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{"title":"Effects of gut microbiota on immune checkpoint inhibitors in multi-cancer and as microbial biomarkers for predicting therapeutic response.","authors":"Yufeng Lin, Mingxu Xie, Harry Cheuk-Hay Lau, Ruijie Zeng, Ruyi Zhang, Luyao Wang, Qing Li, Yiwei Wang, Danyu Chen, Lanping Jiang, William Damsky, Jun Yu","doi":"10.1016/j.medj.2024.10.007","DOIUrl":"10.1016/j.medj.2024.10.007","url":null,"abstract":"<p><strong>Background: </strong>Gut bacteria are related to immune checkpoint inhibitors (ICIs). However, there is inconsistency in ICI-associated species, while the role of non-bacterial microbes in immunotherapy remains elusive. Here, we evaluated the association of trans-kingdom microbes with ICIs by multi-cohort multi-cancer analyses.</p><p><strong>Methods: </strong>We retrieved fecal metagenomes from 1,359 ICI recipients with four different cancers (metastatic melanoma [MM], non-small cell lung carcinoma [NSCLC], renal cell cancer [RCC], and hepatocellular carcinoma) from 12 published datasets. Microbiota composition was analyzed using the Wilcoxon rank test. The performance of microbial biomarkers in predicting ICI response was assessed by random forest. Key responder-associated microbes were functionally examined in vitro and in mice.</p><p><strong>Findings: </strong>Trans-kingdom gut microbiota (bacteria, eukaryotes, viruses, and archaea) was significantly different between ICI responders and non-responders in multi-cancer. Bacteria (Faecalibacterium prausnitzii, Coprococcus comes) and eukaryotes (Nemania serpens, Hyphopichia pseudoburtonii) were consistently enriched in responders of ≥2 cancer types or from ≥3 cohorts, contrasting with the depleted bacterium Hungatella hathewayi. Responder-associated species in each cancer were revealed, such as F. prausnitzii in MM and 6 species in NSCLC. These signature species influenced ICI efficacy by modulating CD8⁺ T cell activity in vitro and in mice. Moreover, bacterial and eukaryotic biomarkers showed great performance in predicting ICI response in patients from discovery and two validation cohorts (MM: area under the receiver operating characteristic curve [AUROC] = 72.27%-80.19%; NSCLC: AUROC = 72.70%-87.98%; RCC: AUROC = 83.33%-89.58%).</p><p><strong>Conclusions: </strong>This study identified trans-kingdom microbial signatures associated with ICI in multi-cancer and specific cancer types. Trans-kingdom microbial biomarkers are potential predictors of ICI response in patients with cancer.</p><p><strong>Funding: </strong>Funding information is shown in the acknowledgments.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100530"},"PeriodicalIF":12.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606524","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":"Precision phenotyping for curating research cohorts of patients with unexplained post-acute sequelae of COVID-19.","authors":"Alaleh Azhir, Jonas Hügel, Jiazi Tian, Jingya Cheng, Ingrid V Bassett, Douglas S Bell, Elmer V Bernstam, Maha R Farhat, Darren W Henderson, Emily S Lau, Michele Morris, Yevgeniy R Semenov, Virginia A Triant, Shyam Visweswaran, Zachary H Strasser, Jeffrey G Klann, Shawn N Murphy, Hossein Estiri","doi":"10.1016/j.medj.2024.10.009","DOIUrl":"10.1016/j.medj.2024.10.009","url":null,"abstract":"<p><strong>Background: </strong>Scalable identification of patients with post-acute sequelae of COVID-19 (PASC) is challenging due to a lack of reproducible precision phenotyping algorithms, which has led to suboptimal accuracy, demographic biases, and underestimation of the PASC.</p><p><strong>Methods: </strong>In a retrospective case-control study, we developed a precision phenotyping algorithm for identifying cohorts of patients with PASC. We used longitudinal electronic health records data from over 295,000 patients from 14 hospitals and 20 community health centers in Massachusetts. The algorithm employs an attention mechanism to simultaneously exclude sequelae that prior conditions can explain and include infection-associated chronic conditions. We performed independent chart reviews to tune and validate the algorithm.</p><p><strong>Findings: </strong>The PASC phenotyping algorithm improves precision and prevalence estimation and reduces bias in identifying PASC cohorts compared to the ICD-10-CM code U09.9. The algorithm identified a cohort of over 24,000 patients with 79.9% precision. Our estimated prevalence of PASC was 22.8%, which is close to the national estimates for the region. We also provide in-depth analyses, encompassing identified lingering effects by organ, comorbidity profiles, and temporal differences in the risk of PASC.</p><p><strong>Conclusions: </strong>PASC precision phenotyping boasts superior precision and prevalence estimation while exhibiting less bias in identifying patients with PASC. The cohort derived from this algorithm will serve as a springboard for delving into the genetic, metabolomic, and clinical intricacies of PASC, surmounting the constraints of prior PASC cohort studies.</p><p><strong>Funding: </strong>This research was funded by the US National Institute of Allergy and Infectious Diseases (NIAID).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100532"},"PeriodicalIF":12.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629209","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":"Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.","authors":"Dimitrios C Ladakis, Kimystian L Harrison, Matthew D Smith, Krista Solem, Sachin Gadani, Larissa Jank, Soonmyung Hwang, Farzaneh Farhadi, Blake E Dewey, Kathryn C Fitzgerald, Elias S Sotirchos, Shiv Saidha, Peter A Calabresi, Pavan Bhargava","doi":"10.1016/j.medj.2024.09.011","DOIUrl":"10.1016/j.medj.2024.09.011","url":null,"abstract":"<p><strong>Background: </strong>Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.</p><p><strong>Methods: </strong>Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters.</p><p><strong>Findings: </strong>In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p = 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4⁺ and Th1/17 cells decreased, while CD4⁺ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups.</p><p><strong>Conclusions: </strong>Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.</p><p><strong>Funding: </strong>National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100522"},"PeriodicalIF":12.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142509385","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":"Recurrent late-onset neutropenia following treatment with different B cell-depleting strategies in multiple sclerosis.","authors":"Maria Protopapa, Muriel Schraad, Katrin Pape, Falk Steffen, Livia Steenken, Frauke Zipp, Vinzenz Fleischer, Stefan Bittner","doi":"10.1016/j.medj.2024.10.006","DOIUrl":"10.1016/j.medj.2024.10.006","url":null,"abstract":"<p><strong>Background: </strong>As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment.</p><p><strong>Methods: </strong>Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab.</p><p><strong>Findings: </strong>In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity.</p><p><strong>Conclusions: </strong>This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment.</p><p><strong>Funding: </strong>This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100529"},"PeriodicalIF":12.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606527","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":"Combination of immune checkpoint blockade in metastatic colorectal cancers with microsatellite instability: A new standard of care?","authors":"Violaine Randrian, Benoit Rousseau","doi":"10.1016/j.medj.2025.100636","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100636","url":null,"abstract":"<p><p>Immunotherapy is highly efficient for the treatment of mismatch-repair-deficient metastatic colorectal cancer. Two recent articles¹^,² challenge the current paradigm of anti-PD-1 monotherapy for the frontline treatment of metastatic mismatch-repair-deficient colorectal cancer, as the combination of an anti-PD-1 and anti-CTLA-4 showed improved response rate and progression-free survival compared to chemotherapy or anti PD-1.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 3","pages":"100636"},"PeriodicalIF":12.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634760","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":"Efficacy and safety of DV in HER2-negative and HER2-low locally advanced or metastatic urothelial carcinoma: Results of a phase 2 study.","authors":"Xieqiao Yan, Juan Li, Huayan Xu, Yiqiang Liu, Li Zhou, Siming Li, Xiaowen Wu, Bixia Tang, Zhihong Chi, Chuanliang Cui, Lu Si, Lili Mao, Bin Lian, Xuan Wang, Rong Duan, Caili Li, Jianmin Fang, Jun Guo, Xinan Sheng","doi":"10.1016/j.medj.2025.100637","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100637","url":null,"abstract":"<p><strong>Background: </strong>Human epidermal growth factor receptor 2 (HER2) has emerged as a new target for metastatic urothelial carcinomas (mUCs). Disitamab vedotin (DV), an anti-HER2 antibody-drug conjugate (ADC), demonstrates a promising efficacy in patients with HER2-positive mUC. However, the role of DV in HER2-negative and HER2-low mUCs remains unknown.</p><p><strong>Methods: </strong>Patients with HER2-negative and HER2-low (immunohistochemistry [IHC] 0 or 1+) mUCs who received ≥1 line of systemic chemotherapy were included. Patients received 2 mg/kg DV intravenously once every 2 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Findings: </strong>Nineteen patients with UC were enrolled from September 2019 to December 2021. The median age was 64.0 years. 15 patients (79%) had visceral metastases. HER2 IHC 0 and 1+ were detected in 6 and 13 patients, respectively. As of September 30, 2022, the confirmed ORR was 31.6% (95% confidence interval [CI]: 12.6, 56.6), and the disease control rate was 94.7% (18/19). The median PFS and OS were 5.5 (95% CI: 3.9, 5.7) and 16.4 (6.8, 26.8) months, respectively. Common treatment related adverse events were mostly grade 1 or 2, including leukopenia (52.6%) and hypoesthesia (47.4%).</p><p><strong>Conclusions: </strong>This is the first exploratory trial demonstrating substantial anti-tumor activity and a manageable safety profile using a HER2-targeting agent in patients with HER2-low mUC. This study was registered at ClinicalTrials.gov (ClinicalTrials.gov: NCT04073602).</p><p><strong>Funding: </strong>The study was funded by the Natural Science Foundation of China, the Natural Science Foundation of Tibet Autonomous Region, the Beijing Xisike Clinical Oncology Research Foundation, and RemeGen, Ltd.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100637"},"PeriodicalIF":12.8,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671273","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":"https://doi.org/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":"2025-03-13","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":"Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug), an insulin receptor antibody, for congenital hyperinsulinism.","authors":"Huseyin Demirbilek, Maria Melikyan, Violeta Iotova, Sonya Galcheva, Mehmet Nuri Ozbek, Antonia Dastamani, Nino Kheladze, Kineret Mazor-Aronovitch, Maria Clemente, Susann Empting, Klaus Mohnike, Henrik Thybo Christesen, Paul S Thornton, Diva D De Leon, Davelyn Hood, Erin O'Boyle, Brian K Roberts","doi":"10.1016/j.medj.2025.100611","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100611","url":null,"abstract":"<p><strong>Background: </strong>Congenital hyperinsulinism (cHI) is a rare, primarily pediatric disease characterized by dysregulated insulin secretion resulting in severe, persistent hypoglycemia, frequently leading to lifelong neurologic impairments. The safety, pharmacokinetics, and glycemic efficacy of ersodetug, a fully human monoclonal antibody that allosterically and reversibly binds the insulin receptor (INSR) and reduces excess insulin action, are being evaluated for the treatment of cHI-related hypoglycemia.</p><p><strong>Methods: </strong>A global, open-label, phase 2b study (ClinicalTrials.gov: NCT04538989) was conducted in 23 patients with cHI with persistent hypoglycemia on standard-of-care (SOC) therapies. Eligible participants (age ≥2 years) received add-on ersodetug at dose levels between 3 and 9 mg/kg intravenously (i.v.) bi-weekly for 8 weeks in 4 sequential dose cohorts.</p><p><strong>Findings: </strong>Enrolled participants (average age = 6.7 years) on SOC (87% medications; 17% previous pancreatectomy) experienced 13 events/week and 23% time in hypoglycemia at baseline. Ersodetug resulted in predictable, dose-proportional pharmacokinetics. No deaths, adverse drug reactions, study withdrawals, or dose-limiting toxicities occurred. Hypoglycemia (<70 mg/dL) events (self-monitored blood glucose) and time (continuous glucose monitoring) improved from baseline by medians of 59% (p < 0.001) and 54% (p < 0.001), respectively, across pooled dose levels and by 48%-84% (events) and 61%-65% (time) at doses of 6 or 9 mg/kg (p < 0.05) with a nearly universal individual patient response rate. Additional hypoglycemia metrics, including overnight hypoglycemia, similarly improved.</p><p><strong>Conclusion: </strong>Ersodetug was generally well tolerated and significantly improved hypoglycemia in participants with cHI. Ersodetug represents a novel INSR-targeted mechanism of action with the potential to be an effective therapy for all forms of cHI, alone or in combination with other therapies.</p><p><strong>Funding: </strong>Rezolute, Inc. (Redwood City, CA), provided funds.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100611"},"PeriodicalIF":12.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664610","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":"https://doi.org/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":"2025-02-28","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}

{"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":"https://doi.org/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":"2025-02-25","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}