tbuckley/cabot-search huggingface dataset:
Novel method for rapid enrichment of high purity circulating tumor cells (CTCs) for prostate cancer (PCa) gene expression profiling.
Authors: Gareth Morrison, Nita Jojo, Alexander Cunha, Yucheng Xu, Peggy S. Robinson, Tanya B. Dorff, David I. Quinn, Amir Goldkorn
Journal: Journal of Clinical Oncology (2018)

271 Background: CTC RNA analysis currently involves single cell recovery that is laborious and expensive, or alternatively lysis of preserved whole blood which yields RNA predominantly from leukocytes which vastly outnumber CTCs. To effectively characterize gene expression in large patient cohorts, new enrichment methodologies are needed that yield high purity CTC populations while preserving RNA integrity. Here we describe a simple yet robust method for enrichment of prostate CTCs for gene expression analysis. Methods: Blood was drawn with informed consent under an IRB-approved protocol. For initial optimization, CFSE-stained PCa cells were spiked into healthy blood and recovered using various combinations of 2 methods: microfluidic enrichment (Parsortix™ system) and CD45 depletion. For assay qualification, a prostate-specific multiplexed qRT-PCR gene expression panel was developed. Enrichment and gene expression were tested initially using PCa cell lines spiked into healthy blood, then metastatic castrate resistant prostate cancer (mCRPC) blood samples in parallel with CellSearch enumeration. Results: Optimal enrichment of live cells was achieved with CD45 depletion followed by microfluidic enrichment, resulting in an average spiked cell recovery of 30% and approximately 100 contaminating background leukocytes. Using this enrichment method, prostate specific genes were detectable by multiplexed qRT-PCR down to 25 cells spiked into 7.5 ml whole blood, and transcripts were not measurable in matched healthy blood controls. When applied to mCRPC patient blood containing CTCs by CellSearch, multiplexed qRT-PCR successfully detected prostate specific genes in all samples. Conclusions: We developed a novel enrichment method capable of rapidly and efficiently recovering live CTCs with high purity, free of magnetic beads and with very few background leukocytes. Captured cells yielded high-quality RNA with high sensitivity and specificity for prostate-specific transcripts. This approach is applicable to high throughput gene expression profiling assays and offers an alternative to laborious single cell recovery or non-cancer-specific whole blood fixation.
GMC seeks junior doctors’ views on new standards for education and training
Authors: Abi Rimmer
Journal: BMJ (2015)

The General Medical Council is seeking the views of junior doctors in a consultation on new standards for undergraduate and postgraduate education and training.

Currently, the standards are contained in two separate pieces of guidance—one for medical students and one for junior doctors. The regulator is consulting on a new set of standards that will cover both.1

The GMC said that the …
TAKOTSUBO CARDIOMYOPATHY IN HUMAN IMMUNODEFICIENCY VIRUS POSITIVE PATIENTS: NATIONAL INPATIENT SAMPLE BASED RETROSPECTIVE REVIEW
Authors: Muhammad Chaudhry, Dhaval Kolte, Wajeeha Saeed, Ahad Khan, Munis Raza, Reema Qureshi, Jinnette D. Abbott, Herbert D. Aronow, Muhammad Sardar
Journal: Journal of the American College of Cardiology (2018)
Brief Report: Novel <i>UNC13D</i> Intronic Variant Disrupting an NF‐κB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis
Authors: Grant S. Schulert, Mingce Zhang, Ammar Husami, Ndate Fall, Hermine Brunner, Kejian Zhang, Randy Q. Cron, Alexei A. Grom
Journal: Arthritis & Rheumatology (2018)

Objective Macrophage activation syndrome (MAS) is a life‐threatening complication of systemic juvenile idiopathic arthritis (JIA) and has pathologic similarity to hemophagocytic lymphohistiocytosis (HLH). Intronic variants in UNC13D are found in patients with familial HLH type 3 (FHLH3), but the role of noncoding variants in MAS is unknown. The objective of this study was to identify deep intronic UNC13D variants in patients with MAS. Methods A custom enrichment library was constructed to sequence a genomic region of ~1 Mb flanking UNC13D in 24 patients with systemic JIA, recurrent MAS, and negative results of prior genetic (exon/coding) testing. The functional consequences of intronic variants were assessed using quantitative polymerase chain reaction in patient‐derived peripheral blood mononuclear cells (PBMCs), electromobility shift assay, in vitro transcriptional enhancer assays, and natural killer (NK) cell degranulation assays. Results We evaluated a patient with systemic JIA and recurrent MAS in whom a novel functional intronic variant in UNC13D , c.117+143A&gt;G, was observed. This variant occurred in a proposed regulatory region that drives lymphocyte‐specific UNC13D expression and is associated with reduced transcript levels in patient PBMCs. This variant also disrupted NF‐κB binding to a functional transcriptional enhancer, leading to reduced enhancer activity in vitro. Partial knockdown of UNC13D expression also led to impaired NK cell degranulation. An additional patient was identified with a previously described UNC13D intronic variant, for a total noncoding variant hit rate of 8.3% (2 of 24). Conclusion These findings highlight the notion that intronic variants in key regulatory regions may be associated with MAS in patients with systemic JIA and support deep sequencing approaches when causative coding variants are not identified.
Learning anatomy online
Authors: Natalie Blencowe
Journal: BMJ (2007)

For many doctors, learning anatomy does not stop in the dissection room in medical school. Anatomy constitutes a large part of both written and oral sections of the examination for membership of the Royal College of Surgeons. So if you want to try an alternative to a textbook why not consider going online? These websites are free, and you do not need to register.

This is the web version of a concise textbook now in its third edition. It's …
Editor’s Choice: Wilful neglect
Authors: Abi Rimmer
Journal: BMJ (2015)

With workforce shortages reported in specialties such as general practice and emergency medicine, you might expect that, from time to time, doctors would find themselves covering several unfilled posts, unable to attend to every patient as quickly as they would like. However, after the introduction of new legislation this is exactly the kind of behaviour that could land doctors in hot water, Pallavi Bradshaw explains this week …
Venous Thromboembolism Quality Measures Fail to Accurately Measure Quality
Authors: Brandyn D. Lau, Michael B. Streiff, Peter J. Pronovost, Elliott R. Haut
Journal: Circulation (2018)

Venous thromboembolism (VTE) is 1 of the most common causes of preventable harm for patients in hospitals. Consequently, the Joint Commission, the Centers for Medicare and Medicaid Services, the Agency for Healthcare Research and Quality, the United Kingdom Care Quality Commission, the Australian Commission on Safety and Quality in Health Care, the Maryland Health Services Cost Review Commission, and the American College of Surgeons have prioritized measuring and reporting VTE outcomes with the goal of reducing the incidence of and preventable harm from VTE. We developed a rubric for defect-free VTE prevention, graded each organizational VTE quality measure, and found that none of the current VTE-related quality measures adequately characterizes VTE prevention efforts or outcomes in hospitalized patients. Effective VTE prevention is multifactorial: clinicians must assess patients’ risk for VTE and prescribe therapy appropriate for each patient’s risk profile, patients must accept the prescribed therapy, and nurses must administer the therapy as prescribed. First, an ideal, defect-free VTE prevention process measure requires: (1) documentation of a standardized VTE risk assessment; (2) prescription of optimal, risk-appropriate VTE prophylaxis; and (3) administration of all risk-appropriate VTE prophylaxis as prescribed. Second, an ideal VTE outcome measure should define potentially preventable VTE as VTE that developed in patients who experienced any VTE prevention process failures.
GAPS BETWEEN AND WITHIN THE KNOWLEDGE OF PATIENTS AND CARDIOLOGISTS CONCERNING THE RISKS AND BENEFITS OF PERCUTANEOUS CORONARY INTERVENTION FOR CHRONIC TOTAL OCCLUSION: A RANDOMIZED CONTROLLED TRIAL OF A DECISION AID
Authors: Rongchong Huang, Dongfeng Zhang, Xiantao Song, Jiaying Xu, Ian Hargraves, Victor Montori, Henry H. Ting
Journal: Journal of the American College of Cardiology (2018)
开发和验证皮肤疣(CWARTS)诊断工具:一种新型皮肤疣临床评估和分类系统
Authors: G.K. Hogendoorn, S.C. Bruggink, K.E. Hermans, S.T.P. Kouwenhoven, K.D. Quint, R. Wolterbeek, J.A.H. Eekhof, M.N.C. de Koning, R. Rissmann, J. Burggraaf, J.N. Bouwes Bavinck
Journal: British Journal of Dermatology (2018)

并非所有皮肤疣的症状都相同。这项在荷兰开展的研究旨在开发并测试精确的诊断工具,以帮助临床医生诊断疣。该项研究的作者根据各种文献和专家访谈定义了九大外观特征,进而开发出了皮肤疣诊断工具(CWARTS诊断工具)。该项研究包括两个部分。在第一个部分(部分A)中,28名研究人员(“观察员”)评估了10种疣的照片,然后该团队调查了这些研究人员之间的共识程度。在第二个部分(部分B)中,6名研究人员再次评估了299种疣的照片,这次该团队测试了这6名观察员的第一次和第二次(相隔一周或更久)评估结果的一致性。对于疣的九种特征,该团队计算了一种广泛使用的可靠性指数,称为同类相关系数(ICC)。换句话说,如果ICC较高,则说明观察员之间达成共识的程度较高或者观察员的结果更加一致。观察员对存在黑点的这一特征的共识程度最高(达到0.85),疣的排列次之(0.65),接着是疣的边缘有红斑(0.64)以及边缘的对比(0.60)。在研究的部分B中,这些结果较为相似。对于第一次和第二次评估之间的一致性,存在黑点这一特征再一次位列第一,其次是边缘有红斑(0.64)以及疣的颜色(0.55)。作者们通过此项研究论证得出,可以利用CWARTS诊断工具可靠地评估皮肤疣的外观。
The Long Neglected Player: Modeling Tumor Uptake to Guide Optimal Dosing
Authors: Leire Ruiz-Cerdá, Eduardo Asín-Prieto, Zinnia P. Parra-Guillen, Iñaki F. Trocóniz
Journal: Clinical Cancer Research (2018)

Pharmacokinetic modeling, traditionally using drug exposure, is widely used to support decision-making in translational medicine and patient care. The development of mechanistic computational models that integrate drug concentrations at the site of action making use of existing knowledge opens a new paradigm in optimal dosing. Clin Cancer Res; 24(14); 3236-8. ©2018 AACRSee related article by Ribba et al., p. 3325.
Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial
Authors: Seth D Crockett, Elizabeth L Barry, Leila A Mott, Dennis J Ahnen, Douglas J Robertson, Joseph C Anderson, Kristen Wallace, Carol A Burke, Robert S Bresalier, Jane C Figueiredo, Dale C Snover, John A Baron
Journal: Gut (2018)

Objective Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically. Design Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D 3 , both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models. Results SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively). Conclusion In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6–10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. Trial registration number NCT00153816; Results.
Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from <scp>ASSURE</scp>‐<scp>CSU</scp>
Authors: G. Sussman, M. Abuzakouk, F. Bérard, W. Canonica, H. Oude Elberink, A. Giménez‐Arnau, C. Grattan, K. Hollis, S. Hunter, A. Knulst, J.‐P. Lacour, C. Lynde, A. Marsland, D. McBride, M. Maurer, A. Nakonechna, J. Ortiz de Frutos, M. Reynolds, C. Sweeney, H. Tian, K. Weller, D. Wolin, M.‐M. Balp
Journal: Allergy (2018)

Abstract Background ASSURE ‐ CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and explore differences between patients with and without angioedema. Methods This international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria ( CSU ). Physicians abstracted angioedema data from medical records, which were compared with patient‐reported data. Patients in the Yes‐angioedema category had angioedema reported in the medical record and a patient‐reported source. For those in the No‐angioedema category, angioedema was reported in neither the medical record nor a patient‐reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes‐angioedema and No‐angioedema categories were conducted for measures of CSU activity, health‐related quality of life ( HRQ oL), productivity and healthcare resource utilization ( HCRU ). Regression analyses explored the relationship between Dermatology Life Quality Index ( DLQI ) score and angioedema, adjusting for important covariates. Results Among evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes‐angioedema , No‐angioedema and Misaligned category, respectively. CSU activity and impact on HRQ oL, productivity, and HCRU was greater for Yes‐angioedema patients than No‐angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQ oL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P &lt; .001). The Misaligned category had similar results with Yes‐angioedema on all outcomes. Conclusions Angioedema in CSU seems to be under‐reported but has significant negative impacts on HRQ oL, daily activities, HCRU and work compared with no angioedema.
Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study
Authors: Michael B. Atkins, F. Stephen Hodi, John A. Thompson, David F. McDermott, Wen-Jen Hwu, Donald P. Lawrence, Nancy A. Dawson, Deborah J. Wong, Shailender Bhatia, Marihella James, Lokesh Jain, Seth Robey, Xinxin Shu, Blanca Homet Moreno, Rodolfo F. Perini, Toni K. Choueiri, Antoni Ribas
Journal: Clinical Cancer Research (2018)

Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR.
Doctor is struck off for sexual assaults on two women after GMC wins appeal
Authors: Clare Dyer
Journal: BMJ (2018)

A hospital doctor has been struck off the UK medical register for sexually assaulting two women in the guise of genuine examinations, after the General Medical Council successfully appealed against a tribunal decision to suspend him for 12 months.

Maher Khetyar, 46, was suspended last October by a medical practitioners’ tribunal, but the GMC appealed to the High Court against the decision. The judge, Mr Justice Andrew Baker, said that the tribunal had gone “badly” wrong and that erasure from the register was the only appropriate punishment.

The judge said that …
A FavorAx study of axitinib in favorable risk patients with metastatic renal cell carcinoma.
Authors: Ilya Tsimafeyeu, Pavel Borisov, Ahmed Abdelgafur, Roman Leonenkov, Olga Novikova, Irina Guseva, Marina Demchenkova, Nadezhda Mikhailova, Andrey Semenov, Zakhar Yurmazov, Irina Sivunova, Madina Ramazanova, Sergey Gamayunov, Dmitry Kosov
Journal: Journal of Clinical Oncology (2018)

666 Background: Targeted therapy with axitinib resulted in a greater objective response rate and prolonged progression-free survival (PFS) compared to sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC) in AXIS study. 75% of patients had intermediate and poor IMDC prognosis. In this phase 2 study, we assessed the activity of axitinib in mRCC patients with favourable risk and a history of prior VEGFR-directed therapy. Methods: Patients were required to have clear cell mRCC, favourable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. The primary endpoint of the study was PFS. Additional endpoints included response rate, safety, and overall survival (OS). Results: A total of 21 patients were enrolled, 62% of whom were male. Median age was 59 years. 11 (52%) patients had 2 and more metastatic sites. 67% and 33% of patients received first-line sunitinib or pazopanib with a median PFS of 17 months (95% CI 14-20). After a median follow-up of 16 months, the median PFS and OS was not yet reached. The current study did achieve its primary endpoint based on the 10-month PFS of 71.4%. 3 (14.3%) patients had confirmed partial responses and 14 (66.7%) had stable disease. No grade 3/4 treatment-related adverse events were observed; the most frequent grade 1/2 treatment-related adverse events were hypertension (57.1%), fatigue (57.1%), GI (33%) and skin (19%) toxicity. 7 patients had dose-escalation of axitinib and 1 patient had dose reduction. Conclusions: The encouraging PFS and favorable safety profile observed in FavorAx study support the administration of axitinib in mRCC patients with favourable IMDC risk and a history of prior sunitinib or pazopanib. Clinical trial information: NCT02700568.
GMC recommends that revalidation go ahead this year
Authors: Caroline White
Journal: BMJ (2012)

The General Medical Council has written to the health secretary for England, Jeremy Hunt, to confirm that all four UK countries are ready to start revalidation this year and to recommend that he authorise its introduction.

On what he described as a “historic day,” Peter Rubin, chairman of the GMC, said that the organisation was “absolutely delighted” that it could make a start on revalidation, subject to the government’s authorisation, which he fully expected to be given.

“This is the biggest change in medical regulation since 1858,” he said, adding, “We are leading the world.”

His letter to the health secretary marks the final stage of a lengthy process that is expected …
Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial
Authors: Fahim Ebrahimi, Stavros Giaglis, Sinuhe Hahn, Claudine A. Blum, Christine Baumgartner, Alexander Kutz, Shane Vontelin van Breda, Beat Mueller, Philipp Schuetz, Mirjam Christ-Crain, Paul Hasler
Journal: European Respiratory Journal (2018)

Neutrophil extracellular traps (NETs) are a hallmark of the immune response in inflammatory diseases. However, the role of NETs in community-acquired pneumonia (CAP) is unknown. This study aims to characterise the impact of NETs on clinical outcomes in pneumonia.This is a secondary analysis of a randomised controlled, multicentre trial. Patients with CAP were randomly assigned to either 50 mg prednisone or placebo for 7 days. The primary end-point was time to clinical stability; main secondary end-points were length of hospital stay and mortality.In total, 310 patients were included in the analysis. Levels of cell-free nucleosomes as surrogate markers of NETosis were significantly increased at admission and declined over 7 days. NETs were significantly associated with reduced hazards of clinical stability and hospital discharge in multivariate adjusted analyses. Moreover, NETs were associated with a 3.8-fold increased adjusted odds ratio of 30-day mortality. Prednisone treatment modified circulatory NET levels and was associated with beneficial outcome.CAP is accompanied by pronounced NET formation. Patients with elevated serum NET markers were at higher risk for clinical instability, prolonged length of hospital stay and 30-day all-cause mortality. NETs represent a novel marker for outcome and a possible target for adjunct treatments of pneumonia.
Complete Metabolic Response of Advanced Melanoma to Vemurafenib Assessed with FDG-PET-CT at 85 Hours
Authors: Pierre Pascal, Laurent Dercle, Kathleen Weyts, Nicolas Meyer, Fréderic Courbon
Journal: Clinical Nuclear Medicine (2018)

Vemurafenib improves the management of advanced melanoma due to selective inhibition of the mutated BRAF V600E kinase. FDG-PET-CT is a tool for the evaluation of the biologic impact of inhibiting mutant BRAF. With vemurafenib at day 15, all the patients had at least partial metabolic response. Reductions in uptake correlate with longer progression free survival. In this case, incomplete information provided by the patient led to the performance of his third PET 85 hours after the introduction of vemurafenib. This early case of complete metabolic response suggests that FDG-PET-CT is a useful marker of early biologic response to vemurafenib.
Indocyanine green-incorporating nanoparticles for cancer theranostics
Authors: Haolu Wang, Xinxing Li, Brian Wan-Chi Tse, Haotian Yang, Camilla A. Thorling, Yuxin Liu, Margaux Touraud, Jean Batiste Chouane, Xin Liu, Michael S. Roberts, Xiaowen Liang
Journal: Theranostics (2018)

Indocyanine green (ICG) is a near-infrared dye that has been used in the clinic for retinal angiography, and defining cardiovascular and liver function for over 50 years.Recently, there has been an increasing interest in the incorporation of ICG into nanoparticles (NPs) for cancer theranostic applications.Various types of ICG-incorporated NPs have been developed and strategically functionalised to embrace multiple imaging and therapeutic techniques for cancer diagnosis and treatment.This review systematically summaries the biodistribution of various types of ICG-incorporated NPs for the first time, and discusses the principles, opportunities, limitations, and application of ICG-incorporated NPs for cancer theranostics.We believe that ICG-incorporated NPs would be a promising multifunctional theranostic platform in oncology and facilitate significant advancements in this research-active area.