Nature Medicine最新文献

{"title":"Digital twins for the personal touch","authors":"Paul Webster","doi":"10.1038/s41591-025-03938-7","DOIUrl":"10.1038/s41591-025-03938-7","url":null,"abstract":"A digital twin, or virtual organ, can help clinicians and patients make better decisions, and can even help in the design of more-efficient clinical trials.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 9","pages":"2826-2829"},"PeriodicalIF":50.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995803","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":"Feasibility and clinical utility of expanded genomic newborn screening in the Early Check program","authors":"Heidi L. Cope, Elizabeth R. Jalazo, Jonathan S. Berg, Jennifer A. Sullivan, Katerina S. Kucera, Scott M. Shone, Hannah E. Frawley, Angela Y. Gwaltney, Ana N. Forsythe, Brooke A. Migliore, Becca Wright, Rebecca R. Moultrie, Laura V. Milko, Rebekah S. Zimmerman, Paul Kruszka, Sharon F. Suchy, Amber Begtrup, Katherine G. Langley, Kristin G. Monaghan, Christina Kraczkowski, Adam J. Guenzel, Kirsty McWalter, Kathleen S. Hruska, Donald B. Bailey, Anne C. Wheeler, Melissa Raspa, Cynthia M. Powell, Holly L. Peay","doi":"10.1038/s41591-025-03945-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03945-8","url":null,"abstract":"<p>Although genomic sequencing presents groundbreaking newborn screening (NBS) opportunities, critical feasibility and utility questions remain. Here we present initial results from the Early Check program—an observational study assessing the feasibility and clinical utility of genomic NBS in North Carolina. Recruitment was statewide through mailed letters with electronic consent. Genome sequencing with analysis of 169 high actionability genes (plus 29 optional lower actionability genes) was performed using residual NBS dried blood spots. In 8 months, 1,979 newborns were screened, with 50 (2.5%) screen positives. Negative results were returned electronically, positive results by genetic counselors. Twenty-eight results (55%) were true positives, all received anticipatory guidance, surveillance and management recommendations, and referral to specialists as appropriate. We report technical feasibility and preliminary clinical utility finding, along with interpretation and follow-up challenges that hinder public health implementation. We propose standardized terminology to facilitate cross-study comparisons and accurate characterization of genomic NBS outcomes.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"42 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995647","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":"Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2 umbrella trial","authors":"Wolfgang Wick, Lisa-Marie Lanz, Antje Wick, Inga Harting, Susan Dettmer, Abigail K. Suwala, Ralf Ketter, Ghazaleh Tabatabai, Corinna Seliger, Martin Glas, Michael C. Burger, Marco Timmer, Florian A. Ringel, Iris Mildenberger, Walter J. Schulz-Schaeffer, Frank Winkler, Laila König, Christel Herold-Mende, Andreas Eisenmenger, Stefan M. Pfister, Mirjam Renovanz, Martin Bendszus, Felix Sahm, Michael Platten, Tobias Kessler","doi":"10.1038/s41591-025-03928-9","DOIUrl":"https://doi.org/10.1038/s41591-025-03928-9","url":null,"abstract":"<p>Advances in molecular understanding and diagnostic precision of glioblastoma enable the identification of key genetic alterations in a timely manner and, in principle, allow treatments with targeted compounds based on molecular markers. Here we report the results of the phase 1/2 umbrella trial NCT Neuro Master Match (N²M²), which evaluated targeted treatments in 228 patients with newly diagnosed glioblastoma without O6-methylguanine DNA-methyltransferase promoter hypermethylation. Stratification for treatment was conducted by a trial-specific molecular tumor board across five subtrials, each evaluating a targeted therapy—alectinib, idasanutlin, palbociclib, vismodegib or temsirolimus—selected according to the best-matching molecular alteration. Patients without matching alterations were randomized between subtrials without strong biomarkers using atezolizumab and asunercept, and the standard of care (SOC), temozolomide. All received radiotherapy. The primary endpoints were dose-limiting toxicities (phase 1) and progression-free survival at 6 months (PFS-6; phase 2). Secondary endpoints included safety and tolerability, as well as overall survival (OS). The subtrials for alectinib and vismodegib did not open as they did not have matching patients. The idasanutlin subtrial (<i>n</i> = 9) was terminated early at the discretion of the manufacturing company. The temsirolimus subtrial (<i>n</i> = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (<i>n</i> = 54), meeting the primary endpoint. The atezolizumab (<i>n</i> = 42), asunercept (<i>n</i> = 26) and palbociclib (<i>n</i> = 41) subtrials did not meet the primary endpoint for efficacy. The safety signals of N²M² match prior experiences with the drugs in quality and quantity; no relevant negative interaction with the parallel radiotherapy was noted. The results of the N²M² trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling. ClinicalTrials.gov registration: NCT03158389.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"16 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995649","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":"Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial","authors":"Barbara Pistilli, Fernanda Mosele, Noemie Corcos, Livia Pierotti, Yoann Pradat, Loic Le Bescond, Magali Lacroix-Triki, Ghada Nachabeh, Alexia Alfaro, Cyril Catelain, Bastien Job, Fathia Mami-Chouaib, Severine Badel, Françoise Farace, Marianne Oulhen, Patricia Kannouche, Diep T. N. Tran, Nathalie Droin, Cecile Vicier, Jean Sebastien Frenel, Veronique D’Hondt, Florence Dalenc, Thomas Bachelot, Agnes Ducoulombier, Marc Antoine Benderra, Delphine Loirat, Didier Mayeur, Elise Deluche, Jacqueline Deneuve, Rasha Cheikh-Hussin, Pierre Guyader, Nicolas Signolle, Karine Godefroy, Hugues Talbot, Maria Vakalopoulou, Stergios Christodoulidis, Elsa Bernard, Yves Koudou, Andrea Sporchia, Fumitaka Suto, Lie Li, David W. Sternberg, Stefan Michiels, Fabrice André, Dalila Sellami, Guillaume Montagnac","doi":"10.1038/s41591-025-03885-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03885-3","url":null,"abstract":"<p>Antibody–drug conjugates have shown impressive clinical outcomes, particularly in metastatic breast cancer, but biomarkers to predict response and resistance remain unidentified. Here we report the results of ICARUS-BREAST01, a phase 2 study evaluating efficacy, safety and biomarkers of response and resistance to patritumab deruxtecan (HER3-DXd), in patients with HR⁺HER2⁻ metastatic breast cancer, who previously progressed on CDK4/6 inhibitors and one line of chemotherapy. From May 2021 to June 2023, 99 patients were enrolled to receive HER3-DXd 5.6 mg kg⁻¹ intravenously every 3 weeks. The study met its primary endpoint, showing an overall response rate of 53.5% (90% confidence interval [44.8–62.1%]). The most frequent adverse events were fatigue (83%), nausea (75%), diarrhea (53%) and alopecia (40%). Exploratory biomarker analysis of baseline tumor samples suggested preliminary associations between overall response rate and both HER3 spatial distribution and absence of estrogen receptor 1 (ESR1) mutations, as well as between progression-free survival and HER3 expression, pending further validation. Analysis of on-treatment tumor samples showed that treatment efficacy seems to be associated with antibody–drug conjugate intratumoral distribution and interferon response. Overall, HER3-DXd showed promising activity and manageable tolerability in patients with HR⁺HER2⁻ metastatic breast cancer who progressed on CDK4/6 inhibitors. These findings highlight the need for larger trials to define HER3-DXd efficacy relative to other drugs, including antibody–drug conjugates (ClinicalTrials.gov Identifier: NCT04965766).</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"114 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987521","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":"Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial","authors":"Elisabeth M. Jongbloed, Noor Wortelboer, Vanja de Weerd, Corine M. Beaufort, Kirsten Ruigrok-Ritstier, Mai N. Van, Jaco Kraan, Annette A. van Zweeden, Annemieke van der Padt-Pruijsten, Lisanne C. Hamming, Inge R. Konings, Gabe S. Sonke, Esther Oomen-de Hoop, John W. M. Martens, Agnes Jager, Saskia M. Wilting","doi":"10.1038/s41591-025-03935-w","DOIUrl":"https://doi.org/10.1038/s41591-025-03935-w","url":null,"abstract":"<p>CDK4/6 inhibitors (CDK4/6i) improve outcome in patients with advanced estrogen receptor-positive, HER2⁻ breast cancer. The phase 3 SONIA trial compared the addition of CDK4/6i to first- versus second-line endocrine therapy for time to disease progression after second-line treatment (progression-free survival after two lines of treatment (PFS2)), as well as for secondary outcomes overall survival, PFS after one line of treatment (PFS1), health-related quality of life (HRQOL), toxicity and cost-effectiveness. No significant difference in PFS2 was observed; however, on an individual patient level this may be different. Using prespecified circulating tumor DNA analyses, we performed an exploratory study to evaluate whether pretreatment circulating tumor DNA (ctDNA) levels in plasma can identify patients that benefit from CDK4/6i during their first-line treatment. Cell free DNA before start of first-line treatment from 409 female patients participating in SONIA was analyzed with the modified fast aneuploidy screening test-sequencing system. This assay yields a genome-wide aneuploidy score, indicative of ctDNA levels. Cox proportional hazard analyses for PFS1 and PFS2 were performed separately for the ctDNA high group (aneuploidy score ≥ 5) and the ctDNA low group (aneuploidy score &lt; 5). In total, 141 of the 409 included patients had a high genome-wide aneuploidy score at baseline. PFS2 in the first- compared to the second-line CDK4/6i strategy showed hazard ratios of 0.58 (95% confidence interval 0.38–0.88) and 1.36 (95% confidence interval 0.95–1.96) in the high and low aneuploidy group, respectively. A significant interaction was demonstrated between treatment strategy and aneuploidy score for PFS2 (<i>P</i> = 0.004). In conclusion, this study demonstrated that pretreatment ctDNA levels can be used to identify patients that benefit from first-line CDK4/6i treatment. ClinicalTrials.gov registration: NCT03425838.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"15 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987498","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":"Cancer genetics in a tube of blood","authors":"Luis A. Diaz Jr","doi":"10.1038/s41591-025-03921-2","DOIUrl":"10.1038/s41591-025-03921-2","url":null,"abstract":"Luis Diaz describes how a molecular blood assay revealed the tiniest traces of DNA from a tumor, changing how we monitor cancer.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 9","pages":"2830-2830"},"PeriodicalIF":50.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987495","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":"Improving the evidence base for COVID-19 vaccines","authors":"Helen Y. Chu, Holly Janes, Marco Carone, Peter B. Gilbert, Stanley Plotkin","doi":"10.1038/s41591-025-03908-z","DOIUrl":"https://doi.org/10.1038/s41591-025-03908-z","url":null,"abstract":"<p>The beginning of the COVID-19 pandemic marked an unprecedented time when safe and effective vaccines were developed, authorized, and approved for use within months of the initial identification of the novel coronavirus¹. These authorizations and approvals were based on large, placebo-controlled trials powered to characterize safety and efficacy against clinically significant infection — appropriate designs given the use of vaccine platforms, such as mRNA technology, and antigens, including the prefusion spike protein, that had not previously been studied at large scale in humans. These early studies were among the largest clinical trials in recent history, enrolling tens of thousands of participants and providing definitive evidence of the safety and efficacy of the SARS-CoV-2 vaccines.</p><p>Since then, the evolution of SARS-CoV-2 has prompted annual updates to COVID-19 vaccine composition to match the predominant circulating strain. Multiple national surveillance platforms provide data on the effectiveness of current vaccines to inform the need for updates⁵. As with other seasonal vaccines (for example, influenza), these updates are based on immunobridging studies that compare neutralizing antibody titers induced by vaccines with new variant inserts to those induced by approved vaccines⁶. Licensure by a regulatory body typically requires non-inferiority of the investigational vaccine versus the approved vaccine, meaning that the investigational vaccine is not clinically significantly worse than the approved vaccine (Fig. 1b). For seasonal vaccines, this is appropriate for several reasons. Annual vaccine updates require considerable lead time for production. For influenza, strain selection decisions are typically made 4–6 months in advance at a semiannual meeting convened by the World Health Organization, followed by a meeting of the US Food and Drug Administration’s Vaccine and Related Biologics Advisory Committee, which recommends strains to domestic vaccine manufacturers. To match the vaccine to circulating strains while also giving manufacturers sufficient time to produce the necessary doses for distribution, strain selection recommendations are made using immunobridging studies that show neutralization of new circulating variants. The timeline for COVID-19 vaccine updates might differ based on the evolution of the virus as well as use of mRNA technology, though it still requires lead time for production and distribution. Immunobridging is a well-established approach for seasonal vaccine strain selection and is standard practice in many countries.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"63 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987497","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":"Author Correction: Shared and disease-specific pathways in frontotemporal dementia and Alzheimer’s and Parkinson’s diseases","authors":"Muhammad Ali, Buddhiprabha Erabadda, Yike Chen, Ying Xu, Katherine Gong, Menghan Liu, Alexa Pichet Binette, Jigyasha Timsina, Daniel Western, Chengran Yang, Gyujin Heo, Jacob W. Vogel, Betty M. Tijms, Varsha Krish, Farhad Imam, Oskar Hansson, Laura Winchester, Carlos Cruchaga","doi":"10.1038/s41591-025-03970-7","DOIUrl":"https://doi.org/10.1038/s41591-025-03970-7","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-025-03833-1, published online 15 July 2025.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"27 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928593","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":"Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial","authors":"Angela DeMichele, Amy S. Clark, Emily Shea, Lauren J. Bayne, Christopher J. Sterner, Killian Rohn, Samantha Dwyer, Tien-chi Pan, Isoris Nivar, Yan Chen, Paul Wileyto, Lindsay R. Berry, Shannon Deluca, Jessica Savage, Igor Makhlin, Dhruv K. Pant, Heather Martin, Adetutu Egunsola, Nathan Mears, Brooke L. Goodspeed, Elizabeth M. Chislock, Jewell Graves, Jianping Wang, Natalie Shih, George K. Belka, Don Berry, Anupma Nayak, Michael Feldman, Lewis A. Chodosh","doi":"10.1038/s41591-025-03877-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03877-3","url":null,"abstract":"<p>Breast cancer recurrence may arise from dormant disseminated tumor cells (DTCs) that persist in bone marrow and other sites. Clinically, DTCs are independently associated with breast cancer recurrence and death. Preclinical studies in mouse models identified autophagy and mammalian target of rapamycin (mTOR) signaling as critical mechanisms of tumor dormancy and escape. We subsequently tested the effects of transient versus chronic inhibition of autophagy with chloroquine or hydroxychloroquine (HCQ) and mTOR signaling with rapamycin (RAPA) or everolimus (EVE) on residual tumor cell (RTC) burden and recurrence-free survival (RFS). In mice harboring dormant RTCs, inhibition of mTOR alone or in combination with autophagy inhibition decreased RTC burden and improved RFS in a duration-dependent manner. RTC number was strongly and inversely correlated with RFS, suggesting that RTC reduction mediated an improvement in RFS. To translate findings clinically, we performed a randomized phase 2 trial (CLEVER) of HCQ, EVE or their combination in breast cancer survivors within 5 years of diagnosis who had detectable DTCs on bone marrow aspirate. Primary endpoints were feasibility and safety; secondary endpoints included DTC reduction/clearance and RFS. In total, 51 DTC⁺ patients initiated HCQ (<i>n</i> = 15), EVE (<i>n</i> = 15) or HCQ + EVE (<i>n</i> = 21). Treatment was feasible and tolerable; only one patient discontinued early for grade 3 toxicity. At 42 months median follow-up, landmark 3-year RFS for HCQ, EVE and HCQ + EVE was 91.7%, 92.9% and 100%, respectively, and was greater in those who cleared DTCs versus those who did not (hazard ratio (HR) = 0.21 (95% confidence interval 0.01–3.4)). Posterior probabilities were 98–99.9% that three cycles of HCQ, EVE or HCQ + EVE led to reduced or undetectable DTCs compared to observation alone, with estimated DTC reductions of 80%, 78% and 87%, respectively. These findings provide proof-of-concept that targeting dormant RTCs with HCQ, EVE or their combination in breast cancer survivors or mouse models depletes minimal residual disease, warranting a definitive human randomized controlled trial. ClinicalTrials.gov registration: NCT03032406.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"13 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928594","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":"Semaglutide targets MASH molecular pathways beyond weight loss","authors":"Maurice Michel,&nbsp;Jörn M. Schattenberg","doi":"10.1038/s41591-025-03927-w","DOIUrl":"10.1038/s41591-025-03927-w","url":null,"abstract":"A proteomic study begins to identify the direct and indirect effects of GLP-1 treatment on metabolic dysfunction-associated steatohepatitis (MASH), and reveals insights into treatment-induced changes in liver histology.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 9","pages":"2865-2866"},"PeriodicalIF":50.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924130","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}