tbuckley/cabot-search huggingface dataset:
Divergent clinical and immunologic outcomes based on STK11 co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade
Authors: Samuel Rosner, Sydney Connor, Khaled Sanber, Marianna Zahurak, Tianbei Zhang, Isha Gurumurthy, Zhen Zeng, Brad Presson, Dipika Singh, Roni Rayes, Lavanya Sivapalan, Gavin Pereira, Zhicheng Ji, Rohit Thummalapalli, Joshua E. Reuss, Stephen R. Broderick, David R. Jones, Julie S. Deutsch, Tricia R. Cottrell, Jamie Chaft, Jonathan Spicer, Janis Taube, Valsamo Anagnostou, Julie R. Brahmer, Drew M. Pardoll, Hongkai Ji, Patrick M. Forde, Kristen A. Marrone, Kellie N. Smith
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 co-mutations in this setting are unknown. Experimental design: We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors. Results: Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT). Conclusions: These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.
Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study
Authors: Tongpeng Xu, Tian Tian, Chen Wang, Xiaofeng Chen, Xiangrong Zuo, Hanyu Zhou, Jianan Bai, Chenhui Zhao, Sujie Fu, Chongqi Sun, Ting Wang, Ling Zhu, Jingzhi Zhang, Enxiu Wang, Ming Sun, Yongqian Shu
Journal: Genome Medicine (2024)

Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.
Racial and Ethnic Differences in Prostate Cancer Epidemiology Across Disease States in the VA
Authors: Shannon R. Stock, Michael T. Burns, Justin Waller, Amanda M. De Hoedt, Joshua A. Parrish, Sameer Ghate, Jeri Kim, Irene M. Shui, Stephen J. Freedland
Journal: JAMA Network Open (2024)

Importance Prostate cancer (PC) care has evolved rapidly as a result of changes in prostate-specific antigen testing, novel imaging, and newer treatments. The impact of these changes on PC epidemiology and racial disparities across disease states remains underexplored. Objective To characterize racial and ethnic differences in the epidemiology of PC states, including nonmetastatic hormone-sensitive PC (nmHSPC), metastatic HSPC (mHSPC), nonmetastatic castration-resistant PC (nmCRPC), and metastatic CRPC (mCRPC). Design, Setting, and Participants This is a retrospective, population-based cohort study of male US veterans aged 40 years and older with known race and ethnicity and no non-PC malignant neoplasm before study entry receiving care through the Veterans Health Administration. The study period was from 2012 to 2020, with follow-up through 2021. To identify active users, data capture included visits 18 months before and after the study period. Data analysis was performed from March to August 2023. Exposure Self-identified race and ethnicity, classified as Black, White, or Hispanic. Main Outcomes and Measures The primary outcomes were annual age-adjusted incidence rates (IRs) and point prevalence for PC states by race and ethnicity. Trends were evaluated using joinpoint regression. Time to disease progression or death was estimated using nonparametric cumulative incidence. Competing risk models adjusted for age assessed the association of race and ethnicity on disease progression. Results The study included 6 539 001 veterans (median [IQR] age, 65 [56-74] years), of whom 476 227 had PC (median [IQR] age, 69 [63-75] years). IRs varied by time frame and disease state. Across all states and years, the relative risk among Black vs White patients ranged from 2.09 (95% CI, 2.01-2.18; P &amp;amp;lt; .001) for nmHSPC in 2012 to 4.12 (95% CI, 3.39-5.02; P &amp;amp;lt; .001) for nmCRPC in 2017. In nmHSPC, hazard ratios for progression to mHSPC and nmCRPC were 1.36 (95% CI, 1.33-1.40) and 1.60 (95% CI, 1.51-1.70), respectively, for Black patients and 1.38 (95% CI, 1.31-1.45) and 1.55 (95% CI, 1.40-1.72), respectively, for Hispanic patients vs White patients. In contrast, in mCRPC, the hazard ratio for death was lower for Black (0.84; 95% CI, 0.81-0.88) and Hispanic (0.76; 95% CI, 0.69-0.83) patients compared with White patients. Conclusions and Relevance This cohort study of veterans found that Black patients had more than 2-fold higher incidence of all disease states vs White patients. Progression risk was higher for Black and Hispanic patients in early-stage disease, but lower in later disease stages. Despite equal access, Black patients disproportionately experience PC, although progression risks relative to White patients differed according to disease state.
Bystander Use of Opioid Overdose Antidote Naloxone Is on the Rise
Authors: Samantha Anderer
Journal: JAMA (2024)

Christopher B. Gage, MHS, NRP; Jonathan R. Powell, MPA, NRP; Alexander Ulintz, MD; Rebecca E. Cash, PhD, MPH; Michael S. Lyons, MD; Henry Wang, MD, MS; Ashish R. Panchal, MD, PhD
Intensive Home Treatment—Clinical and Methodological Issues
Authors: Neil Krishan Aggarwal
Journal: JAMA Network Open (2024)

Andreas Bechdolf, MD; Konstantinos Nikolaidis, MSc; Sebastian von Peter, MD; Gerhard Längle, MD; Peter Brieger, MD; Jürgen Timm, PhD; Reinhold Killian, PhD; Lasse Fischer, MSc; Svenja Raschmann, MSc; Julian Schwarz, MD; Martin Holzke, MA; Sandeep Rout, MD; Constance Hirschmeier, MD; Johannes Hamann, MD; Uwe Herwig, PhD; Janina Richter, PhD; Johanna Baumgardt, PhD; Stefan Weinmann, MD
Trial Supports Acupuncture for Chronic Sciatica Pain
Authors: Samantha Anderer
Journal: JAMA (2024)

Jian-Feng Tu, MD, PhD; Guang-Xia Shi, MD, PhD; Shi-Yan Yan, PhD; Guang-Xia Ni, MD, PhD; Fang-Ting Yu, MS; Guo-Wei Cai, MS; Zhi-Shun Liu, MD, PhD; Chao-Yang Ma, MS; Li-Qiong Wang, PhD; Jing-Wen Yang, MD, PhD; Xiao-Qing Zhou, MD, PhD; Xiu-Li Meng, MD, PhD; Hai-Yang Fu, MD, PhD; Jing Li, MD, PhD; Wen-Jun Wan, MS; Tian-Heng Sun, MS; Xue-Zhou Wang, MS; Cun-Zhi Liu, MD, PhD
Racial and Ethnic Disparities in Prostate Cancer—Correlation With Incidence and Progression
Authors: Chadi Hage Chehade, Neeraj Agarwal
Journal: JAMA Network Open (2024)

Shannon R. Stock, PhD; Michael T. Burns, BA; Justin Waller, MS; Amanda M. De Hoedt, MS; Joshua A. Parrish, BS; Sameer Ghate, PhD; Jeri Kim, MD; Irene M. Shui, PhD; Stephen J. Freedland, MD
Study: Prenatal Cannabis Use Not Associated With Developmental Delays
Authors: Samantha Anderer
Journal: JAMA (2024)

Lyndsay A. Avalos, PhD, MPH; Nina Oberman, MPH; Stacey E. Alexeeff, PhD; Lisa A. Croen, PhD; Meghan N. Davignon, MD; Sara R. Adams, MPH; Deborah Ansley, MD; Christina D. Chambers, PhD, MPH; Kristin Steuerle, MD; Kelly C. Young-Wolff, PhD, MPH
Lower Suicide Risks in Adolescents With Obesity Taking GLP-1 Drugs
Authors: Samantha Anderer
Journal: JAMA (2024)

Joyce M. Lee, MD, MPH; Mona Sharifi, MD, MPH; Lauren Oshman, MD, MPH; Dina H. Griauzde, MD, MSc; Kao-Ping Chua, MD, PhD
From Innovation to Inclusion—Tackling Digital Equity Needs in Health Care
Authors: Sachin D. Shah
Journal: JAMA Network Open (2024)

Lauren E. Russell, MPH, MPP; Portia Y. Cornell, PhD; Christopher W. Halladay, ScM; Meaghan A. Kennedy, MD, MPH; Andrea Berkheimer, LCSW; Emily Drucker, LCSW; Leonie Heyworth, MD, MPH; Sarah M. Leder, MSW; Kathleen M. Mitchell, MPH; Ernest Moy, MD, MPH; Jennifer W. Silva, LCSW-S; Brittany L. Trabaris, LCSW; Lisa E. Wootton, LCSW; Alicia J. Cohen, MD, MSc
Perspectives on Telemedicine Visits Reported by Patients With Cancer
Authors: Sahil D. Doshi, Yasin Khadem Charvadeh, Kenneth Seier, Erin M. Bange, Bobby Daly, Allison Lipitz-Snyderman, Fernanda C. G. Polubriaginof, Michael Buckley, Gilad Kuperman, Peter D. Stetson, Deb Schrag, Michael J. Morris, Katherine S. Panageas
Journal: JAMA Network Open (2024)

Importance The COVID-19 pandemic catalyzed rapid adoption of telemedicine visits for cancer care delivery. However, patients’ experiences with telemedicine remain poorly understood. Objective To understand patients’ satisfaction with telemedicine visits at a comprehensive cancer center. Design, Setting, and Participants This survey study included patients with cancer at a US cancer center between 2020 and 2023. Eligible patients completed surveys in English conducted after their first telemedicine appointment via an online patient portal. Data were analyzed between January and June 2024. Exposures Patient surveys about telemedicine experiences, with a specific comparison with an in-person visit. Structured items elicited satisfaction with the specific visit, preferences for future use of telemedicine, and technical ease of use; unstructured free-text responses were also elicited. Main Outcomes and Measures Proportion of patients who indicated that telemedicine visits were superior or preferred to in-person visits. Secondary outcomes included multivariable analysis of barriers to telemedicine use and variations in patient experiences by demographic characteristics over the observation period, and free-text analysis of unstructured responses describing the telemedicine experience using the BERTopic algorithm and a language model. Results A total of 27 435 telemedicine users completed surveys from May 2020 to October 2023 (median [IQR] age, 65 [55-72] years; 15 072 female [54.9%]; 1771 Asian [6.7%], 1339 Black [5.1%], 22 742 White [85.9%]). Overall, 18 025 of 24 418 patients (73.8%) rated their first telemedicine visit as good as or better than an in-person visit, and 4606 (18.9%) rated it superior to an in-person visit. The proportion of patients rating a telemedicine visit superior to an in-person visit evolved from 17% in 2020 to 20% in 2023. Structured questions revealed a positive view of telemedicine, while free-text analyses highlighted issues with technology. Conclusions and Relevance In this survey study of perspectives on telemedicine visits, a large majority of patients at a comprehensive cancer center expressed satisfaction with telemedicine visits in proportions that remained consistent beyond the end of the pandemic. These findings challenge health care systems to integrate telemedicine into routine cancer care and to overcome remaining technical challenges and barriers to ease of use.
Authors' Reply: Effects of Zibotentan and Dapagliflozin on Fluid Retention in Patients with CKD: Need More Evidence
Authors: Hiddo J.L. Heerspink, Johannes David Smeijer
Journal: Journal of the American Society of Nephrology (2024)

Xu and Xu1 raise methodological questions about our study2 published in JASN concerning the proportional hazard assumption and interval censoring. We agree that the proportional hazard assumption should always be evaluated and confirm that in our study the proportional hazard assumption was met. Mixed censoring in the Cox proportional hazard regression model might induce bias. In the Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) trial, participants were regularly monitored during the 12-week treatment period with study visits occurring at 1, 3, 6, 9, and 12 weeks after randomization. The Cox model assumes that any potential fluid retention event occurred at the end of a study interval, but we cannot exclude the possibility that the fluid retention actually occurred between visits, which may introduce bias. As suggested, we reanalyzed the time-to-event data using the accelerated failure (AFT) model using the cs2ic() and ic_par() R statistical software functions to accommodate interval-censored data. We obtained hazard ratios based on the shape parameter of the Weibull distribution within the AFT model. The AFT model resulted in similar estimates for the hazard ratio for fluid retention compared with the original Cox proportional hazard regression analysis. For example, the hazard ratio of fluid retention for the zibotentan/dapagliflozin 0.25/10 mg group versus dapagliflozin 10 mg group was 1.12 using the AFT model compared with 1.21 for the original model. We thus conclude that mixed interval censoring did not bias our results.
Effects of Zibotentan and Dapagliflozin on Fluid Retention in Patients with CKD
Authors: Lingyu Xu, Yan Xu
Journal: Journal of the American Society of Nephrology (2024)

We read with great interest the recent article by Heerspink et al. titled "Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD" published in JASN.1 The study found that high doses of zibotentan were associated with a higher risk of fluid retention, which was mitigated by using lower doses and adding dapagliflozin. However, we note several biases in the use of the Cox proportional hazards model that the authors did not address. The established criteria may result in mixed censoring outcomes, that is, right-censoring and interval-censoring events.2,3 Fluid retention diagnosed through medical records could result in interval censoring if they occurred between follow-up visits and right censoring if diagnosed between the end of follow-up and the time of data analysis. The Cox proportional hazards model primarily handles right-censored data. By contrast, the accelerated failure time (AFT) model is often preferred for scenarios involving various types of censored data.4 The AFT model can effectively handle left-censored, right-censored, and interval-censored data by appropriately adjusting the likelihood function.5 By using the "survival" and "icenReg" packages, mixed censored data can be fitted and analyzed and event times can be estimated.6 Moreover, the Cox proportional hazards model requires the proportional hazards assumption, meaning that covariate effects are constant over time.7 If this assumption is violated, the model may not provide unbiased estimates of the coefficients, and the predictions may not be reliable. The authors should use Schoenfeld residuals or alternative methods to evaluate the proportional hazards assumption for the association between covariates and the risk of fluid retention. Schoenfeld residuals are calculated as the differences between the observed and expected values of covariates at each failure time.8 If the residuals exhibit a systematic change over time, it suggests that the effect of the covariate may be time dependent. When the proportional hazards assumption does not hold, authors should use a stratified Cox model, a Cox model with time-varying effects, or an AFT model instead of the standard Cox proportional hazards model.4,9 In conclusion, we believe that a re-evaluation considering the potential effect of censoring events and the proportional hazards assumption is necessary. Further research is anticipated to provide more empirical data and clearer insights into this field.
First-Line Lenvatinib Plus Pembrolizumab for Hepatocellular Carcinoma: Post Hoc Analysis of Japanese Patients From the Phase 3 LEAP-002 Trial
Authors: Masatoshi Kudo, Masafumi Ikeda, Hiroshi Aikata, Kazushi Numata, Hiroyuki Marusawa, Tetsuya Hosaka, Naoya Kato, Masayuki Kurosaki, Manabu Morimoto, Tatsuya Yamashita, Hironori Koga, Tsutomu Masaki, Naoyoshi Yatsuzuka, Masato Suzuki, Satoshi Nagao, Shuichi Kaneko, Hiromitsu Kumada
Journal: Liver Cancer (2024)

Introduction: The phase 3 LEAP-002 study (NCT03713593) of advanced hepatocellular carcinoma (HCC) suggested improved antitumor activity of lenvatinib plus pembrolizumab versus lenvatinib alone with manageable safety, although overall survival (OS) and progression-free survival (PFS) did not reach prespecified statistical significance. This post hoc analysis assessed efficacy and safety in Japanese patients. Methods: Patients with advanced HCC without prior systemic treatment were randomly assigned 1:1 to receive 8 mg (body weight &lt;60 kg) or 12 mg (body weight ≥60 kg) oral lenvatinib once daily plus 200 mg intravenous pembrolizumab or placebo every 3 weeks for up to 35 cycles. Dual primary end points were OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary end points were objective response rate, disease control rate, duration of response, and time to progression per RECIST v1.1 by BICR and safety. Results: Overall, 80 patients were enrolled in Japan (lenvatinib plus pembrolizumab, n = 39; lenvatinib plus placebo, n = 41). Median time from randomization to database cutoff (June 21, 2022) was 34.1 months (range, 26.9–39.6). Median OS was 31.4 months (95% CI: 21.2–not reached) for lenvatinib plus pembrolizumab and 21.4 months (95% CI: 14.4–25.4) for lenvatinib plus placebo (hazard ratio [HR] = 0.55 [95% CI: 0.31–0.96]). Median PFS for lenvatinib plus pembrolizumab was 10.4 months (95% CI: 6.2–18.5) and 6.5 months (95% CI: 6.0–8.3) for lenvatinib plus placebo (HR = 0.54 [95% CI: 0.32–0.90]). Grade 3 or 4 treatment-related adverse events occurred in 26 patients (67%) in the lenvatinib plus pembrolizumab group and 24 patients (59%) in the lenvatinib plus placebo group. Conclusion: In Japanese patients enrolled in LEAP-002, findings were consistent with the global population where OS and PFS trended toward improvement; a similar safety profile was observed.
Comparing Torsemide with Furosemide
Authors: Qais Al-Awqati
Journal: Journal of the American Society of Nephrology (2024)

Departments of Medicine and Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York Correspondence: Dr. Qais Al-Awqati, email: [email protected] See related article, "Mechanistic Differences between Torsemide and Furosemide," on pages XXX–XXX.
Megalin: A Sidekick or Nemesis of the Kidney?
Authors: Kalyani Kulkarni, Tahir Hussain
Journal: Journal of the American Society of Nephrology (2024)

Megalin is an endocytic receptor in the proximal tubules that reabsorbs filtered proteins in the kidneys. Recycling of megalin after endocytosis and its expression on the apical plasma membrane of the proximal tubule are critical for its function. The expression of megalin in the kidney undergoes dynamic changes under physiological and pathophysiological conditions. Receptors and various effector signaling components regulate megalin expression and potentially function. Genetic manipulation and rare mutations in megalin suggest that a lack or deficiency in megalin expression/function promotes tubular proteinuria and albuminuria. However, the role of megalin in kidney diseases associated with obesity, diabetes, hypertension, and nephrotoxicity remains unclear. To address these questions, animal and human studies have indicated megalin as a protective, injurious, and potentially urinary marker of nephropathy. This article reviews the literature on the regulation of megalin expression and the role of megalin in the pathophysiology of the kidney under experimental and clinical conditions. Moreover, this review articulates the need for studies that can clarify whether megalin can serve as a therapeutic target, in one way or the other, to treat kidney disease.
Interpreting Health Status Measures in Patients With Heart Failure—What Counts
Authors: James E. Udelson, Clyde W. Yancy, Gregg C. Fonarow
Journal: JAMA Cardiology (2024)

Mohammad Abdel Jawad, MD; Philip G. Jones, MS; Suzanne V. Arnold, MD, MHA; David J. Cohen, MD, MSc; Charles F. Sherrod, MD; Mirza S. Khan, MD; Nobuhiro Ikemura, MD, PhD; Paul S. Chan, MD, MSc; John A. Spertus, MD, MPH
Interpreting Population Mean Treatment Effects in the Kansas City Cardiomyopathy Questionnaire
Authors: Mohammad Abdel Jawad, Philip G. Jones, Suzanne V. Arnold, David J. Cohen, Charles F. Sherrod, Mirza S. Khan, Nobuhiro Ikemura, Paul S. Chan, John A. Spertus
Journal: JAMA Cardiology (2024)

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a commonly used outcome in heart failure trials. While comparing means between treatment groups improves statistical power, mean treatment effects do not necessarily reflect the clinical benefit experienced by individual patients.
Emerging Challenges in Global Health Dermatology: measuring impact and sustainability
Authors: Morvarid Zehtab, L Claire Fuller, Wendemagegn Enbiale, Karolyn A Wanat, Luca Borradori, Henry W Lim, Esther E Freeman
Journal: British Journal of Dermatology (2024)

As initiatives addressing health inequity rise in dermatology there is growing interest among funders and nonprofits in defining and measuring two key aspects of global health success: impact and sustainability. Demands to clearly describe and demonstrate both impact and sustainability in global health dermatology and health equity programs from funders are to ensure accountability, proper use of funds, and mutually beneficial outcomes. There is no one-size-fits-all method for evaluating health interventions. Instead, we highlight approaches that can be tailored to specific global health efforts to better conceptualize both areas to improve operational strategies and their implementation internally and communication with funders externally.