Nature Medicine最新文献

{"title":"Molecular predictors of minimal residual disease in newly diagnosed multiple myeloma treated with quadruplet therapy","authors":"Florence Magrangeas, Mia Cherkaoui, Victor Bessonneau-Gaborit, Jennifer Derrien, Céline Chevalier, Catherine Guérin-Charbonnel, Benjamin Diamond, Mehmet Kemal Samur, Intergroupe Francophone du Myélome (IFM), Cyrille Hulin, Denis Caillot, Lionel Karlin, Bertrand Arnulf, Ola Landgren, Nikhil C. Munshi, Hervé Avet-Loiseau, Ludovic Martinet, Jill Corre, Aurore Perrot, Philippe Moreau, Cyrille Touzeau, Stéphane Minvielle, Eric Letouzé","doi":"10.1038/s41591-026-04692-0","DOIUrl":"https://doi.org/10.1038/s41591-026-04692-0","url":null,"abstract":"Quadruplet therapy, combining anti-CD38 antibodies, immunomodulatory drugs, proteasome inhibitors and dexamethasone, is now the standard induction treatment for newly diagnosed multiple myeloma (NDMM). However, treatment response is heterogeneous and molecular predictors are needed to guide early therapeutic decisions. We performed integrated genomic, transcriptomic and epigenomic profiling of 423 tumor samples from patients with NDMM from the MIDAS cohort to characterize molecular heterogeneity and its association with measurable residual disease (MRD) after quadruplet induction with isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd). Postinduction MRD-negativity rates varied significantly across gene expression subtypes, with HP1/HP3 and MS groups showing superior responses compared to the MF and CD2 subtypes. B cell differentiation was associated with MRD positivity, while proliferation and MYC programs were associated with MRD negativity. These MRD-associated transcriptomic features were independently validated in the CASSIOPEIA cohort. Whole-genome sequencing revealed both known (APOBEC mutagenesis, chromothripsis) and new genomic instability phenotypes validated in the MMRF cohort. New driver alterations were identified with independent validation across three external cohorts with multiple myeloma (MMRF, MANHATTAN and CASSIOPEIA; 1,451 cases). Genomic instability features and driver genes such as CCND1 and MYC correlated with differential MRD outcomes. DNA methylation profiling identified nine MRD-linked subgroups distinguished by the extent of hypomethylation in quiescent chromatin and cis/trans signatures of driver translocations. A multimodal random forest model integrating genomic, transcriptomic and epigenomic features predicted MRD status after induction, with an area under the curve of 0.77, outperforming clinical and genomic models, while providing comparable discrimination and improved calibration relative to the transcriptomic and epigenomic models. These findings define a multiomic classification of NDMM linked to Isa-KRd response. ClinicalTrials.gov identifier: NCT04934475.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"42 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218251","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":"Waiting to get sick enough.","authors":"Jeffrey V Lazarus","doi":"10.1038/s41591-026-04701-2","DOIUrl":"https://doi.org/10.1038/s41591-026-04701-2","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224496","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":"Only time will tell.","authors":"Natalie Healey","doi":"10.1038/s41591-026-04699-7","DOIUrl":"https://doi.org/10.1038/s41591-026-04699-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207487","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":"EGFR-targeted antibody-toxin conjugate in recurrent glioma: a phase 1 trial.","authors":"Vidyalakshmi Chandramohan, James E Herndon, Anjali Barnwal, Katayoun Ayasoufi, Weixuan Yan, Kevin Stevenson, Michelle L Bowie, Michael C Brown, Smita K Nair, Matthias Gromeier, Dina Randazzo, Katherine B Peters, Margaret O Johnson, Roger E McLendon, Daniel Landi, John H Sampson, Ira H Pastan, Allan H Friedman, Henry S Friedman, David M Ashley, Darell D Bigner, Annick Desjardins","doi":"10.1038/s41591-026-04715-w","DOIUrl":"https://doi.org/10.1038/s41591-026-04715-w","url":null,"abstract":"<p><p>D2C7-ATC is a recombinant antibody-toxin conjugate (ATC) targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII). We conducted a single-arm, single-site, open-label phase 1 trial evaluating a single infusion of D2C7-ATC via convection-enhanced delivery in the enhancing disease of 81 patients with biopsy-confirmed recurrent malignant glioma. The primary objective was to determine toxicity and the recommended phase 2 dose (RP2D) of D2C7-ATC. Secondary objectives included describing overall survival (OS) and assessing the association between EGFR expression and OS. The median overall survival (mOS) was 7.9 months among 72 patients with isocitrate dehydrogenase wild-type recurrent glioblastoma (IDHwt rGBM), including 35 patients in the dose-escalation stage (40 to 35,032 ng ml^-1) and 37 patients in the dose-expansion stage (RP2D of 6,920 ng ml^-1). D2C7-ATC was generally well tolerated, with mainly grade 1-2 treatment-related adverse events (67%). The maximum tolerated dose was exceeded at 35,032 ng ml^-1, where four patients experienced dose-limiting toxicities, including grade 4 (N = 2) and grade 3 (N = 2) events. Eight patients died on trial; all deaths were unrelated to D2C7-ATC. Univariate analyses identified survival-associated biomarkers, including tumor D2C7 antibody reactivity, circulating cytokines, a tumor inflammatory gene signature and neutrophils, monocytes and lymphocytes in blood. Notably, patients with IDHwt rGBM with a D2C7 antibody reactivity score of <1.5+ in pre-treatment tumor had an mOS of 17.38 months, whereas those with low IL-8 in post-treatment plasma had an mOS of 16.6 months. These findings indicate that EGFR-targeted D2C7-ATC therapy prolongs survival in a subset of patients with IDHwt rGBM via intratumoral and systemic immune activation. ClinicalTrials.gov identifier: NCT02303678 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207455","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 reality check for autoimmune CAR T cells.","authors":"Marianne Guenot","doi":"10.1038/d41591-026-00052-0","DOIUrl":"https://doi.org/10.1038/d41591-026-00052-0","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207331","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":"Real-world, digital-first delivery of GLP-1 receptor agonist therapy in women.","authors":"John Deanfield, Jamie Lai Chun Wong, Michail Katsoulis, Emma Deanfield, Raj Thakkar, Riyaz Patel, Rachael Joy, Matthew Noble, Donna H Ryan","doi":"10.1038/s41591-026-04687-x","DOIUrl":"https://doi.org/10.1038/s41591-026-04687-x","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial weight reduction and cardiometabolic benefit in randomized trials; however, prospective implementation evidence from digital care models and female sex community populations remains limited. Here we report outcomes from an observational study of 8,127 women initiating GLP-1RA therapy (99.8% tirzepatide) through a structured digital program incorporating mandatory biochemical monitoring, weekly video-supported follow-up and clinician-guided dose titration in the UK. Mean weight reduction was 16.1 kg (95% confidence interval 15.9 to 16.2; P < 0.001), representing 15.5% of baseline weight; 83.1% achieved ≥10% and 22.4% achieved ≥20% weight loss, with consistent responses across age, baseline weight and socioeconomic strata. Among participants with paired biomarker data, mean glycated hemoglobin decreased by 3.3 mmol mol^-¹ (95% confidence interval 3.1 to 3.4; P < 0.001), normalizing in 84.5% of those with baseline diabetes-range values and 96.3% with prediabetes, and lipid parameters improved significantly (reductions in total cholesterol of 0.77 mmol l^-¹, low-density lipoprotein cholesterol of 0.61 mmol l^-¹ and triglycerides of 0.47 mmol l^-¹). Retention was 91.4% at 6 months, with no serious treatment-related adverse events. These findings support the feasibility of delivering structured, digitally enabled obesity pharmacotherapy at scale and provide prospective real-world implementation evidence for this care model. Interpretation is limited by the observational design, absence of a comparator group, self-pay population and 6-month follow-up.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207430","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":"Conversational brain AI for adaptive epilepsy care.","authors":"Samden Lhatoo, Vladimir Vashin","doi":"10.1038/s41591-026-04719-6","DOIUrl":"https://doi.org/10.1038/s41591-026-04719-6","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207498","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":"Hidden race disparities in cancer treatment toxicity.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00050-2","DOIUrl":"https://doi.org/10.1038/d41591-026-00050-2","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195282","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":"Optogenetic therapy shows early promise for treating retinitis pigmentosa.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00051-1","DOIUrl":"https://doi.org/10.1038/d41591-026-00051-1","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195285","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":"Editorial Expression of Concern: Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function.","authors":"Guoying Yu, Argyris Tzouvelekis, Rong Wang, Jose D Herazo-Maya, Gabriel H Ibarra, Anup Srivastava, Joao Pedro Werneck de Castro, Giuseppe DeIuliis, Farida Ahangari, Tony Woolard, Nachelle Aurelien, Rafael Arrojo E Drigo, Ye Gan, Morven Graham, Xinran Liu, Robert J Homer, Thomas S Scanlan, Praveen Mannam, Patty J Lee, Erica L Herzog, Antonio C Bianco, Naftali Kaminski","doi":"10.1038/s41591-026-04733-8","DOIUrl":"https://doi.org/10.1038/s41591-026-04733-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182967","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}