Nature Medicine最新文献

{"title":"Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade","authors":"Emily C. Harrold, Michael B. Foote, Benoit Rousseau, Henry Walch, Yelena Kemel, Allison L. Richards, Fergus Keane, Andrea Cercek, Rona Yaeger, Dana Rathkopf, Neil H. Segal, Zalak Patel, Anna Maio, Matilde Borio, Eileen M. O’Reilly, Diane Reidy, Avni Desai, Yelena Y. Janjigian, Yonina R. Murciano-Goroff, Maria I. Carlo, Alicia Latham, Ying L. Liu, Michael F. Walsh, David Ilson, Jonathan E. Rosenberg, Arnold J. Markowitz, Martin R. Weiser, Anthony M. Rossi, Chad Vanderbilt, Diana Mandelker, Chaitanya Bandlamudi, Kenneth Offit, Michael F. Berger, David B. Solit, Leonard Saltz, Jinru Shia, Luis A. Diaz Jr., Zsofia K. Stadler","doi":"10.1038/s41591-023-02544-9","DOIUrl":"10.1038/s41591-023-02544-9","url":null,"abstract":"Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia development in patients with Lynch syndrome (LS) is unknown. Of 172 cancer-affected patients with LS who had received ≥1 ICB cycles, 21 (12%) developed subsequent malignancies after ICB exposure, 91% (29/32) of which were dMMR, with median time to development of 21 months (interquartile range, 6–38). Twenty-four of 61 (39%) ICB-treated patients who subsequently underwent surveillance colonoscopy had premalignant polyps. Within matched pre-ICB and post-ICB follow-up periods, the overall rate of tumor development was unchanged; however, on subgroup analysis, a decreased incidence of post-ICB visceral tumors was observed. These data suggest that ICB treatment of LS-associated tumors does not eliminate risk of new neoplasia development, and LS-specific surveillance strategies should continue. These data have implications for immunopreventative strategies and provide insight into the immunobiology of dMMR tumors. In a retrospective analysis of patients with Lynch syndrome and primary cancers treated with immune checkpoint inhibitors, 12% developed subsequent malignancies, suggesting that this treatment may not eliminate risk in individuals predisposed to mismatch repair-deficient cancers, and ongoing surveillance is warranted.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 10","pages":"2458-2463"},"PeriodicalIF":82.9,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial","authors":"John M. Kirkwood, Michele Del Vecchio, Jeffrey Weber, Christoph Hoeller, Jean-Jacques Grob, Peter Mohr, Carmen Loquai, Caroline Dutriaux, Vanna Chiarion-Sileni, Jacek Mackiewicz, Piotr Rutkowski, Petr Arenberger, Gaelle Quereux, Tarek M. Meniawy, Paolo A. Ascierto, Alexander M. Menzies, Piyush Durani, Maurice Lobo, Federico Campigotto, Brian Gastman, Georgina V. Long","doi":"10.1038/s41591-023-02583-2","DOIUrl":"10.1038/s41591-023-02583-2","url":null,"abstract":"Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30–0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30–0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 . In this pre-specified interim analysis, patients with resected stage IIB/C melanoma who received adjuvant nivolumab had significantly prolonged recurrence-free survival compared to placebo-treated patients, providing another treatment option for this population.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2835-2843"},"PeriodicalIF":82.9,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial","authors":"Catherine J. Mummery, Anne Börjesson-Hanson, Daniel J. Blackburn, Everard G. B. Vijverberg, Peter Paul De Deyn, Simon Ducharme, Michael Jonsson, Anja Schneider, Juha O. Rinne, Albert C. Ludolph, Ralf Bodenschatz, Holly Kordasiewicz, Eric E. Swayze, Bethany Fitzsimmons, Laurence Mignon, Katrina M. Moore, Chris Yun, Tiffany Baumann, Dan Li, Daniel A. Norris, Rebecca Crean, Danielle L. Graham, Ellen Huang, Elena Ratti, C. Frank Bennett, Candice Junge, Roger M. Lane","doi":"10.1038/s41591-023-02639-3","DOIUrl":"10.1038/s41591-023-02639-3","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":"304-304"},"PeriodicalIF":82.9,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10803246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial","authors":"Stephen A. Harrison, Rebecca Taub, Guy W. Neff, K. Jean Lucas, Dominic Labriola, Sam E. Moussa, Naim Alkhouri, Mustafa R. Bashir","doi":"10.1038/s41591-023-02603-1","DOIUrl":"10.1038/s41591-023-02603-1","url":null,"abstract":"Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (−11.1%, −12.6%), apoB (−15.6%, −18.0%), triglycerides (−15.4%, −20.4%), 16-week hepatic fat (−34.9%, −38.6%), (P < 0.0001) and liver stiffness (−1.02, −1.70) and 52-week hepatic fat (−28.8, −33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ). In the phase 3 MAESTRO-NAFLD-1 trial, the liver-targeted thyroid hormone receptor-β selective agonist resmetirom was well tolerated and improved liver biomarkers in adults with nonalcoholic fatty liver disease.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2919-2928"},"PeriodicalIF":82.9,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keeping the weight off","authors":"","doi":"10.1038/s41591-023-02614-y","DOIUrl":"10.1038/s41591-023-02614-y","url":null,"abstract":"Incretin-based drugs have demonstrated unprecedented efficacy in weight-loss trials, but ensuring that healthy body weight can be maintained is fundamental to sustainable good health.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 10","pages":"2377-2378"},"PeriodicalIF":82.9,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-023-02614-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial","authors":"Thomas A. Wadden, Ariana M. Chao, Sriram Machineni, Robert Kushner, Jamy Ard, Gitanjali Srivastava, Bruno Halpern, Shuyu Zhang, Jiaxun Chen, Mathijs C. Bunck, Nadia N. Ahmad, Tammy Forrester","doi":"10.1038/s41591-023-02597-w","DOIUrl":"10.1038/s41591-023-02597-w","url":null,"abstract":"The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/m2 and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean per cent weight change from randomization to week 72 was met with changes of −18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo (estimated treatment difference −20.8 percentage points (95% confidence interval (CI) −23.2%, −18.5%; P < 0.001). The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; P < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity. Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016 . In the SURMOUNT-3 trial, once-weekly treatment with tirzepatide was demonstrated to result in clinically meaningful additional weight loss in adults with overweight or obesity following initial successful weight loss of at least 5% body weight with intensive lifestyle intervention.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2909-2918"},"PeriodicalIF":82.9,"publicationDate":"2023-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking placebos: embracing synthetic control arms in clinical trials for rare tumors","authors":"César Serrano, Sara Rothschild, Guillermo Villacampa, Michael C. Heinrich, Suzanne George, Jean-Yves Blay, Jason K. Sicklick, Gary K. Schwartz, Sameer Rastogi, Robin L. Jones, Piotr Rutkowski, Neeta Somaiah, Víctor Navarro, Denisse Evans, Jonathan C. Trent","doi":"10.1038/s41591-023-02578-z","DOIUrl":"10.1038/s41591-023-02578-z","url":null,"abstract":"External comparator arms should be used when investigating novel therapies for gastrointestinal stromal tumor and other rare tumors to facilitate drug testing and regulatory approvals.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2689-2692"},"PeriodicalIF":82.9,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41206048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers of aging remain elusive as researchers try to slow the biological clock","authors":"Mike May","doi":"10.1038/s41591-023-02560-9","DOIUrl":"10.1038/s41591-023-02560-9","url":null,"abstract":"Billions of dollars are pouring into longevity biotechs, but measuring success is challenging, given how little is known about the biology of aging.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 11","pages":"2673-2676"},"PeriodicalIF":82.9,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41206044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical AI tools must convey predictive uncertainty for each individual patient","authors":"Christopher R. S. Banerji, Tapabrata Chakraborti, Chris Harbron, Ben D. MacArthur","doi":"10.1038/s41591-023-02562-7","DOIUrl":"10.1038/s41591-023-02562-7","url":null,"abstract":"Artificial intelligence tools usually aim to maximize predictive accuracy, but personalized measures of uncertainty, using new techniques such as conformal prediction, are needed for clinical artificial intelligence to realize its potential and improve human health.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 12","pages":"2996-2998"},"PeriodicalIF":82.9,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41206045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary and commensal yeasts drive aberrant T cell responses in Crohn’s disease","authors":"","doi":"10.1038/s41591-023-02559-2","DOIUrl":"10.1038/s41591-023-02559-2","url":null,"abstract":"Aberrant immune responses to the intestinal microbiome have emerged as major contributors to chronic intestinal inflammation, but the microbial species involved in inflammatory bowel diseases remain unknown. Our study identified dietary and commensal yeasts of the gut that drive the expansion of some cross-reactive CD4+ type 1 helper T cells with cytotoxic effector functions, which potentially contributes to immunopathology in patients with Crohn’s disease.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 10","pages":"2420-2421"},"PeriodicalIF":82.9,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41206046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}