tbuckley/cabot-search huggingface dataset:
Evaluation of RNA-sequencing (RNA-seq) signatures with pembrolizumab (pembro) in patients (pts) with renal cell carcinoma (RCC) from KEYNOTE-427 cohort A.
Authors: David F. McDermott, Jae-Lyun Lee, Georg A. Bjarnason, James M. G. Larkin, Rustem Airatovich Gafanov, Mark D. Kochenderfer, Jahangeer Malik, Alexandr Poprach, Scott S. Tykodi, Sabina Signoretti, Rodolfo F. Perini, Jared Lunceford, Raluca Andreia Predoiu, Andrey Loboda, Qing Zhao, Alexandra Snyder, Charles Schloss, Michael B. Atkins
Journal: Journal of Clinical Oncology (2020)

729 Background: We evaluated the association (assoc) of baseline RNA-seq–based signatures with response/resistance to pembro from the phase 2 KEYNOTE-427 study (NCT02853344) in pts with advanced clear cell RCC enrolled in cohort A (n = 110). Methods: In pembro-treated pts with RNA-seq and clinical data (N = 78), we analyzed the assoc of signatures (18-gene tumor T-cell–inflamed GEP; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying the TME with clinical outcomes. Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were also analyzed through regression testing of response and the residuals of consensus signatures after adjusting for T-cell–inflamed GEP and IMDC scores in the model. P values were adjusted for multiplicity. Database cutoff date for clinical data: March 12, 2019. Results: Pt characteristics for this analysis were similar to those of the overall cohort A population. T-cell–inflamed GEP was statistically significantly assoc with ORR ( P = 0.021) but not PFS ( P = 0.116). When adjusting for PD-L1 expression (CPS by IHC) and IMDC scores, T-cell–inflamed GEP remained statistically significantly assoc with ORR ( P = 0.059). The angiogenesis signature was not assoc with response. PD-L2 RNA-seq expression was not assoc with response with multiplicity-adjusted P values. Like PD-L1 IHC, PD-L2 RNA-seq expression moderately correlated with T-cell–inflamed GEP and did not show independent predictive value when adjusted for T-cell–inflamed GEP and IMDC scores. Conclusions: RNA-seq–based, T-cell–inflamed GEP was assoc with ORR in pts with clear cell RCC receiving first-line pembro monotherapy; no canonical signatures showed statistical significance. Future directions for these data include whole exome sequencing analysis. Clinical trial information: NCT02853344.
Expectations for overall survival in mRCC patients who were selected for upfront cytoreductive nephrectomy in the targeted therapy era.
Authors: E. Jason Abel, Jose A. Karam, Philippe E. Spiess, Jay D. Raman, Wade J. Sexton, Logan Zemp, Alyssa Bilotta, Dattatraya Patil, Glenn O. Allen, Kate V. Lauer, Daniel D. Shapiro, Surena F. Matin, Christopher G. Wood
Journal: Journal of Clinical Oncology (2020)

646 Background: Surgical selection is critical to obtain the best outcomes for mRCC patients treated with cytoreductive nephrectomy (CN). Prior studies suggest that international metastatic disease consortium (IMDC) poor risk patients should not be considered for upfront CN because of expectation for short overall survival (OS). The purpose of this study is to evaluate OS among IMDC risk categories for patients treated with upfront cytoreductive nephrectomy during the targeted therapy era at five independent institutions. Methods: After IRB approval, data for consecutive mRCC patients treated with CN at 5 institutions from 2006-2017 was analyzed. Kaplan-Meier method was used to estimate survival from date of surgery and univariate/multivariable Cox models were used to evaluate associations with OS. Results: Of 1163 patients who were treated with CN at 5 institutions, 914 (79%) patients were treated without neoadjuvant systemic therapies. Preoperative IMDC risk category for upfront CN patients was favorable in 71 (8%), intermediate in 598 (65%), and poor in 245 (27%) patients. Median age was 61 (53-68) and median Charlson co-morbidity index was 1 (0-2). Median (IQR) patient follow-up for patients alive at last follow-up was 42.7 months (23, 69). The median OS (IQR) following upfront nephrectomy was 115.4 months (33,NR) for favorable risk patients, 28.6 months (9-65) for intermediate risk patients and 21.8 months (10-47) for poor risk patients. No differences were identified in OS among 5 different institutions (p=0.11) Of 245 poor risk patients, OS was not associated with co-morbidity status or age were not associated with OS (p=0.77, 0.92). Percentage survival at 1, 2, 3 and 5 years was 69%, 48%, 34%, and 20% in the poor risk cohort. Conclusions: Conclusions: After stratification by the IMDC model, observed survival following upfront cytoreductive nephrectomy in this multi-institutional cohort was longer than expected from prior studies, which may be partially attributed to surgical selection bias.
Decreased Hepatocyte Autophagy Leads to Synergistic IL‐1β and TNF Mouse Liver Injury and Inflammation
Authors: Yang Shen, Shoaib Ahmad Malik, Muhammad Amir, Pradeep Kumar, Francesca Cingolani, Jing Wen, Yunshan Liu, Enpeng Zhao, Alton B. Farris, Reben Raeman, Mark J. Czaja
Journal: Hepatology (2020)

Background and Aims The proinflammatory cytokine IL‐1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL‐1β promotes liver injury in these diseases is unclear, as no IL‐1β receptor‐linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy’s function in hepatotoxicity from proinflammatory cytokines. Approach and Results AML12 cells with decreased autophagy from a lentiviral autophagy‐related 5 ( Atg5 ) knockdown were resistant to toxicity from TNF, but sensitized to death from IL‐1β, which was markedly amplified by TNF co‐treatment. IL‐1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin‐1s to prevent death. IL‐1β/TNF depleted autophagy‐deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL‐1β/TNF‐induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy‐deficient cells. Mice with a tamoxifen‐inducible, hepatocyte‐specific Atg5 knockout were similarly sensitized to cathepsin‐dependent hepatocellular injury and death from IL‐1β/TNF in combination, but neither IL‐1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL‐1β/TNF‐treated, autophagy‐deficient AML12 cells secreted exosomes with proinflammatory damage–associated molecular patterns. Conclusions The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL‐1β/TNF‐induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage–associated molecular patterns.
Advancing age and the risk of adverse pathology at radical prostatectomy in men with biopsy Gleason score 6 prostate cancer.
Authors: Daniel Kim, Ming-Hui Chen, Hartwig Huland, Markus Graefen, Derya Tilki, Anthony Victor D'Amico
Journal: Journal of Clinical Oncology (2020)

289 Background: We evaluated the impact of age &gt; 65 years versus younger on the odds of finding adverse pathologic features (pT3/T4 and/or R1 and/or Gleason score 8, 9, 10) at radical prostatectomy (RP) among men with biopsy Gleason score 6 prostate cancer (PC). Methods: The study cohort comprised 3191 men with biopsy Gleason score 6 PC treated with a RP between February 28, 1992 and February 15, 2016 at the Martini-Klinik Prostate Cancer Center. Multivariable logistic regression was used to evaluate the impact of age &gt; 65 years versus younger on the adjusted odds ratio (AOR) of finding adverse pathology at RP adjusting for pre-RP prostate specific antigen (PSA), clinical tumor category, year of diagnosis, percent positive biopsies (PPB), and PSA density (PSAd). Results: Men age &gt; 65 years as compared to younger had significantly lower median PPB (16.67% vs 20.0%; p = 0.01) and PSAd (0.13 ng/mL vs 0.15 ng/mL; p &lt; 0.0001). Yet, while both increasing PPB (AOR 1.018, 95% CI 1.013, 1.023; p- &lt; 0.0001) and PSAd (AOR 4.28, 95% CI 1.66, 11.01; p = 0.003) were significantly associated with an increased odds of finding adverse pathology at RP, men age &gt; 65 years versus younger had a higher odds of adverse pathology at RP (AOR 1.28, 95% CI 1.002, 1.62; p = 0.048). Conclusions: Despite a more favorable median PPB and PSAd, men with biopsy Gleason score 6 PC and who are age &gt; 65 years compared to younger men are at higher risk for having adverse pathology at RP and may benefit from a multiparametric MRI and targeted biopsy before proceeding with active surveillance. If higher grade/stage disease is discovered and treatment indicated then this information could guide both the use and duration of supplemental androgen deprivation therapy in men considering radiation therapy.
Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond
Authors: Bo Zhao, Yien Che Tsai, Bo Jin, Bufan Wang, Yiyang Wang, Han Zhou, Tomaya Carpenter, Allan M. Weissman, Jun Yin
Journal: Pharmacological Reviews (2020)

Ubiquitin (UB) transfer cascades consisting of E1, E2, and E3 enzymes constitute a complex network that regulates a myriad of biologic processes by modifying protein substrates. Deubiquitinating enzymes (DUBs) reverse UB modifications or trim UB chains of diverse linkages. Additionally, many cellular proteins carry UB-binding domains (UBDs) that translate the signals encoded in UB chains to target proteins for degradation by proteasomes or in autophagosomes, as well as affect nonproteolytic outcomes such as kinase activation, DNA repair, and transcriptional regulation. Dysregulation of the UB transfer pathways and malfunctions of DUBs and UBDs play causative roles in the development of many diseases. A greater understanding of the mechanism of UB chain assembly and the signals encoded in UB chains should aid in our understanding of disease pathogenesis and guide the development of novel therapeutics. The recent flourish of protein-engineering approaches such as unnatural amino acid incorporation, protein semisynthesis by expressed protein ligation, and high throughput selection by phage and yeast cell surface display has generated designer proteins as powerful tools to interrogate cell signaling mediated by protein ubiquitination. In this study, we highlight recent achievements of protein engineering on mapping, probing, and manipulating UB transfer in the cell. SIGNIFICANCE STATEMENT: The post-translational modification of proteins with ubiquitin alters the fate and function of proteins in diverse ways. Protein engineering is fundamentally transforming research in this area, providing new mechanistic insights and allowing for the exploration of concepts that can potentially be applied to therapeutic intervention.
REACT: A feasibility study to test the integration of a cancer registry early case ascertainment process via electronic pathology reporting with an online clinical trial matching tool.
Authors: Hala Borno, Christine Duffy, Sylvia Zhang, Zinnia Loya, Todd Golden, Debora Oh, Anobel Y. Odisho, Scarlett Lin Gomez
Journal: Journal of Clinical Oncology (2020)

207 Background: Representation of diverse patient populations in prostate cancer clinical trials is essential to ensure results are applicable to all men. However, underrepresentation among underserved populations remains a critical problem. Population-based cancer registries provide a potential platform to overcome problems with inclusion of diverse patient populations in clinical research when used as a source for recruitment. Methods: Leveraging statewide implementation of early-case ascertainment (ECA) via electronic pathology for cancer case identification, we performed a feasibility study within the Greater Bay Area Cancer Registry to (1) test a process using ECA to identify new cases of advanced prostate cancer for potential enrollment into clinical trials and (2) test the utility of an online clinical trial matching tool to improve matching of underrepresented patients into clinical trials. All study materials were translated into Spanish, and recruiters were Spanish-speaking. Results: A total of 419 cases were identified from 19 reporting facilities through ECA and sent invitation letters; 18 cases were excluded due to physician contraindication, and 68 (16%) declined participation. All enrolled participants (N=54) completed baseline surveys. To date, 40 participants completed follow-up surveys after using the online matching tool. Most participants were White (80%), of higher income (&gt;$150,000; 41%), and college-educated (70%). Thirty-seven percent indicated awareness of cancer clinical trials, 69% stated interest in participating in clinical research, and 72% held a positive attitude towards cancer clinical trials. However, 46% indicated they would not participate in a randomized study. To assess utility of the matching tool, 65% indicated it increased their interest in participating in a clinical trial. Conclusions: ECA needs to ensure sociodemographic data are available to make it useful as a tool for clinical trials. Preliminary results indicate ECA used in combination with an online clinical trial matching tool may serve as an important recruitment vehicle for prostate cancer clinical trials.
Selepressin for Patients With Septic Shock—Reply
Authors: Derek C. Angus, Pierre-Francois Laterre, Roger J. Lewis
Journal: JAMA (2020)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Association of body composition with survival and efficacy of first-line treatment in patients with castration-resistant prostate cancer.
Authors: Jae Young Joung, Sahyun Pak
Journal: Journal of Clinical Oncology (2020)

115 Background: We aimed to investigate the association of body composition with survival and efficacy of first-line treatments in patients with castration-resistant prostate cancer (CRPC). Methods: Records of CRPC patients who were treated with first-line docetaxel or androgen receptor signaling inhibitors (ARSi) between 2005 and 2018 were reviewed. Skeletal muscle index (SMI), visceral fat index, and subcutaneous fat index were evaluated using pretreatment computed tomography images. Results: Of the 230 eligible patients, 144 patients received docetaxel and 86 received ARSi as the first-line treatment for CRPC. SMI hi (based on median value) group had higher prostate-specific antigen (PSA) progression-free survival (median 13.5 vs. 8.3 months, p=0.030), radiologic progression-free survival (14.9 vs. 9.1 months; p&lt;0.001), and overall survival (24.1 vs. 16.9 months, p=0.015) compared than SMI lo group. In multivariable analysis, SMI was independently associated with risk of PSA progression (HR=0.68; 95% CI, 0.50-0.93; p=0.017), radiologic progression (HR=0.54; 95% CI, 0.39-0.75; p=0.001), and overall survival (HR=0.72; 95% CI, 0.52-0.98; p=0.037), regardless of BMI. In docetaxel-treated patients, PSA progression-free survival (13.5 vs. 5.9 months, p=0.016) and radiologic progression-free survival (14.6 vs. 6.7 months, p&lt;0.001) were higher in SMI hi than SMI lo group. However, PSA progression-free survival and radiologic progression-free survival were similar between two groups in ARSi-treated patients. Based on treatment-specific hazards of radiologic progression, patients with SMI lo are more likely to benefit from ARSi compared than docetaxel. Conclusions: High skeletal muscle mass may be associated with reduced risks of disease progression and mortality in patients with CRPC. However, the significance of these relationships is limited in patients treated with docetaxel. These results suggest that skeletal muscle mass may be helpful in treatment selection and predicting treatment response in CRPC. Further prospective studies are warranted.
A single-arm phase II study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.
Authors: Jessica Hawley, Timothy Geoffrey Bowler, Xinzheng Victor Guo, Matthew Dallos, Emerson A. Lim, Jianhua Hu, Israel Lowy, Charles G. Drake, Mark N. Stein
Journal: Journal of Clinical Oncology (2020)

TPS271 Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. Reprogramming the immune system in the mHSPC setting is a novel approach to delay progression to CRPC. In the hormone-sensitive setting, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules (PD-1 and PD-L1). These effects diminish as castration resistance emerges. Docetaxel causes immunogenic tumor cell death and stimulates antigen presentation. We hypothesize that leveraging the immunogenic effects of ADT with PD-1 blockade and docetaxel will promote antitumor immune killing and improve clinical outcomes. Methods: This is an open-label, single-arm, phase II study of ADT, cemiplimab, and docetaxel in patients with de novo mHSPC (N=20). Subjects will receive continuous ADT, followed by a two-cycle lead-in of cemiplimab prior to the standard six cycles of docetaxel. Cemiplimab will be continued q3weeks for one year or until disease progression or intolerable side effect. The primary endpoint is undetectable PSA at 6 months. Secondary endpoints include time to development of CRPC and radiographic response. Subjects will be monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Correlative studies will determine the effects of ADT and PD-1 blockade on the TME by comparing baseline and on-treatment biopsies using transcriptional data from single-cell RNA-sequencing and standard immunohistochemistry (IHC). Serum samples will also be collected to quantify the effects of therapy on circulating levels of immunosuppressive cytokines. The study is open with 3 patients currently enrolled at the time of submission. Clinical trial information: NCT03951831.
Adjuvant docetaxel after definitive radiotherapy for high-risk prostate cancer: A meta-analysis of randomized clinical trials.
Authors: Ray Manneh Kopp, Mauricio Lema, Linda Ibatá
Journal: Journal of Clinical Oncology (2020)

374 Background: In order to improve long term results for high-risk prostate cancer, several clinical trials have tested the addition of docetaxel chemotherapy. The outcomes of this trials have not led to clear conclusions. We conducted a meta-analysis of randomized phase 3 trials testing the efficacy of docetaxel after radiotherapy in high risk prostate cancer patients. Methods: A systematic review of PubMed (Medline), Embase and the Cochrane Library was conducted. We followed the PRISMA guidelines, three investigators independently selected the articles and verified inclusion criteria. We compared the overall survival and disease-free survival between the intervention group (adjuvant chemotherapy with docetaxel) and the control group (without adjuvant chemotherapy) by calculating the hazard ratio (HR) with 95% confidence intervals (CIs). Pooled effects were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: 382 publications were identified, four phase III trials (STAMPEDE, RTOG0521, SPCG-13, GETUG 12) comparing docetaxel vs standard of care after radiotherapy for high-risk prostate cancer fulfilled the inclusion criteria with data from 2034 patients (1135 in placebo group and 899 in adjuvant docetaxel group). Heterogeneity was not found between the included studies for OS (I 2 0%), but it was found between studies for disease-free survival (I 2 60%). Adjuvant docetaxel chemotherapy showed overall survival benefit when compared to ADT alone (HR 0,72 95% CI 0,54-0,96). Adjuvant docetaxel also improved the disease-free survival when compared to ADT alone (HR 0,74 95% CI 0,64-0,86). No evidence of publication bias was observed. Conclusions: This meta-analysis shows that docetaxel after definitive radiotherapy in high-risk prostate cancer is likely to be more effective than standard of care in terms of overall survival and disease-free survival. Further prospective studies are needed in order to increase the sample that would lead to show a more robust data.
Dermoscopy of Uncommon Melanoma Variants—Perspective From the Pathologist
Authors: Daniel M. Miller, Karolyn A. Wanat
Journal: JAMA Dermatology (2020)

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 Dermatology 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 Dermatology journal