Nature Medicine最新文献

{"title":"Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial.","authors":"Alexander Stein, Eray Goekkurt, Salah-Eddin Al-Batran, Nicolas Moosmann, Thomas J Ettrich, Thorsten Goetze, Barbara Gruen, Nils Homann, Sylvie Lorenzen, Ralf-Dieter Hofheinz, Viktor Rempel, Gabriele Siegler, Christian Müller, Benjamin Thiele, Tobias Broering, Mariana Santos Cruz, Claudia Pauligk, Mascha Binder, Joseph Tintelnot","doi":"10.1038/s41591-025-03979-y","DOIUrl":"https://doi.org/10.1038/s41591-025-03979-y","url":null,"abstract":"<p><p>Perioperative treatment strategies for HER2-positive esophagogastric adenocarcinoma remain suboptimal. Here in the open-label, phase 2 IKF/AIO PHERFLOT trial, we evaluated the safety and efficacy of adding pembrolizumab and trastuzumab to FLOT chemotherapy in patients with localized HER2-positive esophagogastric adenocarcinoma. The primary endpoints are the pathological complete response rate and the 2-year disease-free survival rate. Secondary endpoints include the R0 resection rate, feasibility and safety. Exploratory endpoints include clinical efficacy in molecularly defined subgroups. In this prespecified interim analysis, given the limited median follow-up period of 14.8 months, only one of the primary endpoints, the pathological complete response rate, and selected secondary endpoints, including the R0 resection rate, feasibility and safety, are reported here. Among 31 enrolled patients, 30 proceeded to R0 resection, and one patient declined surgery without disease progression. The combination regimen resulted in grade ≥3 treatment-related serious adverse events in 48.4% of patients (15 out of 31) aligning with established toxicity profiles of the respective agents and no treatment-related deaths. After four cycles of therapy, the pathological complete response rate was 48.4% (95% confidence interval 30.2-66.9; 15 out of 31) in the intention-to-treat population, and the subtotal regression rate (TRG1b according to Becker classification) was 19.4% (95% confidence interval 7.5-37.5; 6 out of 31), resulting in a major pathological response rate of 67.7% (95% confidence interval 48.6-83.3; 21 out of 31). Responses tended to be enriched in tumors with strong HER2 expression (immunohistochemistry 3+), high PD-L1 combined positive scores and lower T stage, but were also observed in substantial fractions of HER2 immunohistochemistry 2+/ISH+, T3 or T4 and combined positive scores <10 tumors. These findings support the feasibility and antitumor activity of perioperative chemoimmunotherapy targeting HER2 and PD-1 and warrant further validation in randomized trials. ClinicalTrials.gov registration: NCT05504720 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318596","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 and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial.","authors":"Georgina V Long, Charlie Garnett-Benson, Sonia Dolfi, Paolo A Ascierto, Jun Guo, Ahmad A Tarhini, Sunandana Chandra, Eva Muñoz-Couselo, Michele Del Vecchio, Andreia Cristina de Melo, Margaret Callahan, Helen Gogas, Reinhard Dummer, Dirk Schadendorf, Peter Koelblinger, Gaelle Quereux, Ioannis Thomas, Jia Xin Yu, Andrew Fisher, Bonnie Wang, Patrick Djidel, Armand Chouzy, Mark Semaan, Bohang Chen, Alicia M Y Cheong, Hussein A Tawbi","doi":"10.1038/s41591-025-04032-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04032-8","url":null,"abstract":"<p><p>Based on RELATIVITY-047, nivolumab plus relatlimab is approved for advanced melanoma. Here, to address a current unmet need for more efficacious adjuvant regimens for completely resected melanoma, the phase 3, double-blind RELATIVITY-098 trial compared adjuvant nivolumab plus relatlimab to nivolumab after complete resection of stage III/IV melanoma. Patients were randomized 1:1 to receive nivolumab 480 mg plus relatlimab 160 mg (n = 547) or nivolumab 480 mg (n = 546) intravenously every 4 weeks for ≤1 year; safety populations totaled 543 and 545 patients, respectively. The primary endpoint was recurrence-free survival (RFS), and the key secondary was overall survival; translational endpoints were exploratory. There was no difference in RFS for nivolumab plus relatlimab versus nivolumab (hazard ratio = 1.01; 95% confidence interval: 0.83-1.22; P = 0.928); therefore, overall survival was not tested. Translational data across trials showed lower circulating LAG-3⁺ T cells in the adjuvant setting (RELATIVITY-098) versus advanced melanoma (RELATIVITY-047), where LAG-3⁺ T cells were enriched in tumor versus blood. The absence of macroscopic tumor and reduced peripheral LAG-3⁺ T cells may explain the lack of added benefit of nivolumab plus relatlimab over nivolumab in resected versus metastatic melanoma. ClinicalTrials.gov identifier: NCT05002569 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318522","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":"Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial.","authors":"Yelena Y Janjigian, Do-Youn Oh, Meredith Pelster, Zev A Wainberg, Subhransu Prusty, Sandahl Nelson, Amy DuPage, Amy Thompson, Daniel O Koralek, Edward Allan R Sison, Sun Young Rha","doi":"10.1038/s41591-025-04022-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04022-w","url":null,"abstract":"<p><p>Dual inhibition of T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed cell death protein 1 (PD-1) may enhance antitumor immunity in advanced gastroesophageal cancers. Here we report the EDGE-Gastric study, an ongoing, multicenter, international, phase 2 study with three cohorts, one in the first-line setting (cohort A) and two in the second-line or greater setting (cohorts B and C). Cohort A comprises four arms: two nonrandomized (A1 and A2) and two randomized (A3 and A4). In arm A1, presented here, dual blockade of TIGIT and PD-1 with domvanalimab (Fc-silent anti-TIGIT) and zimberelimab (anti-PD-1) plus oxaliplatin, leucovorin, fluorouracil (FOLFOX) was evaluated in patients with previously untreated advanced HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Among 41 treated patients, the confirmed objective response rate was 59% (90% confidence interval (CI) 44.5-71.6%), median progression-free survival was 12.9 months (90% CI 9.8-14.6 months) and median overall survival was 26.7 months (90% CI 18.4 months to not estimable (NE)). In patients with tumor area positivity ≥1% (PD-L1 positive) and tumor area positivity ≥5% (PD-L1 high), respectively, the objective response rate was 62% (90% CI 45.1-77.1%) and 69% (90% CI 45.2-86.8%), median progression-free survival was 13.2 months (90% CI 11.3-15.2 months) and 14.5 months (90% CI 11.3 months-NE), and median overall survival was 26.7 months (90% CI 19.5 months-NE) and not reached (90% CI 17.4 months-NE). Immune-related adverse events were reported in 27% of patients; the safety profile was consistent with that reported for anti-PD-1 plus platinum-based chemotherapy. Dual TIGIT and PD-1 blockade with domvanalimab and zimberelimab plus chemotherapy demonstrated encouraging efficacy, and the regimen is being evaluated in the phase 3 STAR-221 trial. ClinicalTrials.gov identifier: NCT05329766 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318523","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":"Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.","authors":"Stefanie Zorn, Rebecca Bounds, Alice Williamson, Katherine Lawler, Ruth Hanssen, Julia Keogh, Elana Henning, Miriam Smith, Barbara A Fielding, A Margot Umpleby, Summaira Yasmeen, Maria Marti-Solano, Claudia Langenberg, Martin Wabitsch, Tinh-Hai Collet, I Sadaf Farooqi","doi":"10.1038/s41591-025-03976-1","DOIUrl":"10.1038/s41591-025-03976-1","url":null,"abstract":"<p><p>Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308600","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":"Characterizing the physiology of circulatory arrest in humans","authors":"Jordan D. Bird,&nbsp;Laura Hornby,&nbsp;Veronica Hirsch-Reinshagen,&nbsp;Chloe P. Allen,&nbsp;George Isac,&nbsp;Peter A. Gooderham,&nbsp;Sam D. Shemie,&nbsp;Sonny Dhanani,&nbsp;Sonny Thiara,&nbsp;Sophie Stukas,&nbsp;Rebecca Grey,&nbsp;Denise A. Foster,&nbsp;Lauren E. Maier,&nbsp;Allana E. LeBlanc,&nbsp;Hussein D. Kanji,&nbsp;Tessa F. Morelli,&nbsp;Andrew M. Agbay,&nbsp;Cheryl L. Wellington,&nbsp;Daljeet Chahal,&nbsp;Eric C. Belanger,&nbsp;Hezhen Ren,&nbsp;Pushwant S. Mattu,&nbsp;Susan Su,&nbsp;Chantelle T. Hrazdil,&nbsp;Jennifer Percy,&nbsp;Parveen Sangha,&nbsp;Laurel V. Plewes,&nbsp;David D. Sweet,&nbsp;Kali R. Romano,&nbsp;Erik N. Vu,&nbsp;Dean R. Chittock,&nbsp;Vinay K. Dhingra,&nbsp;William R. Henderson,&nbsp;Naisan R. Garraway,&nbsp;S. Morad Hameed,&nbsp;Gordon N. Finlayson,&nbsp;David B. MacLeod,&nbsp;Travis D. Gibbons,&nbsp;Philip N. Ainslie,&nbsp;Ryan L. Hoiland,&nbsp;Donald E. Griesdale,&nbsp;Juan J. Ronco,&nbsp;Mypinder S. Sekhon","doi":"10.1038/s41591-025-03889-z","DOIUrl":"10.1038/s41591-025-03889-z","url":null,"abstract":"The dying process from circulatory arrest is an underexplored domain in humans and has transdisciplinary pertinence. Here we conducted a prospective, observational cohort study of the dying process in 39 adults, with a multimodal assessment of cerebrovascular and cardiovascular physiology. We found that cerebral blood velocities and brain tissue oxygen tensions ceased before systemic hemodynamics. The brain exhibited diffusion limitation of oxygen extraction during the dying process compared with extracranial tissues. Anterior and posterior brain circulations had differences in timing of cessation of circulation and physiologic responses during the dying process. Blood-based neurologic biomarkers from the brain did not change during the associated ischemia related to the dying process. Heart pathology was associated with the length of the dying process. This study provides proof-of-concept of an in vivo human model to comprehensively investigate severe cerebral ischemia and the human dying process. ClinicalTrials.gov registration: NCT06130033 . The authors conducted prospective multimodal monitoring of simultaneous brain and heart function to define physiological changes during the human dying process leading to circulatory arrest.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 10","pages":"3542-3552"},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41591-025-03889-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308587","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":"The fragile intelligence of GPT-5 in medicine.","authors":"Rebecca Handler, Sonali Sharma, Tina Hernandez-Boussard","doi":"10.1038/s41591-025-04008-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04008-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308624","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":"MRI-based multi-organ clocks for healthy aging and disease assessment.","authors":"Huizi Cao, Zhiyuan Song, Michael R Duggan, Guray Erus, Dhivya Srinivasan, Ye Ella Tian, Wenjia Bai, Michael S Rafii, Paul Aisen, Daniel W Belsky, Keenan A Walker, Andrew Zalesky, Luigi Ferrucci, Christos Davatzikos, Junhao Wen","doi":"10.1038/s41591-025-03999-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03999-8","url":null,"abstract":"<p><p>Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10^-8). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308585","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":"The promise of psychedelic medicine in psychiatry.","authors":"Natalie Healey","doi":"10.1038/d41591-025-00062-4","DOIUrl":"https://doi.org/10.1038/d41591-025-00062-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308574","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":"A brief digital cognitive test improves Alzheimer's disease detection.","authors":"","doi":"10.1038/s41591-025-04024-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04024-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308572","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":"Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility.","authors":"Changlong Zhang, Wei Zheng, Honghui Zhang, Shuai Zhao, Huiling Hu, Xilin Xu, Xian Wan, Jiaqi Sun, Wei Su, Yang Wang, Ying Cui, Bohan Yang, Changjian Yin, Xin Zhang, Cheng Li, Xin Zhang, Changming Zhang, Zhao Wang, Ying Yuan, Liu Liu, Fei Meng, Jiangtao Zhang, Yongzhi Cao, Yuan Gao, Shigang Zhao, Fei Gong, Keliang Wu, Feng Zhang, Shuyan Tang, Ge Lin, Han Zhao, Zi-Jiang Chen","doi":"10.1038/s41591-025-04001-1","DOIUrl":"https://doi.org/10.1038/s41591-025-04001-1","url":null,"abstract":"<p><p>Oocyte and early embryo competence defects (OECD) represent a recently recognized cause of female infertility with the application of assisted reproductive technology, characterized by impaired oocyte or early embryo development. To investigate the genetic landscape and subtypes of OECD, we performed whole-exome sequencing on 2,140 patients, classifying them into six distinct subtypes. We identified 183 pathogenic/likely pathogenic variants across 28 established genes. Notably, distinct genetic profiles and diagnostic rates emerged across subtypes, with a rate of 53% in the Empty Follicle subtype. Additionally, we identified and validated two potentially causative genes, MLH3 and CENPH. Gene burden analysis, using 2,424 fertile controls, suggested nine potential previously unreported associated genes and offered biological insights into the underlying pathogenic mechanisms of OECD. Collectively, these genetic findings accounted for 12.8-23.1% of OECD cases. This study delineates the genetic architecture of OECD, offering insights that may inform the development of diagnostic genetic screenings and provide a reference for standardized subtyping of patients with OECD.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308635","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}