tbuckley/cabot-search huggingface dataset:
Plans for secondary care doctor inclusion on CCGs “hugely problematic”
Authors: Caroline White
Journal: BMJ (2012)

The statutory composition of clinical commissioning group (CCG) boards could prove “hugely problematic” under current regulations, particularly in rural areas, doctors’ leaders have warned.

In a letter written to parliamentary undersecretary of state at the Department of Health Lord Howe last week, senior doctors from the BMA have pointed out that the conflict of interest regulations will make it difficult to meet the requirement for the inclusion of a secondary care clinician …
Estimating mutation load at 5% LOD from FFPE samples using a targeted next-generation sequencing assay.
Authors: Ruchi Chaudhary, Dinesh Cyanam, Vinay Kumar Mittal, Warren Tom, Janice Au-Young, Seth Sadis, Fiona Hyland
Journal: Journal of Clinical Oncology (2018)

28 Background: High tumor mutation load is a biomarker which positively correlates with response to immune checkpoint inhibitors. Current methods to estimate tumor mutation load often require large amounts of DNA. Herein, we demonstrate the ability of a targeted panel to estimate mutation load from FFPE samples using low input amount of DNA. Methods: We developed a single-sample analysis workflow to estimate mutation load (somatic mutation count per Megabase (Mb)) from FFPE and fresh frozen tumor research samples. The assay utilizes a PCR-based target enrichment panel that covers ~1.7 Mb. Our workflow requires only 10 ng of input DNA, and enables a 2.5-day turn-around time from sample to the final report. The workflow enables &lt; 60 minutes of hands-on time for automated library preparation and templating on a batch of 8 samples. Sequencing is performed using a high throughput semiconductor sequencing platform to achieve sufficient depth (~500x coverage) and accuracy. Our analysis pipeline calls variants with optimized parameters on the tumor sample only, with no matched normal sample required, and applies filters to remove germ-line. Results: An in-silico analysis using 21,000 exomes from COSMIC demonstrated the panel can achieve high sensitivity (&gt;=93%) and specificity (&gt;99%) necessary to stratify high and low mutation burden samples. Matched tumor-normal analyses on 14 lung and colorectal samples showed that our single tumor analysis workflow detects mutation load with strong correlation (r=0.8699) with tumor-normal analysis. Through dilution experiments on engineered control we learned that the workflow provides accurate estimates of mutation load, predicting ± 7% of expected mutation load on &gt;=20% tumor content. To assess reproducibility, we compared mutation load in library replicates for a cohort of 8 samples (FFPE and fresh frozen tumors, engineered control, and NIST cell-lines) and observed high correlation (r=0.9906) among replicates. Conclusions: We developed a simple workflow on the Ion Torrent sequencing platform to estimate mutation load from FFPE and fresh frozen tumor research samples. This solution will advance research in immuno-oncology.
Effect of adjuvant radiation on survival for extra-hepatic cholangiocarcinoma.
Authors: Caitlin Takahashi, Ravi Shridhar, Jamie Huston, Anjan Jayantilal Patel, Richard H. Brown, Kevin Koehler, Pedro Briceno, Ken Lee Meredith
Journal: Journal of Clinical Oncology (2018)

377 Background: Extra-hepatic cholangiocarcinomas (EHC) are low-incidence cancers that are difficult to diagnose and associated with a dismal prognosis. Surgery remains the only option for durable survival however R1 resections are high. We sought to examine the impact of adjuvant therapies on survival in patients with EHC. Methods: Utilizing the National Cancer Database we identified patients who underwent resection for EHC. We then stratified by adjuvant therapy (chemo(AC) or chemoradiation(CRT). Baseline comparisons of patient characteristics were made using Mann-Whitney U, Kruskal Wallis and Pearson’s Chi-square test as appropriate. Survival analyses were performed using the Kaplan-Meier method. Multivariable cox proportional models (MVA) were developed to identify predictors of survival. All statistical tests were two-sided and α &lt; 0.05 was considered significant. Results: We identified 4334 patients who underwent EHC resection: AC = 775, CRT = 1254, no adjuvant (NA) therapy = 2305 and a median age of 67 (18-90) years. R0 resections was performed in 71.6% of patients and the median LN harvest was 9 (3-18). R0 resections and lymph node negative patients demonstrate improved survival p &lt; 0.001 and p &lt; 0.001. Adjuvant therapy did not improve survival in R0 resections, p = 0.2. However survival was benefited in R1 patients, with those receiving CRT demonstrating the most significant improvement: median and overall 5-year survival AC = 16.7 months 8%, CRT = 23.1 months, 20.4%, and NA = 16.1 months and 11.6% p &lt; 0.001. In LN- patients CRT (47.3 months, 47%) but not AC (45 months, 44.5%) demonstrated benefit in survival compared to NA (37.8 months, 40.1) p = 0.04 and p = 0.7. Additionally, patients with LN+ and R1 resection had survival benefit when treated with (CRT 24.9 months and 24.3%), compared to NA (20.2 and 21.1%), p = 0.02. AC (24 months and 24%) did not demonstrate survival in these patients, p = 0.21. MVA demonstrated that age, T-stage, LN+, R0 resection and CRT were predictors of survival. Conclusions: Adjuvant CRT improves survival for patients with EHC who underwent R1 resections, and in LN- and LN+ patients. However, AC only benefited node positive patients with R0 resections. Patients with resected EHC should be referred for adjuvant CRT.
ADULT BONE MARROW CELL THERAPY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS USING CARDIAC MAGNETIC RESONANCE IMAGING
Authors: Anweshan Samanta, Muhammad Afzal, Amy Cantilena, Shubha Deep Roy, Siva Sagar Taduru, Buddhadeb Dawn
Journal: Journal of the American College of Cardiology (2018)
Raman spectroscopy: a novel tool for intraoperative guidance in surgical neuro-oncology
Authors: Babar Vaqas, Imran Patel, Michael Short, Haishan Zeng, Kevin O’Neill
Journal: Neuro-Oncology (2018)

Raman spectroscopy offers an optical label-free and non destructive real-time solution for tissue identification and surgical guidance during Neurosurgery for brain tumours. We evaluate a novel fibre optic point-measurement system during its first use during surgery in a consecutive series of 30 patients with a range of brain tumors. Raman spectroscopy was deployed using a surgical protocol in this single centre study of 30 consecutive craniotomies for tumor. Analysis of tissue was done in-vivo during surgery at the brain surface, on route to the tumor and in superficial and deep tumor zones. Sampling was also performed along the resection margin and all spectra were compared to matched core biopsy samples verified by routine histopathology. Ex-vivo tissue analysis was also performed at different time points to look at change in tissue signal characteristics over time. Over 3,000 Raman spectra from the brain were recorded. Multivariate analysis using PCA/LDA was performed. Most easily identified tumors include meningiomas and metastases. Low grade and high grade gliomas were also identified with high accuracy. Raman spectroscopy represents a new modality for in-vivo tissue characterisation with high accuracy. It has the ability to rapidly recognise healthy brain tissue and tumour tissue and could be a valuable tool aiding complete resection of low grade lesions in eloquent brain regions. Current challenges to more widespread adoption include the modifications necessary for it to work in the OR and patient-patient and machine-machine variability.
EMPAGLIFLOZIN REDUCES MORTALITY AND HOSPITALIZATION FOR HEART FAILURE IN PATIENTS WITH OR WITHOUT A HISTORY OF MYOCARDIAL INFARCTION OR STROKE AT BASELINE
Authors: David H. Fitchett, Silvio E. Inzucchi, Steven Sambevski, Stefan Kaspers, Egon Pfarr, Jyothis T. George, Bernard Zinman
Journal: Journal of the American College of Cardiology (2018)
GMC to introduce formal recognition for trainers, mentors, and educational supervisors
Authors: Caroline White
Journal: BMJ (2012)

The General Medical Council (GMC) is set to formally recognise the role of doctors who train medical students and graduates in a bid to boost educational standards and, ultimately, patient safety.

The move follows a consultation earlier this year in which most respondents supported the GMC’s plans to strengthen the role of trainers, mentors, and educational supervisors.

The new arrangements, which give the organisations who deliver training a clear steer on …
Life after prostate cancer diagnosis: One step beyond.
Authors: Adam Glaser, Amy Downing, Penny Wright, Luke Hounsome, Paul Kind, Peter John Selby, Sarah Wilding, David Donnelly, Hugh Butcher, Eila Watson, Wagland Richard, James Catto, William Cross, Malcolm David Mason, Linda Sharp, Galina Velikova, Rebecca Mottram, Majorie Allen, Therese Kearney, Gavin Anna
Journal: Journal of Clinical Oncology (2018)

40 Background: Prostate cancer (PCa) outcome studies are frequently restricted to specific disease stage or treatments. Interpretation may be restricted through lack of population control data &amp; selection bias. We report a whole population evaluation of health-related quality of life (HRQL) following diagnosis of PCa compared to a general population (GenPop) cohort. Methods: Cross-sectional postal survey of all men diagnosed with PCa in the UK 18-42 months earlier. Measures of generic HRQL (EQ-5D) and PCa specific outcomes (EPIC-26 &amp; interventions for erectile dysfunction), as defined in ICHOM minimum dataset, were utilized. Comparable GenPop data was collected from men never diagnosed with PCa in Northern Ireland. Results: 35,823 PCa survivors responded (60.8% response rate), median age 71, and 2,995 from the GenPop (30%). Overall HRQL was slightly lower in the PCa men than the GenPop, this difference was significant only in stage 4 disease. Men with PCa were less likely to report problems in individual EQ5D domains than men in the GenPop (62.0% vs. 68.8%). Both populations were most likely to report pain/discomfort, this was lower in PCa men than the GenPop (42.1% vs. 60.8%). Problems increased with age in all domains, with the exception of anxiety/depression. Men generally reported good function on EPIC-26; however PCa survivors reported poorer sexual function (78.9% vs 48%) except in the oldest. Medications/devices/services to aid or improve erections were offered to 45.4%, 26.0% &amp; 16.9% respectively (and considered helpful by 14.7%, 7.5% &amp; 3.2%). Men with PCa reported more problems with urinary leakage (13.1% vs. 7.1%), particularly after surgery. Hormonal symptoms were linked with receiving Androgen Deprivation Therapy and, to a lesser extent, external beam radiation. Conclusions: 18-42 months following diagnosis of PCa significant sexual and urinary morbidity is experienced relative to the GenPop. Specialist support for sexual dysfunction is not always offered. With the exception of men with stage 4 disease, overall HRQL is only mildly reduced. Funding The Life After Prostate Cancer Diagnosis study was funded by the Movember Foundation, in partnership with Prostate Cancer UK, as part of the Prostate Cancer Outcomes programme, grant number BO26/MO.
Abstract P4-06-12: Different patterns of risk reducing decisions in affected or unaffected BRCA mutation carriers
Authors: EG Lee, H Kang, SJ Park, JH Han, S-Y Jung, S Lee, H-S Kang, B Park, S-Y Kong, MC Lim, S-Y Park, ES Lee
Journal: Cancer Research (2018)

Abstract BACKGROUND Risk-reducing (RR) management decreases the risk of breast cancer and BRCA related gynecologic cancer. However, there are fewer reports on the RR management in Asia compared to Western countries.The aim of this study is to identify risk reducing management patterns with BRCA1 or BRCA2 mutation carriers. METHODS The study group consisted of all consecutive 1104 breast cancer, ovarian patients and their families of high-risk patients who underwent BRCA gene testing in National Cancer Center, Korea from 2008 to 2016. A total 220 BRCA mutations (19.9%) were detected with 125(11.3%) of BRCA1 gene and 95 (8.6%) of BRCA2 gene. RESULTS Out of 220 BRCA mutations carriers, they were consisted of 83 breast cancers, 10 ovarian cancers, 7 both cancers, and 120 unaffected carriers. Among them, 42 were men and 178 were women. About 90 % (198/ 220) had the familial history of breast, ovarian or both malignancies (113 in BRCA1 and 85 in BRCA2 mutation (p=0.821)). All 42 men chose surveillance. Among 178 female BRCA mutation carriers, 98(55.1%) underwent risk reducing management including 18(10.1%) of chemoprevention, and 80(49.9%) had risk-reducing surgeries (RRSs) (1 case of risk-reducing mastectomy, 76 of risk reducing bilateral salphingo-oophorectomy (RRSO), and 3 of both) and 80 (54.9%) chose only intensive surveillance for both of breast and ovary cancer. In affected carriers with breast cancer, 59 (71.1%) underwent RR management (1 case of risk reducing mastectomy, 53 of RRSO, 3 of both surgery, and 2 of chemoprevention). There was no risk reducing management in affected carrier with ovarian cancer patients. In 78 unaffected women carriers, 39(50.0%) women received RR management (23(29.5%) cases of RRSO and 16(20.5%) cases of chemoprevention). The rates of RRSs have increased annually since the 2013 year, (prior to 2013 vs. since 2013, RRSs 28.6% (6 cases/21 carriers) vs. 37.2% (74/199), p&amp;lt;0.01). CONCLUSION This study was conducted on the largest numbers of BRCA mutation carriers in Asian countries. RRSO is the more preferred management for affected carriers with breast cancer or unaffected carriers. The results might be explained by the severity of the illness and that RRSO was only reimbursed RR strategy from the Korean Government Insurance. Tailored genetic counseling and insurance policy may enhance overall levels of RR management. Citation Format: Lee EG, Kang H, Park SJ, Han JH, Jung S-Y, Lee S, Kang H-S, Park B, Kong S-Y, Lim MC, Park S-Y, Lee ES. Different patterns of risk reducing decisions in affected or unaffected BRCA mutation carriers [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 P4-06-12.
Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12-week blinded randomised controlled trial
Authors: Desirée M J Dorleijn, Pim A J Luijsterburg, Max Reijman, Margreet Kloppenburg, Jan A N Verhaar, Patrick J E Bindels, Pieter Koen Bos, Sita M A Bierma-Zeinstra
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> Guidelines recommend intra-articular glucocorticoid injection in patients with painful hip osteoarthritis. However, intra-articular hip injection is an invasive procedure. The efficacy of systemic glucocorticoid treatment for pain reduction in hip osteoarthritis is unknown. This randomised, double-blind, trial assessed effectiveness in hip pain reduction of an intramuscular glucocorticoid injection compared with a placebo injection in patients with hip osteoarthritis. <h3>Methods</h3> Patients with painful hip osteoarthritis were randomised to either 40 mg triamcinolone acetate or placebo with an intramuscular injection into the gluteus muscle. The primary outcomes were severity of hip pain at rest, during walking (0–10) and WOMAC pain at 2-week postinjection. We used linear mixed models for repeated measurements at 2, 4, 6 and 12 weeks for the intention-to-treat data analysis. <h3>Results</h3> Of the 107 patients randomised, 106 could be analysed (52 in the glucocorticoid group, 54 in the placebo group). At 2-week follow-up, compared with placebo injection, the intramuscular glucocorticoid injection showed a significant and clinically relevant difference in hip pain reduction at rest (difference −1.3, 95% CI −2.3 to −0.3). This effect persisted for the entire 12-week follow-up. For hip pain during walking, the effect was present at 4-week, 6-week and 12-week follow-ups, and for WOMAC pain the effect was present at 6-week and 12-week follow-up. <h3>Conclusions</h3> An intramuscular glucocorticoid injection showed effectiveness in patients with hip osteoarthritis on one of the three primary outcomes at 2-week postinjection. All primary outcomes showed effectiveness from 4 to 6 weeks, up to a 12-week follow-up. <h3>Trial registration number</h3> NTR2966.
Royal college to pilot new system of workplace based assessments
Authors: Helen Jaques
Journal: BMJ (2012)

The Joint Royal Colleges of Physicians’ Training Board is this summer piloting a new system of workplace based assessments for trainees in medical specialties, with a view to changing the current approach in August 2013.

The one year pilots, which will start this August, will take place in three deaneries (East Midlands, Northern, and Wales) in a mix …
Reversal of Sepsis‐Like Features of Neutrophils by Interleukin‐1 Blockade in Patients With Systemic‐Onset Juvenile Idiopathic Arthritis
Authors: Nienke M. ter Haar, Tamar Tak, Michal Mokry, Rianne C. Scholman, Jenny M. Meerding, Wilco de Jager, Anouk Verwoerd, Dirk Foell, Thomas Vogl, Johannes Roth, Pieter H. C. Leliefeld, Jorg van Loosdregt, Leo Koenderman, Sebastiaan J. Vastert, Sytze de Roock
Journal: Arthritis & Rheumatology (2018)

Neutrophils are the most abundant innate immune cells in the blood, but little is known about their role in (acquired) chronic autoinflammatory diseases. This study was undertaken to investigate the role of neutrophils in systemic-onset juvenile idiopathic arthritis (JIA), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation.Fifty patients with systemic-onset JIA who were receiving treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) were analyzed at disease onset and during remission. RNA sequencing was performed on fluorescence-activated cell-sorted neutrophils from 3 patients with active systemic-onset JIA and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (ROS), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic-onset JIA and 15 healthy controls.Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of rIL-1Ra therapy. RNA-sequencing analysis revealed a substantial up-regulation of inflammatory processes in neutrophils from patients with active systemic-onset JIA, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic-onset JIA displayed a primed phenotype that was characterized by increased ROS production, CD62L shedding, and secretory vesicle degranulation, which was reversed by rIL-1Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to rIL-1Ra, whereas patients with symptoms for >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1Ra. In vitro, rIL-1Ra antagonized the priming effect of IL-1β on neutrophils from healthy subjects.These results strongly support the notion that neutrophils play an important role in systemic-onset JIA, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic-onset JIA are both susceptible to IL-1 blockade.
Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.
Authors: Manuel M. Hidalgo, Ron Epelbaum, Valeriya Semenisty, Ravit Geva, Talia Golan, Erkut Hasan Borazanci, Salomon M. Stemmer, Mitesh J. Borad, Joon Oh Park, Katrina Pedersen, Brian M. Wolpin, Robert A. Ramirez, Carlos Becerra, Steven Shaw, Galia Oberkovitz, Abi Vainstein Haras, Ella Sorani, Tzipora M Lustig, Amnon Peled, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2018)

88 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.
IMPACT OF PATIENT BODY MASS INDEX ON NURSE RADIATION DOSE DURING CORONARY ANGIOGRAPHY
Authors: Lahdan Refahiyat, Austin Clarey, Jacob Bundy, Edwin Mandieka, David Benavides, Thomas Crane, Sheetal Maragiri, Erica Osip, Emily Pardington, Abbey Mulder, Taylor Ten Brock, Jessica Parker, Stacie VanOosterhout, Ryan Madder
Journal: Journal of the American College of Cardiology (2018)
Management of fatigue in children and adolescents with cancer and in paediatric recipients of haemopoietic stem-cell transplants: a clinical practice guideline
Authors: Paula D Robinson, Sapna Oberoi, Deborah Tomlinson, Nathan Duong, Hailey Davis, Danielle Cataudella, Nicole Culos-Reed, Faith Gibson, Miriam Götte, Pamela Hinds, Sanne L Nijhof, Patrick van der Torre, Sandra Cabral, L Lee Dupuis, Lillian Sung
Journal: The Lancet Child & Adolescent Health (2018)
SELF-REPORTED FUNCTIONAL CAPACITY BY DASI AND KCCQ ARE POORLY ASSOCIATED WITH OBJECTIVE MEASURES ON CARDIOMETABOLIC STRESS TESTING IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Authors: Albree Tower-Rader, Brian Griffin, Milind Desai, Harry Lever, Maran Thamilarasan, Zoran Popovic, L. Leonardo Rodriguez, Richard Grimm, Rory Hachamovitch
Journal: Journal of the American College of Cardiology (2018)