of care quality
Authors: Abi Rimmer
Journal: BMJ (2013)

Last month the government accepted 281 of the 290 recommendations made by Robert Francis in his report into failings at Mid Staffordshire NHS Foundation Trust. Many of the recommendations for changes to medical training related to areas for which the General Medical Council has responsibility. In its response the government said that the GMC had already “accepted the spirit of all recommendations aimed at them” and would build them into a review of quality assurance of education that would be published later in the year.

Francis described junior doctors as “invaluable eyes and ears in a hospital setting” and said that any concerns they raised should be taken seriously. In light of this the government has made it clear that a greater focus would be placed on listening to the concerns of medical students and junior doctors.

One of the recommendations accepted by the government was that the GMC should amend its standards for undergraduate medical education to include a requirement …
A novel zebrafish xenograft model for immunotherapeutic drug screening
Authors: Lloyd Hamilton, Dirk Sieger, Belen Rubio Ruiz, Asier Unciti-broceta
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is most aggressive and frequently occurring form of glioma. GBM resists multimodal therapies and has a median survival rate of less than 14 months. Microglia are the resident macrophage of the brain and are the initial myeloid cell type to infiltrate brain tumours. The extent of microglia infiltration into glioblastoma has been directly correlated with glioma grade and invasiveness. Furthermore microglia have been shown to directly support tumour growth, invasion and immunosuppression. Thus microglia represent an attractive immunotherapeutic target in cancer research. Hence, we have developed a novel zebrafish xenograft model as a tool for drug screening in order to identify novel immunotherapeutic compounds. Well established human U87-nls-mKate2 glioblastoma cell lines were xenografted into the brains of transgenic mpeg1:EGFP zebrafish in which all macrophages and microglia are labelled with GFP. Our confocal live imaging results showed distinct interactions between microglia and U87. Importantly these interactions do not appear to be anti-tumoral as zebrafish microglia do not engulf and phagocytose the human glioblastoma cells. Finally, xenotransplants into the irf8-/- zebrafish mutant that lacks microglia, as well as pharmacological inhibition of the CSF-1 receptor on microglia, confirm a prominent role for zebrafish microglia in promoting human glioblastoma cell growth. In addition, we have extended this new xenograft model to test the potential of palladium mediated prodrug into drug conversion in the brain by BioOrthogonal OrganoMetallic (BOOM) reactions. Metallic palladium beads were implanted into the living brains of U87 xenografted zebrafish and the effects of BOOM reactions on tumour cells and microglia could be followed in real time. The proposed zebrafish xenograft model has shown promising potential to be used in compound testing and in the development of future immunotherapeutics within glioma.
Chronic neutrophilic leukemia: new science and new diagnostic criteria
Authors: Natasha Szuber, Ayalew Tefferi
Journal: Blood Cancer Journal (2018)

Abstract Chronic neutrophilic leukemia (CNL) is a distinct myeloproliferative neoplasm defined by persistent, predominantly mature neutrophil proliferation, marrow granulocyte hyperplasia, and frequent splenomegaly. The seminal discovery of oncogenic driver mutations in CSF3R in the majority of patients with CNL in 2013 generated a new scientific framework for this disease as it deepened our understanding of its molecular pathogenesis, provided a biomarker for diagnosis, and rationalized management using novel targeted therapies. Consequently, in 2016, the World Health Organization (WHO) revised the diagnostic criteria for CNL to reflect such changes in its genomic landscape, now including the presence of disease-defining activating CSF3R mutations as a key diagnostic component of CNL. In this communication, we provide a background on the history of CNL, its clinical and hemopathologic features, and its molecular anatomy, including relevant additional genetic lesions and their significance. We also outline the recently updated WHO diagnostic criteria for CNL. Further, the natural history of the disease is reviewed as well as potential prognostic variables. Finally, we summarize and discuss current treatment options as well as prospective novel therapeutic targets in hopes that they will yield meaningful improvements in patient management and outcomes.
How do I go about pursuing a career in management consultancy? I am disillusioned with the NHS and I am an average medical graduate from a northern university (that is, not Oxford or Cambridge).
Authors: Adam Poole
Journal: BMJ (2005)

Have 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.
THE FREQUENCY OF MUTATIONS IN KNOWN CARDIOMYOPATHY GENES AMONG CHILDREN WITH HYPERTROPHIC CARDIOMYOPATHY: THE NATIONAL HEART, LUNG AND BLOOD INSTITUTE-FUNDED MULTICENTER PEDIATRIC CARDIOMYOPATHY REGISTRY STUDY
Authors: Elfriede Pahl, Stephanie Ware, Ling Shi, Debra Dodd, Steven Colan, James Wilkinson, Arthi Sridhar, Jeffrey Schubert, Charles Canter, Daphne Hsu, Steven A. Webber, Melanie Everitt, Paul Kantor, Linda Addonizio, Joseph Rossano, John L. Jeffries, Wendy Chung, Teresa Lee, Jeffrey Towbin, Paolo Rusconi, Ashwin Lal, Bruce Aronow, Lisa Martin, Erin Miller, Steven Lipshultz
Journal: Journal of the American College of Cardiology (2018)
Shape of Training recognises need to move away from specialisation, says college president
Authors: Abi Rimmer
Journal: BMJ (2015)

The Shape of Training review recognises the need for medical training to move away from specialisation, Ian Ritchie, president of the Royal College of Surgeons of Edinburgh, has said.

The UK-wide Shape of Training review, carried out by David Greenaway, vice chancellor of Nottingham University, recommended that the UK should train more doctors to be generalists.1

The review “reflects and recognises that there has been a trend towards specialism which is not perhaps in the …
FDG PET and MRI Findings in a Case of Bing-Neel Syndrome
Authors: Caroline Bund, Benoît Lhermitte, Jérôme De Seze, Stéphane Kremer, Izzie-Jacques Namer
Journal: Clinical Nuclear Medicine (2018)

A 64-year-old man was admitted for expressive aphasia with lack of words. He had been diagnosed with Waldenström 4 years before. At that time, he received 6 cycles of single-agent fludarabine, and remission was obtained. Because of acute expressive aphasia, he underwent brain MRI, which showed frontoparietal and insular subcortical gadolinium enhancement; Bing-Neel syndrome was suspected. Fronto-temporo-insular hypometabolism and left parietal hypometabolism were highlighted on FDG PET/CT. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and reinforced the diagnosis.
Results of POUT: A phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC).
Authors: Alison Jane Birtle, John David Chester, Robert Jones Jones, Mark Johnson, Michaela Hill, Richard T Bryan, James Catto, Jenny Donovan, Ann French, Chris Harris, Francis Keeley, Roger Kockelbergh, Thomas Powles, Rachel Todd, Lucy Tregellas, Caroline Wilson, Andrew Winterbottom, Rebecca Lewis, Emma Hall
Journal: Journal of Clinical Oncology (2018)

407 Background: The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027; NCT01993979) addresses whether adjuvant chemotherapy improves disease free survival (DFS) for pts with histologically confirmed pT2-T4 N0-3 M0 UTUC. Methods: Pts (max n = 345) ≤90 days post NU were randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly cross sectional imaging and cystoscopy for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. The trial was powered to detect a hazard ratio (HR) of 0.65 (i.e. improvement in 3 year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p &lt; 0.001) early stopping rules for efficacy &amp; inefficacy. Secondary endpoints included metastasis-free survival (PFS), overall survival (OS), toxicity &amp; quality of life. Results: Between May 2012 &amp; Sept 2017, 248 pts were recruited (123 surveillance; 125 chemotherapy) at 57 UK centres. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (data snapshot 05/09/2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Pts had median age 69 years (range 36-88), 30% pT2, 65% pT3; 91% pN0;. Grade ≥3 toxicities were reported in 60% chemotherapy pts &amp; 24% surveillance pts. 47/123 (surveillance) &amp; 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favour of chemotherapy (log-rank p = 0.0009). Two year DFS was 51% for surveillance (95% CI: 39, 61) and 70% for chemotherapy (95% CI: 58, 79). PFS favoured chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p = 0.003). Conclusions: Adjuvant chemotherapy improved PFS in UTUC. POUT is the largest randomised trial in this pt population; the trial was terminated early because of efficacy favouring the chemotherapy arm. Whilst follow up for OS continues, this should be considered a new standard of care in these patients. Clinical trial information: ISRCTN98387754.
Progressive Massive Fibrosis in Coal Miners From 3 Clinics in Virginia
Authors: David J. Blackley, Laura E. Reynolds, Connie Short, Ron Carson, Eileen Storey, Cara N. Halldin, A. Scott Laney
Journal: JAMA (2018)

This study describes the demographic and radiographic characteristics of 416 coal miners with progressive massive pulmonary fibrosis (PMF) identified by pneumoconiosis screening as part of the US Coal Workers' Health Surveillance Program.