Pub Date : 2026-03-19DOI: 10.1038/s41591-026-04290-0
Tiantian Li,Hang Du,Peng Du
{"title":"Integrating health equity into energy transitions and climate governance.","authors":"Tiantian Li,Hang Du,Peng Du","doi":"10.1038/s41591-026-04290-0","DOIUrl":"https://doi.org/10.1038/s41591-026-04290-0","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"49 3 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483436","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}
Burkitt's lymphoma (BL) is common in sub-Saharan Africa, yet diagnosis is often delayed due to limited pathology capacity. Here we evaluated blood-based liquid biopsies from 377 children and young adults with clinically suspected lymphoma at four hospitals in Tanzania and Uganda, assessing diagnostic accuracy and turnaround time (TAT). After extensive pathology capacity building, a gold-standard diagnosis was established using tissue morphology, a limited validated immunohistochemistry panel and independent dual histopathologist review. Using clinical features and circulating tumor DNA markers (MYC mutations, MYC-immunoglobulin translocations and Epstein-Barr virus fragmentomics), we trained six penalized logistic regression models with tenfold crossvalidation (n = 212). The best-performing model was externally validated in a prospective real-world cohort (n = 56). Diagnostic accuracy, yield and TAT were compared head to head between liquid biopsy and the gold standard in 58 participants. The comprehensive model achieved the highest performance (area under the curve (AUC) 0.95, 95% confidence interval (95% CI) 0.901-0.981, sensitivity 0.86, specificity 0.95), confirmed by external validation (AUC 0.98, 95% CI 0.942-1.000). Liquid biopsy was the only diagnostic result available at the multidisciplinary review in 42% of participants and reduced median diagnostic TAT from 46.8 d to 6.5 d (P = 4.42 × 10-10). These findings demonstrate that liquid biopsy enables fast, highly accurate molecular diagnosis of EBV+ BL and may substantially reduce treatment delays in resource-limited settings.
{"title":"Liquid biopsy for the diagnosis of EBV-positive Burkitt's lymphoma in endemic areas.","authors":"Clara Chamba,Heavenlight Christopher,Emmanuel Josephat,Julius Sseruyange,Alisen Ayitewala,Kieran Howard,Helene Dreau,Adam Burns,Ismail Legason,Isaac Otim,Priscus Mapendo,Leah Mnango,Advera Ngaiza,Alex Mremi,Edrick Elias,Carol Achola,William Mawalla,Rehema Shungu,Eli Mkwizu,Lulu Chirande,Hadija Mwamtemi,Salama Mahawi,Godlove Sandi,Heronima J Kashaigili,Sıla Gerlevik,Paul Shadrack Ntemi,Erick Magorosa,Daniel Mbwambo,Malale Tungu,Martin Ogwang,Faraja Chiwanga,Sam M Mbulaiteye,Claire El Mouden,Emmanuel Balandya,Anthony Cutts,Liz Morrell,Dimitrios Vavoulis,Anna Schuh","doi":"10.1038/s41591-026-04291-z","DOIUrl":"https://doi.org/10.1038/s41591-026-04291-z","url":null,"abstract":"Burkitt's lymphoma (BL) is common in sub-Saharan Africa, yet diagnosis is often delayed due to limited pathology capacity. Here we evaluated blood-based liquid biopsies from 377 children and young adults with clinically suspected lymphoma at four hospitals in Tanzania and Uganda, assessing diagnostic accuracy and turnaround time (TAT). After extensive pathology capacity building, a gold-standard diagnosis was established using tissue morphology, a limited validated immunohistochemistry panel and independent dual histopathologist review. Using clinical features and circulating tumor DNA markers (MYC mutations, MYC-immunoglobulin translocations and Epstein-Barr virus fragmentomics), we trained six penalized logistic regression models with tenfold crossvalidation (n = 212). The best-performing model was externally validated in a prospective real-world cohort (n = 56). Diagnostic accuracy, yield and TAT were compared head to head between liquid biopsy and the gold standard in 58 participants. The comprehensive model achieved the highest performance (area under the curve (AUC) 0.95, 95% confidence interval (95% CI) 0.901-0.981, sensitivity 0.86, specificity 0.95), confirmed by external validation (AUC 0.98, 95% CI 0.942-1.000). Liquid biopsy was the only diagnostic result available at the multidisciplinary review in 42% of participants and reduced median diagnostic TAT from 46.8 d to 6.5 d (P = 4.42 × 10-10). These findings demonstrate that liquid biopsy enables fast, highly accurate molecular diagnosis of EBV+ BL and may substantially reduce treatment delays in resource-limited settings.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483426","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}
Pub Date : 2026-03-19DOI: 10.1038/s41591-026-04277-x
Esperanza Elías-Cabot,Sara Romero-Martín,José Luis Raya-Povedano,Alejandro Rodríguez-Ruiz,Marina Álvarez-Benito
Artificial intelligence (AI) systems have been demonstrated to improve the accuracy of screening mammograms. Here this prospective, paired, noninferiority clinical trial evaluated whether AI could safely reduce workload by excluding low-risk exams from radiologist reading. Between March 2022 and January 2024, 31,301 women were included in the trial and underwent routine mammograms. Two reading strategies were applied in parallel: standard double-blind reading and partially autonomous AI-supported screening, where cases classified by AI as low risk were assessed as normal and the rest were double read with AI support. The primary outcomes were radiologist workload, cancer detection rate and recall rate. In the AI strategy, radiologist workload was 63.6% lower; the cancer detection rate was 15.2% higher (95% confidence interval 6.6%, 24.4%), increasing from 6.3 of 1,000 to 7.3 of 1,000, P < 0.001; and the recall rate was not noninferior and was 14.8% higher (95% confidence interval 9.0%, 20.6%). Subanalyses by modality highlighted a similar workload reduction in digital mammography (-62.1%) and digital breast tomosynthesis (-65.5%). However, in digital mammography, the cancer detection rate increased by 1.6 of 1,000 and the recall rate by 1.3%, while both remained stable in digital breast tomosynthesis. These results demonstrate the feasibility of a partially automated AI workflow in breast cancer screening, avoiding human reading of studies classified as low risk. ClinicalTrials.gov: NCT04849776 .
{"title":"AI-based triage and decision support in mammography and digital tomosynthesis for breast cancer screening: a paired, noninferiority trial.","authors":"Esperanza Elías-Cabot,Sara Romero-Martín,José Luis Raya-Povedano,Alejandro Rodríguez-Ruiz,Marina Álvarez-Benito","doi":"10.1038/s41591-026-04277-x","DOIUrl":"https://doi.org/10.1038/s41591-026-04277-x","url":null,"abstract":"Artificial intelligence (AI) systems have been demonstrated to improve the accuracy of screening mammograms. Here this prospective, paired, noninferiority clinical trial evaluated whether AI could safely reduce workload by excluding low-risk exams from radiologist reading. Between March 2022 and January 2024, 31,301 women were included in the trial and underwent routine mammograms. Two reading strategies were applied in parallel: standard double-blind reading and partially autonomous AI-supported screening, where cases classified by AI as low risk were assessed as normal and the rest were double read with AI support. The primary outcomes were radiologist workload, cancer detection rate and recall rate. In the AI strategy, radiologist workload was 63.6% lower; the cancer detection rate was 15.2% higher (95% confidence interval 6.6%, 24.4%), increasing from 6.3 of 1,000 to 7.3 of 1,000, P < 0.001; and the recall rate was not noninferior and was 14.8% higher (95% confidence interval 9.0%, 20.6%). Subanalyses by modality highlighted a similar workload reduction in digital mammography (-62.1%) and digital breast tomosynthesis (-65.5%). However, in digital mammography, the cancer detection rate increased by 1.6 of 1,000 and the recall rate by 1.3%, while both remained stable in digital breast tomosynthesis. These results demonstrate the feasibility of a partially automated AI workflow in breast cancer screening, avoiding human reading of studies classified as low risk. ClinicalTrials.gov: NCT04849776 .","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"85 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483429","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}
Pub Date : 2026-03-18DOI: 10.1038/s41591-026-04266-0
Chirag J Patel,John P A Ioannidis,Arjun K Manrai
Nongenetic exposures comprising the 'exposome', including diet, lifestyle, infections and pollutants, shape many clinical phenotypes yet the evidence remains fragmented. Here we conducted an exposome-wide association study incorporating 619 exposure indicators and 305 quantitative phenotypes across ten independent waves of the US Centers for Disease Control and Prevention National Health and Nutrition Examination Survey. Replicable and stable signals were most concentrated in cardiometabolic and anthropometric phenotypes, linking objective nutrient biomarkers and lipophilic pollutants with body mass index, glycated hemoglobin and lipid profiles. Triglycerides, an important marker for cardiovascular risk, emerged as the phenotype most strongly associated with multidomain exposures, notably trans fatty acids, persistent pollutants and vitamin E isoforms. In pulmonary traits, tobacco-specific and carcinogen biomarkers were more prominently associated with reduced lung function than short-lived nicotine metabolites, refining exposomic links to forced expiratory volume in 1 s. Whereas individual exposures showed modest effects, aggregate 'poly-exposomic' models explained phenotypic variation comparable to genome-wide polygenic scores. Exposome globes further reveal an interconnected architecture where exposures rarely act in isolation, complicating causal attribution while providing a more holistic view of environmental risk. Our findings highlight which exposures are most likely to add value to disease risk assessment, population surveillance as well as further exposure prioritization and next-generation longitudinal exposomics.
{"title":"An atlas of exposome-phenome associations in health and disease risk.","authors":"Chirag J Patel,John P A Ioannidis,Arjun K Manrai","doi":"10.1038/s41591-026-04266-0","DOIUrl":"https://doi.org/10.1038/s41591-026-04266-0","url":null,"abstract":"Nongenetic exposures comprising the 'exposome', including diet, lifestyle, infections and pollutants, shape many clinical phenotypes yet the evidence remains fragmented. Here we conducted an exposome-wide association study incorporating 619 exposure indicators and 305 quantitative phenotypes across ten independent waves of the US Centers for Disease Control and Prevention National Health and Nutrition Examination Survey. Replicable and stable signals were most concentrated in cardiometabolic and anthropometric phenotypes, linking objective nutrient biomarkers and lipophilic pollutants with body mass index, glycated hemoglobin and lipid profiles. Triglycerides, an important marker for cardiovascular risk, emerged as the phenotype most strongly associated with multidomain exposures, notably trans fatty acids, persistent pollutants and vitamin E isoforms. In pulmonary traits, tobacco-specific and carcinogen biomarkers were more prominently associated with reduced lung function than short-lived nicotine metabolites, refining exposomic links to forced expiratory volume in 1 s. Whereas individual exposures showed modest effects, aggregate 'poly-exposomic' models explained phenotypic variation comparable to genome-wide polygenic scores. Exposome globes further reveal an interconnected architecture where exposures rarely act in isolation, complicating causal attribution while providing a more holistic view of environmental risk. Our findings highlight which exposures are most likely to add value to disease risk assessment, population surveillance as well as further exposure prioritization and next-generation longitudinal exposomics.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478744","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}
Pub Date : 2026-03-18DOI: 10.1038/s41591-026-04289-7
Arthur David,Sarah Lennon,Fabien Mercier,Jihene Bouhlel,Jade Chaker,Brice M R Appenzeller,Karine Audouze,Kolawole I Ayeni,Ludovic Bailly-Chouriberry,Souleiman El Balkhi,Robert Barouki,Lidia Belova,Tarik Benmarhnia,Bénilde Bonnefille,Vincent Bessonneau,Nathalie Bonvallot,Valérie Bouchart,Céline Bouvier-Capely,Corinne Buisson,Daniel Bury,Adrian Covaci,Xavier Coumoul,Laurent Debrauwer,Raphaël Delépée,Sebastien Denys,Clémentine Dereumeaux,Max L Feuerstein,Clémence Fillol,Pablo Gago-Ferrero,Patrice Garcia,Thomas Gicquel,Ruben Gil-Solsona,Nathalie Grova,Baninia Habchi,Vinicius V Hernandes,Alba Iglesias-González,Emilien L Jamin,Holger M Koch,Sophie Lefèvre-Arbogast,Christian Lindh,Mari-Vorgan Louyer,Linda R Macheka,Jonathan W Martin,Montse Marques,Hans Mol,Sophie Ndaw,Amivi Oleko,Stefano Papazian,Petra Přibylová,Elliott J Price,Emma L Schymanski,Solveig Thiele,Benedikt Warth,Florence Zeman,Etienne Blanc,Jean-Philippe Antignac,Bruno Le Bizec,Michel Samson
{"title":"Mapping the human chemical exposome for public health.","authors":"Arthur David,Sarah Lennon,Fabien Mercier,Jihene Bouhlel,Jade Chaker,Brice M R Appenzeller,Karine Audouze,Kolawole I Ayeni,Ludovic Bailly-Chouriberry,Souleiman El Balkhi,Robert Barouki,Lidia Belova,Tarik Benmarhnia,Bénilde Bonnefille,Vincent Bessonneau,Nathalie Bonvallot,Valérie Bouchart,Céline Bouvier-Capely,Corinne Buisson,Daniel Bury,Adrian Covaci,Xavier Coumoul,Laurent Debrauwer,Raphaël Delépée,Sebastien Denys,Clémentine Dereumeaux,Max L Feuerstein,Clémence Fillol,Pablo Gago-Ferrero,Patrice Garcia,Thomas Gicquel,Ruben Gil-Solsona,Nathalie Grova,Baninia Habchi,Vinicius V Hernandes,Alba Iglesias-González,Emilien L Jamin,Holger M Koch,Sophie Lefèvre-Arbogast,Christian Lindh,Mari-Vorgan Louyer,Linda R Macheka,Jonathan W Martin,Montse Marques,Hans Mol,Sophie Ndaw,Amivi Oleko,Stefano Papazian,Petra Přibylová,Elliott J Price,Emma L Schymanski,Solveig Thiele,Benedikt Warth,Florence Zeman,Etienne Blanc,Jean-Philippe Antignac,Bruno Le Bizec,Michel Samson","doi":"10.1038/s41591-026-04289-7","DOIUrl":"https://doi.org/10.1038/s41591-026-04289-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"51 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478742","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}
Pub Date : 2026-03-17DOI: 10.1038/s41591-026-04217-9
Thuy Doan, Daisy Yan, Ahmed M. Arzika, Amza Abdou, Ramatou Maliki, Bawa Aichatou, Ismael Mamane Bello, Diallo Beidi, Nasser Galo, Naser Harouna, Alio M. Karamba, Sani Mahamadou, Moustapha Abarchi, Almou Ibrahim, Lina Zhong, Cindi Chen, YuHeng Liu, Danny Yu, Thomas Abraham, Angela S. Cheng, Brittany Peterson, Catherine E. Oldenburg, Travis C. Porco, Benjamin F. Arnold, Armin Hinterwirth, Elodie Lebas, Kieran S. O’Brien, Thomas M. Lietman
Repeated semiannual azithromycin mass drug administration (MDA) to children has been shown to reduce all-cause childhood mortality. However, antibiotic resistance is a major public health concern as the program is being implemented in sub-Saharan Africa. In the double-blind, cluster-randomized, placebo-controlled trial (AVENIR) in Niger, we evaluated the impact of azithromycin MDA targeting different age groups on mortality and on the gut and nasopharyngeal microbiome and resistome of children in participating communities. A total of 3,000 communities were randomized in a 1:1:1 allocation to 3 arms: 2 years of semiannual MDA of (1: child–azithromycin) azithromycin to 1–59-month olds, (2: infant–azithromycin) azithromycin to 1–11-month olds and placebo to 12–59-month olds or (3: placebo) placebo to 1–59-month olds. Mortality (co-primary endpoint) and safety data have previously been published. Here we report on resistance (the co-primary endpoint). One hundred fifty communities (50 per arm) were selected for this analysis. A total of 4,382 rectal and 4,402 nasopharyngeal samples were included. The co-primary outcomes included changes in gut and nasopharynx macrolide AMR. The trial met its primary AMR endpoint for the gut but not for the nasopharynx. The gut macrolide AMR burden in fold change between arms was highest in child–azithromycin compared with placebo (1.16, 95% confidence interval (CI): 1.06–1.28; P < 0.01), followed by child–azithromycin compared with infant–azithromycin (1.13, 95% CI: 1.02–1.23; P = 0.01), and infant–azithromycin compared with placebo (1.04×, 95% CI: 0.94–1.15×; P = 0.66). There were no statistically significant differences in macrolide AMR selection fold change in the nasopharynx between arms: 2.14 (95% CI: 0.93–4.99) for child–azithromycin versus placebo, 2.08 (95% CI: 0.93–4.69) for infant–azithromycin versus placebo, and 1.03 (95% CI: 0.46–2.30) for child–azithromycin versus infant–azithromycin. Close monitoring of AMR should be an essential component of MDA for childhood mortality. ClinicalTrials.gov registration: NCT04224987
{"title":"Mass azithromycin distribution and antibiotic resistance in the gut and nasopharynx: a cluster-randomized trial","authors":"Thuy Doan, Daisy Yan, Ahmed M. Arzika, Amza Abdou, Ramatou Maliki, Bawa Aichatou, Ismael Mamane Bello, Diallo Beidi, Nasser Galo, Naser Harouna, Alio M. Karamba, Sani Mahamadou, Moustapha Abarchi, Almou Ibrahim, Lina Zhong, Cindi Chen, YuHeng Liu, Danny Yu, Thomas Abraham, Angela S. Cheng, Brittany Peterson, Catherine E. Oldenburg, Travis C. Porco, Benjamin F. Arnold, Armin Hinterwirth, Elodie Lebas, Kieran S. O’Brien, Thomas M. Lietman","doi":"10.1038/s41591-026-04217-9","DOIUrl":"https://doi.org/10.1038/s41591-026-04217-9","url":null,"abstract":"Repeated semiannual azithromycin mass drug administration (MDA) to children has been shown to reduce all-cause childhood mortality. However, antibiotic resistance is a major public health concern as the program is being implemented in sub-Saharan Africa. In the double-blind, cluster-randomized, placebo-controlled trial (AVENIR) in Niger, we evaluated the impact of azithromycin MDA targeting different age groups on mortality and on the gut and nasopharyngeal microbiome and resistome of children in participating communities. A total of 3,000 communities were randomized in a 1:1:1 allocation to 3 arms: 2 years of semiannual MDA of (1: child–azithromycin) azithromycin to 1–59-month olds, (2: infant–azithromycin) azithromycin to 1–11-month olds and placebo to 12–59-month olds or (3: placebo) placebo to 1–59-month olds. Mortality (co-primary endpoint) and safety data have previously been published. Here we report on resistance (the co-primary endpoint). One hundred fifty communities (50 per arm) were selected for this analysis. A total of 4,382 rectal and 4,402 nasopharyngeal samples were included. The co-primary outcomes included changes in gut and nasopharynx macrolide AMR. The trial met its primary AMR endpoint for the gut but not for the nasopharynx. The gut macrolide AMR burden in fold change between arms was highest in child–azithromycin compared with placebo (1.16, 95% confidence interval (CI): 1.06–1.28; P < 0.01), followed by child–azithromycin compared with infant–azithromycin (1.13, 95% CI: 1.02–1.23; P = 0.01), and infant–azithromycin compared with placebo (1.04×, 95% CI: 0.94–1.15×; P = 0.66). There were no statistically significant differences in macrolide AMR selection fold change in the nasopharynx between arms: 2.14 (95% CI: 0.93–4.99) for child–azithromycin versus placebo, 2.08 (95% CI: 0.93–4.69) for infant–azithromycin versus placebo, and 1.03 (95% CI: 0.46–2.30) for child–azithromycin versus infant–azithromycin. Close monitoring of AMR should be an essential component of MDA for childhood mortality. ClinicalTrials.gov registration: NCT04224987","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"110 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465321","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}
Pub Date : 2026-03-16DOI: 10.1038/s41591-026-04306-9
Kohei Shitara, Hirokazu Shoji, Nicola Fazio, Sara Lonardi, Keun-Wook Lee, Li-Yuan Bai, Kensei Yamaguchi, Jean-Philippe Metges, Gianluca Masi, Denis Smith, Tae-Yong Kim, Maria Matsangou, Archita Shrivastava, Miaomai Zhou, Jason Hill, Abraham Guerrero, Xuewei Wang, Aziz Zaanan, Samuel J. Klempner
There is an unmet need for effective and safe treatments for patients with metastatic gastric/gastroesophageal junction (mG/GEJ) adenocarcinoma. Targeting claudin 18 isoform 2 (CLDN18.2) and programmed death ligand 1 (PD-L1), represents a promising strategy. Zolbetuximab, a CLDN18.2-targeting antibody, plus chemotherapy improved survival outcomes in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative mG/GEJ adenocarcinoma. Cohort 4 of the global, open-label, phase 2 ILUSTRO study examined first-line zolbetuximab plus mFOLFOX6 and nivolumab (a PD-L1 inhibitor). Here we report results from cohorts 4A (safety lead-in phase) and 4B (expansion phase). The primary endpoint of ILUSTRO was specific to cohort 1 and was previously published; the main efficacy endpoint of interest for cohort 4 was progression-free survival (PFS), as assessed by the investigators per Response Evaluation Criteria in Solid Tumors version 1.1. At data cutoff (2 September 2025) for this final analysis, 77 patients were enrolled in 4A + 4B (85.5% with CLDN18.2-high tumors). Cohort 4B median follow-up was 11.5 months, and median PFS (95% confidence interval (CI)) was 14.8 months (8.3–not estimable) overall (n = 71) and 18.0 months (11.1–not estimable) in patients with CLDN18.2-high tumors (n = 59). Objective response rate (measurable disease; 95% CI) was 62.1% (48.4–74.5) in 4B overall (n = 58) and 68.1% (52.9–80.9) in CLDN18.2-high (n = 47). In 4A + 4B, the most common treatment-emergent adverse events were nausea (80.5%) and decreased appetite (72.7%). Efficacy and safety data support randomized evaluation of zolbetuximab plus chemoimmunotherapy in patients with CLDN18.2-positive and PD-L1-positive mG/GEJ adenocarcinoma in the ongoing phase 3 LUCERNA study. ClinicalTrials.gov: NCT03505320.
{"title":"First-line zolbetuximab plus mFOLFOX6 and nivolumab in unresectable CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: a phase 2 trial","authors":"Kohei Shitara, Hirokazu Shoji, Nicola Fazio, Sara Lonardi, Keun-Wook Lee, Li-Yuan Bai, Kensei Yamaguchi, Jean-Philippe Metges, Gianluca Masi, Denis Smith, Tae-Yong Kim, Maria Matsangou, Archita Shrivastava, Miaomai Zhou, Jason Hill, Abraham Guerrero, Xuewei Wang, Aziz Zaanan, Samuel J. Klempner","doi":"10.1038/s41591-026-04306-9","DOIUrl":"https://doi.org/10.1038/s41591-026-04306-9","url":null,"abstract":"There is an unmet need for effective and safe treatments for patients with metastatic gastric/gastroesophageal junction (mG/GEJ) adenocarcinoma. Targeting claudin 18 isoform 2 (CLDN18.2) and programmed death ligand 1 (PD-L1), represents a promising strategy. Zolbetuximab, a CLDN18.2-targeting antibody, plus chemotherapy improved survival outcomes in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative mG/GEJ adenocarcinoma. Cohort 4 of the global, open-label, phase 2 ILUSTRO study examined first-line zolbetuximab plus mFOLFOX6 and nivolumab (a PD-L1 inhibitor). Here we report results from cohorts 4A (safety lead-in phase) and 4B (expansion phase). The primary endpoint of ILUSTRO was specific to cohort 1 and was previously published; the main efficacy endpoint of interest for cohort 4 was progression-free survival (PFS), as assessed by the investigators per Response Evaluation Criteria in Solid Tumors version 1.1. At data cutoff (2 September 2025) for this final analysis, 77 patients were enrolled in 4A + 4B (85.5% with CLDN18.2-high tumors). Cohort 4B median follow-up was 11.5 months, and median PFS (95% confidence interval (CI)) was 14.8 months (8.3–not estimable) overall (n = 71) and 18.0 months (11.1–not estimable) in patients with CLDN18.2-high tumors (n = 59). Objective response rate (measurable disease; 95% CI) was 62.1% (48.4–74.5) in 4B overall (n = 58) and 68.1% (52.9–80.9) in CLDN18.2-high (n = 47). In 4A + 4B, the most common treatment-emergent adverse events were nausea (80.5%) and decreased appetite (72.7%). Efficacy and safety data support randomized evaluation of zolbetuximab plus chemoimmunotherapy in patients with CLDN18.2-positive and PD-L1-positive mG/GEJ adenocarcinoma in the ongoing phase 3 LUCERNA study. ClinicalTrials.gov: NCT03505320.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"26 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465384","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}
Pub Date : 2026-03-13DOI: 10.1038/s41591-026-04311-y
{"title":"Keep up the momentum for gene therapies.","authors":"","doi":"10.1038/s41591-026-04311-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04311-y","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"5 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446918","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}
Pub Date : 2026-03-13DOI: 10.1038/s41591-026-04310-z
{"title":"Modifiable risk factors drive a large share of the global cancer burden.","authors":"","doi":"10.1038/s41591-026-04310-z","DOIUrl":"https://doi.org/10.1038/s41591-026-04310-z","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"127 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446920","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}
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