Med最新文献

{"title":"A progranulin variant causing childhood interstitial lung disease responsive to anti-TNF-α biologic therapy.","authors":"John C Kennedy, Sara O Vargas, Martha P Fishman, Nicola Alesi, Seung-Han Baek, Damir Khabibillin, Craig D Platt, Carolina Garcia-de-Alba, Pankaj B Agrawal, Nikkola E Carmichael, Lauren A Henderson, Andrew Wehrman, Sebastian Boland, Tobias Walther, Robert V Farese, Alicia M H Casey, John P Manis, Lauren V Collen, Maria Lvova, Alessandro Barbieri, Brendan Sullivan, Benjamin A Raby","doi":"10.1016/j.medj.2025.100607","DOIUrl":"10.1016/j.medj.2025.100607","url":null,"abstract":"<p><strong>Background: </strong>Childhood interstitial and diffuse lung diseases are a collection of rare disorders with significant associated morbidity. Only a small subset of these diseases have precise diagnostic or therapeutic options identified to date.</p><p><strong>Methods: </strong>Whole-exome sequencing in a family identified a candidate pathogenic variant predicted to be causing fibrotic lung and liver disease in a child. Digital spatial mRNA profiling of clinical lung biopsies was done to identify aberrant signaling pathways. ELISA confirmed low circulating protein levels in the patient.</p><p><strong>Findings: </strong>We identified homozygosity of the p.Cys139Arg loss-of-function progranulin (GRN) variant and an alveolar macrophage transcriptomic signature consistent with tumor necrosis factor alpha (TNF-α) pathway activation. This motivated treatment with anti-TNF monoclonal antibodies, resulting in dramatic improvement of the patient's lung and liver disease.</p><p><strong>Conclusions: </strong>These findings demonstrate the clinical utility of convergent multiomics in the evaluation and implementation of precision therapeutics in rare diseases.</p><p><strong>Funding: </strong>This work was supported by a grant from the Chan Zuckerberg Initiative Patient-Partnered Collaboration for single-cell analysis of rare inflammatory pediatric disease, the Corkin Family Fund for Research, and in part by cooperative agreement U01TR002623 from the National Center for Advancing Translational Sciences/NIH and the PrecisionLink Project at Boston Children's Hospital.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100607"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultra-rapid droplet digital PCR enables intraoperative tumor quantification.","authors":"Zachary R Murphy, Emilia C Bianchini, Andrew Smith, Lisa I Körner, Teresa Russell, David Reinecke, Nader Maarouf, Yuxiu Wang, John G Golfinos, Alexandra M Miller, Matija Snuderl, Daniel A Orringer, Gilad D Evrony","doi":"10.1016/j.medj.2025.100604","DOIUrl":"10.1016/j.medj.2025.100604","url":null,"abstract":"<p><strong>Background: </strong>The diagnosis and treatment of tumors often depend on molecular-genetic data. However, rapid and iterative access to molecular data is not currently feasible during surgery, complicating intraoperative diagnosis and precluding measurement of tumor cell burdens at surgical margins to guide resections.</p><p><strong>Methods: </strong>Here, we introduce Ultra-Rapid droplet digital PCR (UR-ddPCR), a technology that achieves the fastest measurement, to date, of mutation burdens in tissue samples, from tissue to result in 15 min. Our workflow substantially reduces the time from tissue biopsy to molecular diagnosis and provides a highly accurate means of quantifying residual tumor infiltration at surgical margins.</p><p><strong>Findings: </strong>We demonstrate UR-ddPCR assays for the IDH1 R132H and BRAF V600E clonal mutations that are present in many low-grade gliomas and melanomas, respectively, and whose intraoperative detection would shape surgical decision-making. We illustrate the clinical feasibility of UR-ddPCR by performing it intraoperatively for 22 brain tumor cases, and we further combine UR-ddPCR tumor cell percentage measurements with UR-stimulated Raman histology intraoperatively to estimate tumor cell densities ranging from >1,300 tumor cells/mm² within a tumor core to <5 tumor cells/mm² at tumor margins. UR-ddPCR measurements were virtually identical to standard ddPCR measurements performed on the same samples (R² = 0.995).</p><p><strong>Conclusions: </strong>The technology and workflow developed here enable intraoperative molecular-genetic assays with unprecedented speed and sensitivity. We anticipate that our method will facilitate novel point-of-care diagnostics and molecularly guided surgeries that improve clinical outcomes.</p><p><strong>Funding: </strong>This study was funded by the National Institutes of Health and NYU Grossman School of Medicine institutional funds. Reagents and instruments were provided in kind by Bio-Rad.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100604"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer.","authors":"Marjolein F Lansbergen, Mark P G Dings, Jan Koster, Mariette Labots, Emile D Kerver, Anouk Jochems, Marjolein Y V Homs, Judith de Vos-Geelen, Mathijs P Hendriks, Michael W T Tanck, Johanna W Wilmink, Hanneke W M van Laarhoven, Maarten F Bijlsma","doi":"10.1016/j.medj.2025.100601","DOIUrl":"10.1016/j.medj.2025.100601","url":null,"abstract":"<p><strong>Background: </strong>First-line chemotherapy (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin [FOLFIRINOX]) benefits few patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Prognostic markers for treatment-related survival are needed. This study validated the added benefit of whole-genome sequencing (WGS) to transcriptome-based classification in modeling FOLFIRINOX-related survival.</p><p><strong>Methods: </strong>Patients with mPDAC planning to start FOLFIRINOX were included in a prospective nationwide cohort. Pretreatment biopsies were submitted to WGS and RNA sequencing. Samples of non-FOLFIRINOX-treated patients were included for exploratory analyses.</p><p><strong>Findings: </strong>WGS was performed in biopsies from 108 FOLFIRINOX-treated patients and 51 non-FOLFIRINOX-treated patients. 12% of the tumors were KRAS wild type. These tumors had more targetable alterations (42% vs. 17%) and were associated with a longer median overall survival (mOS) than KRAS mutant tumors (7.8 months in KRAS mutant vs. 17.7 months in wild-type tumors, p = 0.0024). Transcriptome-based clustering revealed a tumor subgroup showing low classical and basal-like gene expression, enriched for KRAS wild-type status (p < 0.0001), a so-called \"classifier-negative\" subtype. The gene expression of these classifier-negative tumors correlated with neural-like signatures. For patients with a homologous recombination-deficient (HRD) tumor, mOS was not increased (8.0 months in homologous recombination-proficient [HRP] vs. 13.3 months in HRD tumors, p = 0.21).</p><p><strong>Conclusions: </strong>KRAS wild-type tumors are a distinct PDAC subgroup with a better prognosis. Consequently, KRAS status assessment before transcriptome-based subtyping can stratify patients into three prognostic molecular subgroups (KRAS wild type, KRAS mutant classical, and KRAS mutant basal like). This integrative way of classification should be validated prior to incorporation in diagnostic practice.</p><p><strong>Funding: </strong>ZonMw \"Good Use of Medicine\" program (848101012).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100601"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Point of view: Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors.","authors":"Fabio Conforti, Tommaso De Pas","doi":"10.1016/j.medj.2025.100625","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100625","url":null,"abstract":"<p><p>In this issue of Med,¹ Möhrmann et al. present a comprehensive analysis of 81 advanced thymic epithelial tumors (TETs). The study offers insights into the tumor mutational landscape, germline alterations, and the identification of different immunological subsets. An interesting finding is the identification of \"hot\" and \"cold\" subsets of thymic carcinoma (TC), the hot subset showing better outcome with immune checkpoint inhibitor (ICI) treatment.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 6","pages":"100625"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Q&A with Madeleine Ballard.","authors":"Madeleine Ballard","doi":"10.1016/j.medj.2025.100745","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100745","url":null,"abstract":"<p><p>Dr. Madeleine Ballard is the CEO of Community Health Impact Coalition (CHIC), a global movement transforming healthcare by making professional community health workers the norm. Through research, advocacy, and organizing with community health workers, she has driven policy changes that ensure quality care for millions-including those who provide it. Dr. Ballard holds a PhD from the University of Oxford, where she was a Rhodes Scholar, and is a faculty member at the Icahn School of Medicine at Mount Sinai. Her work alongside CHIC has appeared in The New York Times, Forbes, The Lancet, and more. She is the recipient of the Skoll Award for Social Innovation, the Roux Prize, and the Schwab Social Innovator of the Year-honors that reflect both her significant contributions to population health and her leadership in building powerful coalitions that achieve breakthrough reforms at a large scale.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 6","pages":"100745"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors.","authors":"Lino Möhrmann, Lysann Rostock, Maximilian Werner, Małgorzata Oleś, Jonas S Arnold, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Arne Jahn, Marie Arlt, Elena E Möhrmann, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E Heilig, Maria-Veronica Teleanu, Daniel B Lipka, Katja Beck, Annika Baude-Müller, Andreas Mock, Ivan Jelas, Damian T Rieke, Marcel Wiesweg, Christian Brandts, Melanie Boerries, Anna L Illert, Alexander Desuki, Thomas Kindler, Angela M Krackhardt, C Benedikt Westphalen, Petros Christopoulos, Leonidas Apostolidis, Albrecht Stenzinger, Michael Allgäuer, Olaf Neumann, Irina A Kerle, Peter Horak, Christoph Heining, Heidrun Grosch, Evelin Schröck, Daniel Hübschmann, Stefan Fröhling, Hanno Glimm","doi":"10.1016/j.medj.2025.100612","DOIUrl":"10.1016/j.medj.2025.100612","url":null,"abstract":"<p><strong>Background: </strong>Thymic epithelial tumors (TETs) are rare malignancies with limited treatment options and underexplored molecular features.</p><p><strong>Methods: </strong>We examined the genomic landscape and therapeutic outcomes in 81 patients with advanced TETs, including thymic carcinomas (TCs), thymomas, and thymic neuroendocrine neoplasms (TNENs), who were enrolled in the MASTER trial, a prospective observational precision oncology trial.</p><p><strong>Findings: </strong>Using whole-genome-sequencing and whole-exome-sequencing analysis, transcriptome analysis, and methylome analysis, we identified distinct molecular features across TET subtypes, including a higher tumor mutational burden in TC and pathogenic germline variants in 18% of cases. We performed transcriptome- and methylome-based unsupervised clustering and were able to divide TCs into immunologically hot and cold subsets, with hot TCs exhibiting higher T cell infiltration and significantly longer overall survival. In 65 out of 76 (86%) patients, we recommended molecularly informed therapies, which were applied in 29 out of 65 (45%) cases, leading to a disease control rate of 62% and an objective response rate of 23% (both n = 26). The progression-free survival ratio (PFSr) was > 1.3 in 8 out of 24 (33%) patients, 7 of them having TC. Among TCs, patients achieved a mean PFSr of 1.4, indicating potential therapeutic advantages in this subgroup. The PFSr between the PFS of immune checkpoint inhibition and preceding therapies was significantly higher in the hot cluster compared to the cold cluster (median 1.7 vs. 0.3; p = 0.01945).</p><p><strong>Conclusions: </strong>Our findings expand the understanding of TET biology and emphasize the role of precision oncology in informing treatment decisions and improving outcomes for patients with advanced TETs, particularly in TCs.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100612"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perioperative immunotherapy in lung cancer: Time to push the frontiers?","authors":"Nicolas Girard","doi":"10.1016/j.medj.2025.100672","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100672","url":null,"abstract":"<p><p>Perioperative immunotherapy is a new standard of care for the management of resectable non-small cell lung cancer (NSCLC). The TOGATHER trial assessed perioperative immunotherapy in patients with primarily nonresectable NSCLC, pushing a new concept that led to a re-evaluation of the frontiers of resectability, surgical approaches, and chemoradiotherapy.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 6","pages":"100672"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toripalimab plus platinum-doublet chemotherapy as perioperative therapy for initially unresectable NSCLC: An open-label, phase 2 trial.","authors":"Liang Zeng, Huan Yan, Wenjuan Jiang, Haoyue Qin, Jiacheng Dai, Yuda Zhang, Shiyou Wei, Shanmei Chen, Li Liu, Yi Xiong, Haiyan Yang, Yizhi Li, Zhan Wang, Li Deng, Qinqin Xu, Ling Peng, Ruiguang Zhang, Chao Fang, Xue Chen, Jun Deng, Jing Wang, Ting Li, Hong Liu, Gao Zhang, Nong Yang, Yongchang Zhang","doi":"10.1016/j.medj.2025.100574","DOIUrl":"10.1016/j.medj.2025.100574","url":null,"abstract":"<p><strong>Background: </strong>Perioperative treatment with toripalimab combined with chemotherapy was efficacious and safe in resectable stage II-IIIA non-small cell lung cancer (NSCLC); however, little is known about whether this treatment regimen could convert unresectable NSCLC to resectable.</p><p><strong>Methods: </strong>This study enrolled 40 treatment-naive patients with initially unresectable stage IIIA-IIIB NSCLC. Toripalimab (240 mg) and platinum-doublet chemotherapy were administered every 3 weeks for 2-4 cycles. Surgical resection was decided after assessing the efficacy of induction therapy. The primary outcome was the R0 resection rate. The secondary outcomes included safety, overall survival, disease-free survival, event-free survival, objective response rate, major pathological response (MPR), and pathological complete response (pCR). Available baseline tumor biopsy samples were used for molecular biomarker analyses, including bulk RNA sequencing and multiplex immunostaining. This study was registered at ClinicalTrials.gov: NCT04144608.</p><p><strong>Findings: </strong>Of the 40 patients who received induction toripalimab plus chemotherapy, 29 (72.5%) patients received surgery, and all achieved R0 resection (100% R0 rate). Of these patients, 17 (58.6%) achieved MPR, with 10 (34.5%) patients evaluated as pCR. With a median follow-up of 31.8 months (95% confidence interval [CI]: 24.2-39.4), the median event-free survival and overall survival were not reached. Molecular analyses revealed highly expressed gene sets for germinal center B cells (signatures of tertiary lymphoid structure [TLS]) at baseline among patients with pCR compared to patients with non-pCR, suggesting that the TLS status of the patients was associated with the induction of immunotherapy responses.</p><p><strong>Conclusions: </strong>Toripalimab-based induction treatment of initially unresectable NSCLC yielded a high R0 rate and MPR rate, with a good safety profile and encouraging survival outcomes.</p><p><strong>Funding: </strong>This work was funded by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100574"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMPL-306 in relapsed or refractory IDH1- and/or IDH2-mutated acute myeloid leukemia: A phase 1 study.","authors":"Lijuan Hu, Xudong Wei, Weili Zhao, Yu Hu, Juan Li, Yugang Dong, Tiejun Gong, Xuhan Zhang, Yajing Xu, Yu Zhang, Chongyuan Xu, Cheng Zhang, Zhen Cai, Hongmei Jing, Ruihua Mi, Wen Wu, Wenjuan He, Hehua Wang, Qinghua Tang, Zhiping Jiang, Hui Liu, Guo Chen, Jie Sun, Jian Chen, Sai Yan, Huan Yan, Jiaxuan Wangwu, Zeyu Zhong, Linfang Wang, Songhua Fan, Michael Shi, Weiguo Su, Xiaojun Huang","doi":"10.1016/j.medj.2025.100575","DOIUrl":"10.1016/j.medj.2025.100575","url":null,"abstract":"<p><strong>Background: </strong>HMPL-306 has equally high inhibitory activity against mutated isocitrate dehydrogenases 1 and 2 (mIDH1/2).</p><p><strong>Methods: </strong>This first-in-human, phase 1 dose-escalation/dose-expansion study (this study was registered at ClinicalTrials.gov: NCT04272957) enrolled patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) harboring mIDH1 and/or mIDH2. Patients received 25-250 mg of HMPL-306 orally once daily (QD) in a 28-day treatment cycle. Primary objectives were safety, tolerability, and recommended phase 2 dose (RP2D), and the secondary objective was preliminary efficacy.</p><p><strong>Findings: </strong>A total of 76 patients were enrolled. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. RP2D was 250 mg QD for cycle 1 and 150 mg QD from cycle 2 onward. Common (≥10%) grade ≥3 treatment-related adverse events included platelet count decreased, anemia, neutrophil count decreased, and white blood cell count decreased. In patients who received 150 mg, 250 mg, or the RP2D (N = 59), rates of complete remission (CR)+CR with partial hematologic recovery were 34.6% and 36.4% in the mIDH1 (n = 26) and mIDH2 (n = 33) subgroups, respectively, and among these, CR with minimal residual disease negative rates were 77.8% and 50.0%, respectively. The median overall survival was 13.4 months in patients with mIDH1 and 13.1 months in patients with mIDH2.</p><p><strong>Conclusions: </strong>HMPL-306 showed an acceptable safety profile and promising preliminary efficacy. A phase 3, randomized study of HMPL-306 in R/R AML (this study was registered at ClinicalTrials.gov: NCT06387069) has been initiated.</p><p><strong>Funding: </strong>HUTCHMED Limited, National Key Research and Development Program of China, National Natural Science Foundation of China, and Peking University Medicine Fund for world's leading discipline or discipline cluster development.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100575"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome.","authors":"Alan K Percy, Robin Ryther, Eric D Marsh, Jeffrey L Neul, Timothy A Benke, Elizabeth M Berry-Kravis, Timothy Feyma, David N Lieberman, Amitha L Ananth, Cary Fu, Colleen Buhrfiend, Amy Barrett, Dilesh Doshi, Mona Darwish, Di An, Kathie M Bishop, James M Youakim","doi":"10.1016/j.medj.2025.100608","DOIUrl":"10.1016/j.medj.2025.100608","url":null,"abstract":"<p><strong>Background: </strong>Trofinetide is the first available treatment for Rett syndrome (RTT) and is approved in the United States in adults and pediatric patients aged ≥2 years. The DAFFODIL study was conducted in girls aged 2-4 years with RTT to examine the safety, tolerability, and efficacy of trofinetide and to validate that the recommended dosage, according to body weight, achieved target exposure.</p><p><strong>Methods: </strong>DAFFODIL was a phase 2/3, open-label study of trofinetide consisting of two treatment periods (12 weeks [period A] and ∼21 months [period B]). Pharmacokinetic samples were collected at regular intervals during period A. Assessments included treatment-emergent adverse events (TEAEs) and exploratory efficacy (Clinical Global Impressions-Improvement [CGI-I], CGI-Severity, caregiver GI-I [CaGI-I], and overall quality of life rating of the Impact of Childhood Neurologic Disability Scale [ICND-QoL]). Optional caregiver exit interviews were also conducted.</p><p><strong>Findings: </strong>Fifteen participants were enrolled. Overall, the most common TEAEs were diarrhea (80.0%) and vomiting (53.3%), which were mild or moderate in severity. Steady-state exposure at clinical doses fell within the target exposure range. RTT symptoms improved throughout the study as measured by the CGI-I, CaGI-I, and change from baseline in the ICND-QoL. In caregiver interviews (n = 7), all caregivers reported they were \"very satisfied\" or \"satisfied\" with trofinetide benefits.</p><p><strong>Conclusions: </strong>Trofinetide has acceptable tolerability in girls 2-4 years of age with RTT and provides long-term efficacy. Weight-based dosage achieves target exposure in younger children.</p><p><strong>Funding: </strong>The study was supported by Acadia Pharmaceuticals (San Diego, CA). This study was registered at ClinicalTrials.gov (NCT04988867).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100608"},"PeriodicalIF":12.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}