Nature Medicine最新文献

{"title":"Sacituzumab govitecan in HR+HER2− metastatic breast cancer: the randomized phase 3 EVER-132-002 trial","authors":"Binghe Xu, Shusen Wang, Min Yan, Joohyuk Sohn, Wei Li, Jinhai Tang, Xiaojia Wang, Ying Wang, Seock-Ah Im, Dongdong Jiang, Theresa Valdez, Anandaroop Dasgupta, Yiran Zhang, Yilin Yan, Kimberly M. Komatsubara, Wei-Pang Chung, Fei Ma, Ming-Shen Dai","doi":"10.1038/s41591-024-03269-z","DOIUrl":"https://doi.org/10.1038/s41591-024-03269-z","url":null,"abstract":"<p>Sacituzumab govitecan (SG) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR⁺HER2⁻) metastatic breast cancer (mBC) in the global TROPiCS-02 study. TROPiCS-02 enrolled few Asian patients. Here we report results of SG in Asian patients with HR⁺HER2⁻ mBC from the EVER-132-002 study. Patients were randomized to SG (<i>n</i> = 166) or chemotherapy (<i>n</i> = 165). The primary endpoint was met: PFS was improved with SG versus chemotherapy (hazard ratio of 0.67, 95% confidence interval 0.52–0.87; <i>P</i> = 0.0028; median 4.3 versus 4.2 months). OS also improved with SG versus chemotherapy (hazard ratio of 0.64, 95% confidence interval 0.47–0.88; <i>P</i> = 0.0061; median 21.0 versus 15.3 months). The most common grade ≥3 treatment-emergent adverse events were neutropenia, leukopenia and anemia. SG demonstrated significant and clinically meaningful improvement in PFS and OS versus chemotherapy, with a manageable safety profile consistent with prior studies. SG represents a promising treatment option for Asian patients with HR⁺HER2⁻ mBC (ClinicalTrials.gov identifier no. NCT04639986).</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330382","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":"Increased frequency of repeat expansion mutations across different populations","authors":"Kristina Ibañez, Bharati Jadhav, Matteo Zanovello, Delia Gagliardi, Christopher Clarkson, Stefano Facchini, Paras Garg, Alejandro Martin-Trujillo, Scott J. Gies, Valentina Galassi Deforie, Anupriya Dalmia, Davina J. Hensman Moss, Jana Vandrovcova, Clarissa Rocca, Loukas Moutsianas, Chiara Marini-Bettolo, Helen Walker, Chris Turner, Maryam Shoai, Jeffrey D. Long, Pietro Fratta, Douglas R. Langbehn, Sarah J. Tabrizi, Mark J. Caulfield, Andrea Cortese, Valentina Escott-Price, John Hardy, Henry Houlden, Andrew J. Sharp, Arianna Tucci","doi":"10.1038/s41591-024-03190-5","DOIUrl":"https://doi.org/10.1038/s41591-024-03190-5","url":null,"abstract":"<p>Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions and technological limitations leading to underascertainment. Here, leveraging whole-genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modeling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating underdiagnosis and/or incomplete penetrance. While some REDs are population specific, for example, Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (that is, Europeans, Africans, Americans, East Asians and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counseling of REDs.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330384","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":"Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab","authors":"Tyler J. Alban, Nadeem Riaz, Prerana Parthasarathy, Vladimir Makarov, Sviatoslav Kendall, Seong-Keun Yoo, Rachna Shah, Nils Weinhold, Raghvendra Srivastava, Xiaoxiao Ma, Chirag Krishna, Juk Yee Mok, Wim J. E. van Esch, Edward Garon, Wallace Akerley, Benjamin Creelan, Nivedita Aanur, Diego Chowell, William J. Geese, Naiyer A. Rizvi, Timothy A. Chan","doi":"10.1038/s41591-024-03240-y","DOIUrl":"https://doi.org/10.1038/s41591-024-03240-y","url":null,"abstract":"<p>Neoantigen immunoediting drives immune checkpoint blockade efficacy, yet the molecular features of neoantigens and how neoantigen immunogenicity shapes treatment response remain poorly understood. To address these questions, 80 patients with non-small cell lung cancer were enrolled in the biomarker cohort of CheckMate 153 (CA209-153), which collected radiographic guided biopsy samples before treatment and during treatment with nivolumab. Early loss of mutations and neoantigens during therapy are both associated with clinical benefit. We examined 1,453 candidate neoantigens, including many of which that had reduced cancer cell fraction after treatment with nivolumab, and identified 196 neopeptides that were recognized by T cells. Mapping these neoantigens to clonal dynamics, evolutionary trajectories and clinical response revealed a strong selection against immunogenic neoantigen-harboring clones. We identified position-specific amino acid and physiochemical features related to immunogenicity and developed an immunogenicity score. Nivolumab-induced microenvironmental evolution in non-small cell lung cancer shared some similarities with melanoma, yet critical differences were apparent. This study provides unprecedented molecular portraits of neoantigen landscapes underlying nivolumab’s mechanism of action.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329551","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 role of FDA advisory committees","authors":"Emily C. Helms Williams, Namandjé N. Bumpus, Robert M. Califf","doi":"10.1038/s41591-024-03242-w","DOIUrl":"https://doi.org/10.1038/s41591-024-03242-w","url":null,"abstract":"FDA advisory committees provide useful recommendations for decision-making, but optimization efforts could help reduce burdens and improve public understanding.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329584","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":"Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial","authors":"F. D. Richard Hobbs, Richard J. McManus, Clare J. Taylor, Nicholas R. Jones, Joy K. Rahman, Jane Wolstenholme, Sungwook Kim, Joseph Kwon, Louise Jones, Jennifer A. Hirst, Ly-Mee Yu, Sam Mort","doi":"10.1038/s41591-024-03263-5","DOIUrl":"https://doi.org/10.1038/s41591-024-03263-5","url":null,"abstract":"<p>Chronic kidney disease (CKD) is associated with a substantial risk of progression to end-stage renal disease and vascular events. The nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone, offers cardiorenal protection for people with CKD and diabetes, but there is uncertainty if the steroidal MRA, spironolactone, provides the same protection. In this prospective, randomized, open, blinded endpoint trial, we assessed the effectiveness of 25 mg spironolactone in addition to usual care or usual care alone for reducing cardiovascular outcomes in stage 3b CKD among an older community cohort (mean age = 74.8 years and s.d. = 8.1). We recruited 1,434 adults from English primary care, of whom 1,372 (96%) were included in the primary analysis. The primary outcome was time from randomization until the first occurrence of death, hospitalization for heart disease, stroke, heart failure, transient ischemic attack or peripheral arterial disease, or first onset of any condition listed not present at baseline. Across 3 years of follow-up, the primary endpoint occurred in 113 of 677 participants randomized to spironolactone (16.7%) and 111 of 695 participants randomized to usual care (16.0%) with no significant difference between groups (hazard ratio = 1.05, 95% confidence interval: 0.81–1.37). Two-thirds of participants randomized to spironolactone stopped treatment within 6 months, predominantly because they met prespecified safety stop criteria. The most common reason for stopping spironolactone was a decrease in the estimated glomerular filtration rate that met prespecified stop criteria (<i>n</i> = 239, 35.4%), followed by participants being withdrawn due to treatment side effects (<i>n</i> = 128, 18.9%) and hyperkalemia (<i>n</i> = 54, 8.0%). In conclusion, we found that spironolactone was frequently discontinued due to safety concerns, with no evidence that it reduced cardiovascular outcomes in people with stage 3b CKD. Spironolactone should not be used for people with stage 3b CKD without another explicit treatment indication. ClinicalTrials.gov registration: ISRCTN44522369.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329546","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":"GLP-1 analogs and childhood obesity","authors":"","doi":"10.1038/d41591-024-00071-9","DOIUrl":"https://doi.org/10.1038/d41591-024-00071-9","url":null,"abstract":"Daily injection with the weight-loss drug liraglutide was more effective than placebo (both combined with lifestyle interventions) at reducing weight in children 6–12 years of age with obesity.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329916","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 economic value of reducing avoidable mortality","authors":"Angela Y. Chang, Gretchen A. Stevens, Diego S. Cardoso, Bochen Cao, Dean T. Jamison","doi":"10.1038/s41591-024-03253-7","DOIUrl":"https://doi.org/10.1038/s41591-024-03253-7","url":null,"abstract":"<p>Living longer and healthier boosts individual and family welfare. As part of the World Bank’s Healthy Longevity Initiative, we quantified the economic value of achieving the highest possible life span. We estimated the economic value of reducing avoidable mortality, defined as the difference between observed (or projected) mortality and lowest achieved (or projected) mortality, by world regions, sex, and age, between 2000 and 2021, with projection to 2050. In 2019, 69% of mortality, or 40 million deaths, was avoidable. The economic value of avoidable mortality globally was 23% of annual income, meaning that, globally, populations would be willing to give up about one-fifth of their current income in exchange for a year living at the lowest achieved mortality rate. This value ranges from 19% in China to 34% in sub-Saharan Africa. Under the rapid-progress scenario, in which countries experience fast but plausible mortality reductions from 2019 to 2050, we would expect globally the gap between projected and frontier life expectancy to be halved by 2050, and the economic value after achieving this scenario is equivalent to 14% of annual income. Our work provides supportive evidence on the high economic value placed on improving health.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321965","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":"Cytokine-mediated CAR T therapy resistance in AML","authors":"Anand S. Bhagwat, Leonel Torres, Olga Shestova, Maksim Shestov, Patrick W. Mellors, Han R. Fisher, Saamia N. Farooki, Benjamin F. Frost, Michael R. Loken, Avery L. Gaymon, Diane Frazee, Walter Rogal, Noelle Frey, Elizabeth O. Hexner, Selina M. Luger, Alison W. Loren, Mary Ellen Martin, Shannon R. McCurdy, Alexander E. Perl, Edward A. Stadtmauer, Jennifer L. Brogdon, Joseph A. Fraietta, Wei-Ting Hwang, Don L. Siegel, Gabriela Plesa, Richard Aplenc, David L. Porter, Carl H. June, Saar I. Gill","doi":"10.1038/s41591-024-03271-5","DOIUrl":"https://doi.org/10.1038/s41591-024-03271-5","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123⁺ cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5–0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07–0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126).</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321960","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 economic value of reducing mortality due to noncommunicable diseases and injuries","authors":"Stéphane Verguet, Sarah Bolongaita, Angela Y. Chang, Diego S. Cardoso, Gretchen A. Stevens","doi":"10.1038/s41591-024-03248-4","DOIUrl":"https://doi.org/10.1038/s41591-024-03248-4","url":null,"abstract":"<p>With population aging, national health systems face difficult trade-offs in allocating resources. The World Bank launched the Healthy Longevity Initiative to generate evidence for investing in policies that can improve healthy longevity and human capital. As part of this initiative, we quantified the economic value of reducing avoidable mortality from major noncommunicable diseases and injuries. We estimated avoidable mortality—the difference between lowest-achieved mortality frontiers and projected mortality trajectories—for each cause of death, for 2000, 2019 and 2050, and for geographic regions, with high-income countries, India and China considered separately; we applied economic values to these estimates. The economic value of reducing cardiovascular disease avoidable mortality would be large for both sexes in all regions, reaching 2–8% of annual income in 2019. For cancers, it would be 5–6% of annual income in high-income countries and China, and for injuries, it would be around 5% in sub-Saharan Africa and Latin America and the Caribbean. Despite the large uncertainty surrounding our estimates, we offer economic values for reducing avoidable mortality by cause and metrics comparable to annual incomes, which enable multisectoral priority setting and are relevant for high-level policy discussions around budget and resource allocations.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321956","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":"SARS-CoV-2-specific plasma cells are not durably established in the bone marrow long-lived compartment after mRNA vaccination","authors":"Doan C. Nguyen, Ian T. Hentenaar, Andrea Morrison-Porter, David Solano, Natalie S. Haddad, Carlos Castrillon, Martin C. Runnstrom, Pedro A. Lamothe, Joel Andrews, Danielle Roberts, Sagar Lonial, Ignacio Sanz, F. Eun-Hyung Lee","doi":"10.1038/s41591-024-03278-y","DOIUrl":"https://doi.org/10.1038/s41591-024-03278-y","url":null,"abstract":"<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines are effective at protecting from severe disease, but the protective antibodies wane rapidly even though SARS-CoV-2-specific plasma cells can be found in the bone marrow (BM). Here, to explore this paradox, we enrolled 19 healthy adults at 2.5–33 months after receipt of a SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus- or SARS-CoV-2-specific antibody-secreting cells (ASCs) in long-lived plasma cell (LLPC) and non-LLPC subsets within the BM. Only influenza- and tetanus-specific ASCs were readily detected in the LLPCs, whereas SARS-CoV-2 specificities were mostly absent. The ratios of non-LLPC:LLPC for influenza, tetanus and SARS-CoV-2 were 0.61, 0.44 and 29.07, respectively. In five patients with known PCR-proven history of recent infection and vaccination, SARS-CoV-2-specific ASCs were mostly absent from the LLPCs. We show similar results with measurement for secreted antibodies from BM ASC culture supernatant. While serum IgG titers specific for influenza and tetanus correlated with IgG LLPCs, serum IgG levels for SARS-CoV-2, which waned within 3–6 months after vaccination, were associated with IgG non-LLPCs. In all, our studies suggest that rapid waning of SARS-CoV-2-specific serum antibodies could be accounted for by the absence of BM LLPCs after these mRNA vaccines.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321955","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}