tbuckley/cabot-search huggingface dataset:
Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression
Authors: E.J. Aguilar, B. Ricciuti, J.F. Gainor, K.L. Kehl, S. Kravets, S. Dahlberg, M. Nishino, L.M. Sholl, A. Adeni, S. Subegdjo, S. Khosrowjerdi, R.M. Peterson, S. Digumarthy, C. Liu, J. Sauter, H. Rizvi, K.C. Arbour, B.W. Carter, J.V. Heymach, M. Altan, M.D. Hellmann, M.M. Awad
Journal: Annals of Oncology (2019)

BackgroundIn non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%–100% predict for even greater benefit to pembrolizumab is currently unknown.Patients and methodsIn this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes.ResultsAmong 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5–8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%–89% (N = 107), patients with an expression level of 90%–100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33–0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21–0.70), P = 0.002].ConclusionAmong patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
Thirty‐year risk of ischemic stroke in individuals with sickle cell trait and modification by chronic kidney disease: The atherosclerosis risk in communities (ARIC) study
Authors: Melissa C. Caughey, Vimal K. Derebail, Nigel S. Key, Alexander P. Reiner, Rebecca F. Gottesman, Abhijit V. Kshirsagar, Gerardo Heiss
Journal: American Journal of Hematology (2019)

Abstract Sickle cell trait (SCT) has been associated with hypercoagulability, chronic kidney disease (CKD), and ischemic stroke. Whether concomitant CKD modifies long‐term ischemic stroke risk in individuals with SCT is uncertain. We analyzed data from 3602 genotyped black adults (female = 62%, mean baseline age = 54 years) who were followed for a median 26 years by the Atherosclerosis Risk in Communities Study. Ischemic stroke was verified by physician review. Associations between SCT and ischemic stroke were analyzed using repeat‐events Cox regression, adjusted for potential confounders. SCT was identified in 236 (7%) participants, who more often had CKD at baseline than noncarriers (18% vs 13%, P = .02). Among those with CKD, elevated factor VII activity was more prevalent with SCT genotype (36% vs 22%; P = .05). From 1987‐2017, 555 ischemic strokes occurred in 436 individuals. The overall hazard ratio of ischemic stroke associated with SCT was 1.31 (95% CI: 0.95‐1.80) and was stronger in participants with concomitant CKD (HR = 2.18; 95% CI: 1.16‐4.12) than those without CKD (HR = 1.09; 95% CI: 0.74‐1.61); P for interaction = .04. The hazard ratio of composite ischemic stroke and/or death associated with SCT was 1.20 (95% CI: 1.01‐1.42) overall, 1.44 (95% CI: 1.002‐2.07) among those with CKD, and 1.15 (95% CI: 0.94‐1.39) among those without CKD; P for interaction = .18. The long‐term risk of ischemic stroke associated with SCT relative to noncarrier genotype appears to be modified by concomitant CKD.
<i>Clostridioides difficile</i>: diagnosis and treatments
Authors: Benoit Guery, Tatiana Galperine, Frédéric Barbut
Journal: BMJ (2019)

Clostridioides difficile (formerly Clostridium) is a major cause of healthcare associated diarrhea, and is increasingly present in the community. Historically, C difficile infection was considered easy to diagnose and treat. Over the past two decades, however, diagnostic techniques have changed in line with a greater understanding of the physiopathology of C difficile infection and the use of new therapeutic molecules. The evolution of diagnosis showed there was an important under- and misdiagnosis of C difficile infection, emphasizing the importance of algorithms recommended by European and North American infectious diseases societies to obtain a reliable diagnosis. Previously, metronidazole was considered the reference drug to treat C difficile infection, but more recently vancomycin and other newer drugs are shown to have higher cure rates. Recurrence of infection represents a key parameter in the evaluation of new drugs, and the challenge is to target the right population with the adapted therapeutic molecule. In multiple recurrences, fecal microbiota transplantation is recommended. New approaches, including antibodies, vaccines, and new molecules are already available or in the pipeline, but more data are needed to support the inclusion of these in practice guidelines. This review aims to provide a baseline for clinicians to understand and stratify their choice in the diagnosis and treatment of C difficile infection based on the most recent data available.
Regulatory innate lymphoid cells suppress innate immunity and reduce renal ischemia/reperfusion injury
Authors: Qi Cao, Ruifeng Wang, Yiping Wang, Zhiguo Niu, Titi Chen, Chengshi Wang, Li Jin, Qingsong Huang, Qing Li, Xin Maggie Wang, Farhana Azmi, Vincent W.S. Lee, Yuan Min Wang, Guoping Zheng, Stephen I. Alexander, David C.H. Harris
Journal: Kidney International (2019)
Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies
Authors: Aung Naing, Jeffrey Infante, Sanjay Goel, Howard Burris, Chelsea Black, Shannon Marshall, Ikbel Achour, Susannah Barbee, Rena May, Chris Morehouse, Kristen Pollizzi, Xuyang Song, Keith Steele, Nairouz Elgeioushi, Farzana Walcott, Joyson Karakunnel, Patricia LoRusso, Amy Weise, Joseph Eder, Brendan Curti, Michael Oberst
Journal: Journal for ImmunoTherapy of Cancer (2019)

The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies. MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.5, 2.5, 10 or 20 mg/kg. Two cohorts received 20 mg/kg once a week for 2 or 4 weeks, then 20 mg/kg Q2W. All were treated for 12 months or until progression. The primary endpoint was safety. Secondary endpoints were efficacy and pharmacokinetics. Exploratory endpoints included pharmacodynamics. Fifty-eight patients were treated. Median age was 62.5 years and 81% were male. Most had kidney cancer (n = 36) or melanoma (n = 9). There were no dose-limiting toxicities. Treatment-related adverse events occurred in 83% and were grade ≥ 3 in 21%. Objective clinical responses occurred in 8/58 patients (14%): 5 with kidney cancer, including 1 with a complete response, and 3 with melanoma. The relationship between dose and serum levels was predictable and linear, with apparent receptor saturation at 10 mg/kg Q2W and all 20 mg/kg cohorts. MEDI0680 induced peripheral T-cell proliferation and increased plasma IFNγ and associated chemokines regardless of clinical response. CD8+ T-cell tumor infiltration and tumoral gene expression of IFNG, CD8A, CXCL9, and granzyme K (GZMK) were also increased following MEDI0680 administration. NCT02013804 ; date of registration December 12, 2013.
Association of Concussion Symptoms With Testosterone Levels and Erectile Dysfunction in Former Professional US-Style Football Players
Authors: Rachel Grashow, Marc G. Weisskopf, Karen K. Miller, David M. Nathan, Ross Zafonte, Frank E. Speizer, Theodore K. Courtney, Aaron Baggish, Herman A. Taylor, Alvaro Pascual-Leone, Lee M. Nadler, Andrea L. Roberts
Journal: JAMA Neurology (2019)

Small studies suggest that head trauma in men may be associated with low testosterone levels and sexual dysfunction through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage. Athletes in contact sports may be at risk for pituitary insufficiencies or erectile dysfunction (ED) because of the high number of head traumas experienced during their careers. Whether multiple symptomatic concussive events are associated with later indicators of low testosterone levels and ED is unknown.To explore the associations between concussion symptom history and participant-reported indicators of low testosterone levels and ED.This cross-sectional study of former professional US-style football players was conducted in Boston, Massachusetts, from January 2015 to March 2017. Surveys on past football exposures, demographic factors, and current health conditions were sent via electronic and postal mail to participants within and outside of the United States. Analyses were conducted in Boston, Massachusetts; the data analysis began in March 2018 and additional analyses were performed through June 2019. Of the 13 720 male former players eligible to enroll who were contacted, 3506 (25.6%) responded.Concussion symptom score was calculated by summing the frequency with which participants reported 10 symptoms, such as loss of consciousness, disorientation, nausea, memory problems, and dizziness, at the time of football-related head injury.Self-reported recommendations or prescriptions for low testosterone or ED medication served as indicators for testosterone insufficiency and ED.In 3409 former players (mean [SD] age, 52.5 [14.1] years), the prevalence of indicators of low testosterone levels and ED was 18.3% and 22.7%, respectively. The odds of reporting low testosterone levels or ED indicators were elevated for previously established risk factors (eg, diabetes, sleep apnea, and mood disorders). Models adjusted for demographic characteristics, football exposures, and current health factors showed a significant monotonically increasing association of concussion symptom score with the odds of reporting the low testosterone indicator (highest vs lowest quartile, odds ratio, 2.39; 95% CI, 1.79-3.19; P < .001). The ED indicator showed a similar association (highest quartile vs lowest, odds ratio, 1.72; 95% CI, 1.30-2.27; P < .001).Concussion symptoms at the time of injury among former football players were associated with current participant-reported low testosterone levels and ED indicators. These findings suggest that men with a history of head injury may benefit from discussions with their health care clinicians regarding testosterone deficiency and sexual dysfunction.
Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10
Authors: Jame Abraham, Albert J. Montero, Rachel C. Jankowitz, Mohamad Adham Salkeni, Jan H. Beumer, Brian F. Kiesel, Fanny Piette, Laura M. Adamson, Rebecca J. Nagy, Richard B. Lanman, Jeff Sperinde, Weidong Huang, Carmen J. Allegra, Ashok Srinivasan, Ying Wang, Katherine L. Pogue-Geile, Peter C. Lucas, Samuel A. Jacobs
Journal: Journal of Clinical Oncology (2019)

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab.In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally.Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell-free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue.We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.
Predictors and trajectories of fatigue in ovarian and uterine cancer.
Authors: Hanneke Poort, Belle Hadewijch de Rooij, Shicheng Weng, Nicole Ezendam, Lonneke V van de Poll-Franse, Alexi A. Wright
Journal: Journal of Clinical Oncology (2019)

11603 Background: Fatigue is one of the most common and distressing symptoms reported by patients with gynecological cancers, but few studies have empirically examined whether it resolves without intervention. The aims of this study were to identify: 1) clinically-distinct subgroups of patients with fatigue over time and 2) medical and psychological predictors of clinically-significant fatigue one-year post-diagnosis. Methods: Secondary analysis of a prospective cohort study. Symptoms of fatigue, depression, and anxiety were assessed at diagnosis, 6-months, and 12-months with the 10-item Fatigue Assessment Scale (FAS), and the Hospital Anxiety and Depression Scale (HADS), respectively. Group-based trajectory modeling was used to classify patients by their fatigue scores over time, and logistic regression models were fit to examine associations between clinically-significant fatigue and demographic, clinical, and psychosocial characteristics. Patients with recurrent or primary progressive cancers were excluded from the primary analysis. Results: Among 312 participants with newly diagnosed ovarian (n = 112) or endometrial (n = 200) cancers, the median age was 66 years (IQR = 60-72 years), 36% had ovarian cancer, and 79% had early stage disease. At baseline, 49% reported clinically significant fatigue and one year later, 42% had persistent fatigue. During the year after diagnosis, there were three distinct trajectories of fatigue that persisted: (1) severe fatigue (15%), (2) moderate fatigue (45%), and (3) no fatigue (41%). Patients with ≥2 comorbid conditions (odds ratio [OR] 2.52, 95% confidence interval [CI] = 1.21-5.27, P = 0.01), clinically significant fatigue at baseline (OR 5.47, 95% CI = 2.71-11.03, P &lt; .0001), and those reporting depressive symptoms at baseline (OR 3.45, 95% CI = 1.13-10.55, P = 0.03) were more likely to report clinically-significant fatigue at 12 months. Conclusions: Half of women with gynecologic cancers have clinically-significant fatigue at diagnosis and 42% of survivors have persistent fatigue one year later, suggesting spontaneous regression of symptoms is rare. Importantly, depressive symptoms contribute to persistent fatigue and are modifiable with psychological interventions. Future studies should test scalable psychological interventions to address depressive symptoms, reduce fatigue, and improve quality of life in women with gynecologic cancers.
Debating the new haemodynamic definition of pulmonary hypertension: much ado about nothing?
Authors: Gabor Kovacs, Horst Olschewski
Journal: European Respiratory Journal (2019)

<b>The change in the haemodynamic definition of PH represents a step towards physiological haemodynamic thresholds, but does not relevantly increase the number of patients that will be classified as having pre-capillary PH associated with SSc</b>http://bit.ly/2xZGoDC
Whole-transcriptome sequencing reveals heightened inflammation and defective host defence responses in chronic rhinosinusitis with nasal polyps
Authors: Yang Peng, Xiao-Xue Zi, Teng-Fei Tian, Bernett Lee, Josephine Lum, See Aik Tang, Kai Sen Tan, Qian-Hui Qiu, Jing Ye, Li Shi, Wei-Jie Guan, Anand Kumar Andiappan, De Yun Wang
Journal: European Respiratory Journal (2019)

The pathways underlying chronic rhinosinusitis with nasal polyps (CRSwNP) are unclear. We conducted genome-wide gene expression analysis to determine pathways and candidate gene sets associated with CRSwNP.We performed whole-transcriptome RNA sequencing on 42 polyp (CRSwNP-NP) and 33 paired nonpolyp inferior turbinate (CRSwNP-IT) tissues from patients with CRSwNP and 28 inferior turbinate samples from non-CRS controls (CS-IT). We analysed the differentially expressed genes (DEGs) and the gene sets that were enriched in functional pathways.Principal component-informed analysis revealed cilium function and immune regulation as the two main Gene Ontology (GO) categories differentiating CRSwNP patients from controls. We detected 6182 and 1592 DEGs between CRSwNP-NP versus CS-IT and between CRSwNP-NP versus CRSwNP-IT tissues, respectively. Atopy status did not have a major impact on gene expression in various tissues. GO analysis on these DEGs implicated extracellular matrix (ECM) disassembly, O-glycan processing, angiogenesis and host viral response in CRSwNP pathogenesis. Ingenuity Pathway Analysis identified significant enrichment of type 1 interferon signalling and axonal guidance canonical pathways, angiogenesis, and collagen and fibrotic changes in CRSwNP (CRSwNP-NP and CRSwNP-IT) tissues compared with CS-IT. Finally, gene set enrichment analysis implicated sets of genes co-regulated in processes associated with inflammatory response and aberrant cell differentiation in polyp formation.Gene signatures involved in defective host defences (including cilia dysfunction and immune dysregulation), inflammation and abnormal metabolism of ECM are implicated in CRSwNP. Functional validation of these gene expression patterns will open opportunities for CRSwNP therapeutic interventions such as biologics and immunomodulators.
Rammya Mathew: The pursuit of being a good doctor
Authors: Rammya Mathew
Journal: BMJ (2019)

The aspiration to be a good doctor is probably common to us all, but what does it really mean? Has anyone defined “good?” I’m reminded of many personal statements I’ve read over the years in which students, vying for a highly sought after place in medical school, claim to be cut out for the job because they’re empathetic or willing to go the extra mile to help others.

Empathy is an ambiguous concept, but in medicine it can be loosely defined as an emotional experience between clinician and patient, where the clinician identifies with …
A prognostic role for non-thyroidal illness syndrome in chronic renal failure:a systematic review and meta-analysis
Authors: Huaiyu Xiong, Peijing Yan, Qiangru Huang, Tiankui Shuai, Jingjing Liu, Lei Zhu, Jiaju Lu, Xiue Shi, Kehu Yang, Jian Liu
Journal: International Journal of Surgery (2019)
Does It Ever Go Away?
Authors: Katherine E. Reeder-Hayes
Journal: JAMA Pediatrics (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
The global burden of HIV and prospects for control
Authors: Abhishek Pandey, Alison P Galvani
Journal: The Lancet HIV (2019)

HIV/AIDS continues to have devastating health effects globally, with over 39 million HIV/AIDS-related deaths to date and more than 36 million people living with HIV currently.1,2 Despite great advancements in antiretroviral therapy (ART) and worldwide progress towards implementation of treatment-as-prevention programmes, approximately 2 million people become newly infected with HIV every year.2,3 Retrospectively, evaluations of the HIV burden are integral to the assessment of control approaches.
SF3B2-Mediated RNA Splicing Drives Human Prostate Cancer Progression
Authors: Norihiko Kawamura, Keisuke Nimura, Kotaro Saga, Airi Ishibashi, Koji Kitamura, Hiromichi Nagano, Yusuke Yoshikawa, Kyoso Ishida, Norio Nonomura, Mitsuhiro Arisawa, Jun Luo, Yasufumi Kaneda
Journal: Cancer Research (2019)

Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by in silico and CRISPR/Cas9 analyses, is a critical determinant of AR-V7 expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer. SIGNIFICANCE: RNA splicing factor SF3B2 is essential for the generation of an androgen receptor (AR) variant that renders prostate cancer cells resistant to AR-targeting therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5204/F1.large.jpg.