tbuckley/cabot-search huggingface dataset:
The outcome of checkpoint inhibitor therapy in patients with cancer and solid organ transplant: A systematic review of the literature.
Authors: Noha Abdelwahab Hassan, Ala Abudayyeh, Mohsin Shah, Daniel Hartman Johnson, Maria E. Suarez-Almazor, Adi Diab
Journal: Journal of Clinical Oncology (2018)

41 Background: Solid organ transplant recipients have been excluded from Checkpoint inhibitors (CPI) clinical trials because of the concern of allo-immunity and possible organ rejection. Methods: We searched 5 databases through September 2017. Studies describing the use of CPI to treat cancer in solid organ transplant Patients (pts), and provided detailed description of each case were included. Results: Sixteen publications met inclusion criteria, reporting on 19 cases. Median age of pts was 59 (14-77) yrs and 74% were male. Cancer types included melanoma (n=11), cutaneous squamous cell carcinoma (ca) (n=3), non-small cell lung ca and hepatocellular ca (n=2 each), and duodenal ca (n=1). Median time to start CPI after organ transplant was 11 (1-25) yrs. Nivolumab (nivo) was used in 53%, ipilimumab (ipi) in 26%, and pembrolizumab (pem) in 21%. Most pts were maintained on low dose prednisone (≤ 10 mg), mTOR inhibitors, and other immunosuppressives prior to initiating CPI. Graft rejection occurred in 10 of 19 pts (7/12 kidney, 2/5 liver, and 1/2 heart transplants), 90% after receiving anti PD-1, and CPI was discontinued. Median time to rejection was 21 (5-60) days, and obtained biopsies were suggestive of a T-cell mediated rejection process. Only a cardiac transplant recipient with a bioposy proven cellular rejection after nivo, had improved ejection fraction after pulse steroids. Aside from rejection no other immune related adverse events (irAEs) reported. Nivo re-challenge was recommended for a kidney recipient 12 weeks after the rejection process, and the pt had partial tumor response but remained on hemodialysis. Of the 9 pts who had no rejection, 4 had irAEs (hepatitis, colitis, pneumonitis, and dermatitis), including 3 who required high-dose steroids with subsequent improvement, and the remaining 5 pts did not experience any irAEs. Clinical benefit rate was 57% of all pts. Two pts with liver transplants died within 1 month of nivo treatment secondary to acute liver rejection, and 2 others died because of progressive cancer. Conclusions: CPI seem to be associated with high rate of rejection. Multi-institutional collaborative studies are warranted to enhance our understanding of the pathogenesis and plan optiomal therapy that maintain graft tolerance without dampening antitumor clinical benefits.
Immune deserts: Correlation of low CD8 gene expression with non-response to checkpoint inhibition.
Authors: Mark Gardner, Sarabjot Pabla, Marc S. Ernstoff, Igor Puzanov, Jeffrey M. Conroy, Mary Nesline, Sean T. Glenn, Antonios Papanicolau-Sengos, Blake Burgher, Jonathan Andreas, Vincent Giamo, Maochun Qin, Felicia L. Lenzo, Carl Morrison
Journal: Journal of Clinical Oncology (2018)

23 Background: Associations between presence and density of effector T-cells (CD8+) and response to checkpoint inhibitors (CPIs) has been established for protein biomarkers using immunohistochemistry but less work has been done to characterize this relationship through gene expression. Methods: We collected clinical response data (RECIST v1.1) for 184 patients who had been treated with CPIs across tumor types with FDA indications. We tested formalin-fixed paraffin embedded (FFPE) samples by NGS with a comprehensive immune response panel which interrogates the gene expression profile of 54 validated immune-related genes. Ranked gene expression was compared to a reference population. 85/184 (46%) cases were considered “responders” after six months, and 66/184 cases (36%) were considered responders after twelve months on treatment. We hypothesized that patients with in the bottom quartile of CD8 expression, as measured by the rank of the sum of normalized CD8A and CD8B transcripts compared to a reference population, would be unlikely to respond to checkpoint therapy (immune deserts), and that “hot” tumor environments (TME) with the highest quartile of expression would be most likely to respond. Results: After six months of therapy, 13/40 (32.5%) patients with immune desert tumors responded to therapy, whereas 39/82 patients (47.6%) in the middle 50% of expression responded, and 33/62 (53.2%) of patients with “hot” TME responded to treatment. The two-tailed p-value of the null hypothesis, that TME status does not correlate with response, was 0.018 and could be rejected. After twelve months of observation, 9/40 (22.5%) immune desert patients were considered “responders”. 28/82 (34.2%) of the middle 50% of expression were classified as responders, and 29/62 (46.8%) of top quartile samples came from responders. The two-tailed p-value of the null hypothesis was 0.005 and could be rejected. Conclusions: Gene expression of CD8 as measured by RNA-seq from FFPE samples can be used to compare these samples versus a reference population to predict an increase or decrease in likelihood of response to CPIs. Patients in the lowest quartile of CD8 expression were the least likely to respond to these promising therapies.
Geolocalisation of athletes for out-of-competition drug testing: ethical considerations. Position statement by the WADA Ethics Panel
Authors: Pascal Borry, Timothy Caulfield, Xavier Estivill, Sigmund Loland, Michael McNamee, Bartha Maria Knoppers
Journal: British Journal of Sports Medicine (2018)

Through the widespread availability of location-identifying devices, geolocalisation could potentially be used to place athletes during out-of-competition testing. In light of this debate, the WADA Ethics Panel formulated the following questions: (1) should WADA and/or other sponsors consider funding such geolocalisation research projects?, (2) if successful, could they be proposed to athletes as a complementary device to Anti-Doping Administration and Management System to help geolocalisation and reduce the risk of missed tests? and (3) should such devices be offered on a voluntary basis, or is it conceivable that they would be made mandatory for all athletes in registered testing pools? In this position paper, the WADA Ethics Panel concludes that the use of geolocalisation could be useful in a research setting with the goal of understanding associations between genotype, phenotype and environment; however, it recognises that the use of geolocalisation as part of or as replacement of whereabouts rules is replete with ethical concerns. While benefits remain largely hypothetical and minimal, the potential invasion of privacy and the data security threats are real. Considering the impact on privacy, data security issues, the societal ramifications of offering such services and various pragmatic considerations, the WADA Ethics Panel concludes that at this time, the use of geolocalisation should neither be mandated as a tool for disclosing whereabouts nor implemented on a voluntary basis.
Call to cap orthopaedic training posts is based on “flawed” evidence, surgeons say
Authors: Abi Rimmer
Journal: BMJ (2014)

Recommendations to cap the number of recruits into trauma and orthopaedic surgery specialty training are based on flawed evidence, surgeons have warned.

Last month the Centre for Workforce Intelligence (CFWI) said that recruitment into trauma and orthopaedic surgery in the third year of specialty training (ST3) should be capped at 122 posts a year in 2014-15 and 2015-16.1

Paul Manning, chair of the British Orthopaedic Association’s forum of training programme directors, and Tim Briggs, former president of the British Orthopaedic Association, have warned that …
Effect of detecting asymptomatic recurrence after radical cystectomy on prognosis in patients with muscle invasive bladder cancer.
Authors: Shingo Hatakeyama, Ayumu Kusaka, Hirotake Kodama, Noriko Tokui, Hayato Yamamoto, Takahiro Yoneyama, Yasuhiro Hashimoto, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2018)

428 Background: The prognostic benefit of oncological follow-up to detect asymptomatic recurrence after radical cystectomy (RC) remains unclear. We aimed to assess whether routine follow-up to detect asymptomatic recurrence after RC improves patient survival. Methods: We retrospectively analyzed 581 RC cases for muscle invasive bladder cancer at four hospitals between May 1996 and February 2017. All patients had regular follow-up examinations with urine cytology, blood biochemical tests, and computed tomography after RC. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of recurrence (asymptomatic group vs. symptomatic group) was estimated using the Kaplan–Meier method with the log–rank test. Cox proportional hazards regression analysis via inverse probability of treatment weighting (IPTW) was used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: Of the 581 patients, 175 experienced relapse. Among those, 12 without adequate data were excluded. Of the remaining 163 patients, 76 (47%) were asymptomatic and 87 (53%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes (47%) and pain (53%), respectively. Time of overall survival after RC and from recurrence to death were significantly longer in the asymptomatic group than symptomatic group. A multivariate Cox regression analysis using IPTW showed that in the patients with symptomatic recurrence was an independent risk factor for overall survival after RC and survival from recurrence to death. Conclusions: Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RC.
<i>Notes from the Field:</i><i>Brucella abortus</i> Vaccine Strain RB51 Infection and Exposures Associated with Raw Milk Consumption — Wise County, Texas, 2017
Authors: Caitlin M. Cossaboom, Grishma A. Kharod, Johanna S. Salzer, Rebekah V. Tiller, Lindsay P. Campbell, Karen Wu, María E. Negrón, Naomi Ayala, Nicole Evert, Jill Radowicz, Jennifer Shuford, Shelley Stonecipher
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Genomic and phenotypic evidence for prostate cancer osteomimicry in circulating tumor cells from men with metastatic castration resistant prostate cancer (mCRPC) treated with radium-223.
Authors: Andrew J. Armstrong, Santosh Gupta, Patrick Healy, Gabor Kemeny, Lauren Beth Leith, Michael Zalutsky, Charles Spritzer, Catrin Davies, Katie Ware, Jason Somarelli, Kris Wood, Wayne Glover, Shiaowen David Hsu, Drew Gerber, Colin Rothwell, Kelly Mundy, Monika Anand, Simon Gregory, Susan Halabi, Daniel J. George
Journal: Journal of Clinical Oncology (2018)

160 Background: Radium-223 is a targeted alpha therapy that improves survival in men with mCRPC. The biologic basis for radium-223 efficacy is not completely understood. We hypothesized that PC osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to the intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods: We conducted a pharmacodynamic study of radium-223 in men with bone predominant mCRPC to investigate genomic and phenotypic alterations in circulating tumor cells (CTCs), ctDNA, and metastases. Prior to radium and 3 and 6 months after radium, liquid and metastatic biopsies were collected, including CTCs for phenotypic characterization and CTC/ctDNA genomic analysis. The primary objective was to describe the prevalence of CTC bone alkaline phosphatase (BAP) over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. Results: We enrolled 20 men with heavily pre-treated symptomatic bone predominant mCRPC and treated with radium-223 over a median of 6 doses. 55% had elevated serum BAP. PFS was 5.5 mo; OS was 13.3 mo; 10% had unfavorable (≥5) to favorable ( &lt; 5) Cellsearch CTC conversion; 5% had ≥30% PSA decline. We found evidence of persistent CTC BAP expression in both EpCAM+ and EpCAM- CTCs in the majority of men over time during radium treatment. We identified genomic gain of key osteomimicry regions in CTC DNA, including loci for BAP, osteopontin, and OB-cadherin. Radium-223 uptake was observed in tumor to a greater degree than surrounding normal bone. CTC DNA and matched ctDNA and CTC cultures suggested persistence of CTCs with aggressive genomic alterations such as AR, FOXA1, and MYC gain and PTEN and RB1 loss. We established multiple CTC cultures and one CTC PDX; cells exhibited evidence of epithelial plasticity with BAP expression. Conclusions: Osteomimicry may contribute to the uptake of Radium-223 within bone metastases and may thereby enhance the therapeutic benefit of radium-223. We found genomic and phenotypic evidence of osteomimicry in CTCs and CTC cultures from men with mCRPC. Clinical trial information: NCT02204943.
The impact of PD-L1 on survival and values of nivolumab, atezolizumab, and pembrolizumab compared with docetaxel in second-line non-small cell lung cancer.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2018)

141 Background: The impact of programmed death receptor-ligand1 (PD-L1) on values of the immune check point inhibitors (ICPI) has received minimal attention. Objectives: Grade survival and weigh values of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc) in 2 nd -line non-squamous non-small-cell lung cancer (NSCLC). Methods: Previously reported median overall survival (OS), adverse events and prices posted by the parent companies were utilized. The OS gains in days over controls were graded (gr) from A to D. Docetaxel costs x 6 -12 cycles and ICPI x one year were calculated separately from adverse events treatment costs (AEsTC). Costs/life-year gain (C/LYG) were computed as drug C/OS gain x 360. Relative Values were expressed as $100,000/C/LYG. Results: Docetaxel costs of 9 cycles were $35,802, OS/gr 87/C, AEs gr ¾ &gt; 20%, AEsTC $4,940 and C/LYG $148,146. Nivo, Atezo and Pembro gr ¾ &lt; 20% were at $1,480 costs. In non-squamous NSCLC, Nivo OS/gr were 84/C and C/LYG $545,754. The results improved in PD-L1 &gt; 10% to 264/A and $177,645 respectively. Atezolizumab demonstrated OS/gr 99/C and C/LYG $551,407 improving in PD-L1 50% to 348/A and $151,193. Pembrolizumab in PD-L1 &gt; 1.0%, the OS/gr were 57/C and C/LYG $659,059 improving in &gt; 50% to 201/A and $186,897. PD-L1 enrichment increased relative values of Nivo from 0.19 to 0.56, Atezo from 0.19 to 0.66 and Pembro from 0.15 to 0.53. Conclusions: In 2 nd -line non-squamous NSCLC, the OS of Doc, Nivo, Atezo and Pembro were limited. In PD-L1 enriched, the ICPI resulted in unprecedented OS, improved grades and enhanced values at justifiable costs.
ICU Admission and Mortality Among Elderly Adults—Reply
Authors: Bertrand Guidet, Dominique Pateron, Ariane Boumendil
Journal: JAMA (2018)

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Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry
Authors: Holger Winkels, Erik Ehinger, Melanie Vassallo, Konrad Buscher, Huy Q. Dinh, Kouji Kobiyama, Anouk A.J. Hamers, Clément Cochain, Ehsan Vafadarnejad, Antoine-Emmanuel Saliba, Alma Zernecke, Akula Bala Pramod, Amlan K. Ghosh, Nathaly Anto Michel, Natalie Hoppe, Ingo Hilgendorf, Andreas Zirlik, Catherine C. Hedrick, Klaus Ley, Dennis Wolf
Journal: Circulation Research (2018)

Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is poorly understood.We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single-cell RNA-sequencing and mass cytometry (cytometry by time of flight) to define an atlas of the immune cell landscape in atherosclerosis.Using single-cell RNA-sequencing of aortic leukocytes from chow diet- and Western diet-fed Apoe-/- and Ldlr-/- mice, we detected 11 principal leukocyte clusters with distinct phenotypic and spatial characteristics while the cellular repertoire in healthy aortas was less diverse. Gene set enrichment analysis on the single-cell level established that multiple pathways, such as for lipid metabolism, proliferation, and cytokine secretion, were confined to particular leukocyte clusters. Leukocyte populations were differentially regulated in atherosclerotic Apoe-/- and Ldlr-/- mice. We confirmed the phenotypic diversity of these clusters with a novel mass cytometry 35-marker panel with metal-labeled antibodies and conventional flow cytometry. Cell populations retrieved by these protein-based approaches were highly correlated to transcriptionally defined clusters. In an integrated screening strategy of single-cell RNA-sequencing, mass cytometry, and fluorescence-activated cell sorting, we detected 3 principal B-cell subsets with alterations in surface markers, functional pathways, and in vitro cytokine secretion. Leukocyte cluster gene signatures revealed leukocyte frequencies in 126 human plaques by a genetic deconvolution strategy. This approach revealed that human carotid plaques and microdissected mouse plaques were mostly populated by macrophages, T-cells, and monocytes. In addition, the frequency of genetically defined leukocyte populations in carotid plaques predicted cardiovascular events in patients.The definition of leukocyte diversity by high-dimensional analyses enables a fine-grained analysis of aortic leukocyte subsets, reveals new immunologic mechanisms and cell-type-specific pathways, and establishes a functional relevance for lesional leukocytes in human atherosclerosis.
IOC consensus statement: dietary supplements and the high-performance athlete
Authors: Ronald J Maughan, Louise M Burke, Jiri Dvorak, D Enette Larson-Meyer, Peter Peeling, Stuart M Phillips, Eric S Rawson, Neil P Walsh, Ina Garthe, Hans Geyer, Romain Meeusen, Lucas J C van Loon, Susan M Shirreffs, Lawrence L Spriet, Mark Stuart, Alan Vernec, Kevin Currell, Vidya M Ali, Richard GM Budgett, Arne Ljungqvist, Margo Mountjoy, Yannis P Pitsiladis, Torbjørn Soligard, Uğur Erdener, Lars Engebretsen
Journal: British Journal of Sports Medicine (2018)

Nutrition usually makes a small but potentially valuable contribution to successful performance in elite athletes, and dietary supplements can make a minor contribution to this nutrition programme. Nonetheless, supplement use is widespread at all levels of sport. Products described as supplements target different issues, including (1) the management of micronutrient deficiencies, (2) supply of convenient forms of energy and macronutrients, and (3) provision of direct benefits to performance or (4) indirect benefits such as supporting intense training regimens. The appropriate use of some supplements can benefit the athlete, but others may harm the athlete’s health, performance, and/or livelihood and reputation (if an antidoping rule violation results). A complete nutritional assessment should be undertaken before decisions regarding supplement use are made. Supplements claiming to directly or indirectly enhance performance are typically the largest group of products marketed to athletes, but only a few (including caffeine, creatine, specific buffering agents and nitrate) have good evidence of benefits. However, responses are affected by the scenario of use and may vary widely between individuals because of factors that include genetics, the microbiome and habitual diet. Supplements intended to enhance performance should be thoroughly trialled in training or simulated competition before being used in competition. Inadvertent ingestion of substances prohibited under the antidoping codes that govern elite sport is a known risk of taking some supplements. Protection of the athlete’s health and awareness of the potential for harm must be paramount; expert professional opinion and assistance is strongly advised before an athlete embarks on supplement use.
Senior doctors’ non-clinical work may suffer because of revalidation, says academy
Authors: Sally Carter
Journal: BMJ (2012)

Most hospital doctors believe that revalidation will take substantial time over and above their time for appraisal, and as a result some input into non-clinical activities may be lost, says a report of a survey by the Academy of Medical Royal Colleges. 

However, no strong evidence was found that the direct care of patients would be compromised in the short term by the requirements of the revalidation process, the academy reports.

Its survey, which was done in 2011 to explore how revalidation would affect the responsibilities of hospital doctors, contains the views of more than 2600 doctors working in the NHS (80% of whom were consultants and 20% staff and associate specialist (SAS) doctors) in …
Second letter to the GMC chair regarding Hadiza Bawa-Garba
Authors: Nick Ross
Journal: BMJ (2018)

The following is a letter of 5 February 2018 to the chair of the General Medical Council.

Dear Professor Stephenson,

My last letter to you about Hadiza Bawa-Garba (9 November 2017)1 was followed by a stream of similar comments in the medical and national presses and on social media, mostly from doctors and the Academy of Royal Medical Colleges but also from non-medics like me and, not least, of course, from Jeremy Hunt. I do not think it is an exaggeration to say that in striking a physician off the medical register for making mistakes you may have called into question the future of the GMC.

In statements since, you have sought to pour oil on troubled water, and your splendid chief executive, Charlie Massey, and counsel, Anthony Omo, met me with much courtesy and did their best to persuade me that you had no choice but to seek Bawa-Garba’s erasure and that you have learned important lessons from the affair.

Of course those two things are incompatible.

Many of us still find it hard to follow your logic. Your principal defence has been that to allow Bawa-Garba to continue to practise would “unpick the criminal court conviction.” That is not so. Only the courts of appeal can do that, and I hope they will.

You opted to go further than the criminal courts, and it was …