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{"title":"Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy.","authors":"Alessandro Rossi, Roberta Romano, Simona Fecarotta, Margherita Dell'Anno, Valentina Pecorella, Roberta Passeggio, Stefano Zancan, Giancarlo Parenti, Francesca Santamaria, Francesco Borgia, Federica Deodato, Silvia Funghini, Charles A Rupar, Chitra Prasad, Mar O'Callaghan, John J Mitchell, Maria Grazia Valsecchi, Giancarlo la Marca, Stefania Galimberti, Alberto Auricchio, Nicola Brunetti-Pierri","doi":"10.1016/j.medj.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.021","url":null,"abstract":"<p><strong>Background: </strong>Mucopolysaccharidosis type VI (MPS VI) is due to a deficiency of the lysosomal enzyme arylsulfatase B (ARSB) that results in multi-organ accumulation of glycosaminoglycans (GAGs). Limitations of current treatments prompted the development of a liver-directed gene therapy clinical trial for MPS VI.</p><p><strong>Methods: </strong>We report the long-term follow-up of patients with MPS VI who discontinued enzyme replacement therapy (ERT) and received a single intravenous infusion of high-dose (6 × 10¹² genome copies/kg) recombinant adeno-associated virus serotype 8 (AAV8) vector expressing ARSB under the control of a liver-specific promoter (ClinicalTrials.gov: NCT03173521). Primary outcomes were safety and urinary GAG excretion. Secondary outcomes were endurance and respiratory function.</p><p><strong>Findings: </strong>Median follow-up time was 45 months (n = 4, three females and one male; age range: 5-10 years). No late-emergent safety events were observed. Patients showed sustained serum ARSB activity (38%-67% of mean healthy reference values), a modest increase in urinary GAG concentrations, and no relevant changes in endurance, cardiac, or pulmonary function. In one of the four patients, ERT was restarted because of elevated urinary GAGs without decreased serum ARSB activity up to about 2.5 years after gene transfer. Liver and spleen size remained within the reference ranges.</p><p><strong>Conclusions: </strong>A single intravenous administration of AAV8.TBG.hARSB was safe and resulted in sustained ARSB expression and a modest increase in urinary GAGs in most patients, thus supporting liver-directed gene therapy for MPS VI.</p><p><strong>Funding: </strong>This study was sponsored by the Telethon Foundation ETS, the European Union, the Isaac Foundation, and the Italian Ministry of University and Research.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639949","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 cluster randomized trial of xylitol chewing gum for prevention of preterm birth: The PPaX trial.","authors":"Gregory C Valentine, Kathleen M Antony, Haleh Sangi-Haghpeykar, Alexis C Wood, Rose Chirwa, Saukani Petro, Mary Dumba, Deborah Nanthuru, Cynthia Shope, Jesse Mlotha-Namarika, Jeffrey Wilkinson, Joshua Aagaard, Ellen J Aagaard, Maxim D Seferovic, Judy Levison, Peter Kazembe, Kjersti M Aagaard","doi":"10.1016/j.medj.2024.10.016","DOIUrl":"10.1016/j.medj.2024.10.016","url":null,"abstract":"<p><strong>Background: </strong>Maternal periodontal disease is associated with preterm and low-birthweight deliveries, but randomized trials of likely efficacious treatments (e.g., dental scaling and root planing) during pregnancy have not reduced these adverse outcomes. As an alternative, we hypothesized that periconception initiation of xylitol chewing gum would reduce the occurrence of preterm or low-birthweight deliveries among a historical high-prevalence population in Malawi.</p><p><strong>Methods: </strong>We conducted an open-label, parallel-enrollment, matched-pair, cluster-randomized, controlled clinical trial across eight health centers (sites) in and around Lilongwe, Malawi. Sites were paired by anticipated delivery volume and randomized to prenatal and oral health education alone (active control) or with twice-daily xylitol chewing gum (intervention) throughout the periconception and antenatal periods. For the primary prevention of preterm (<37 weeks) and low-birthweight (<2,500 g) deliveries (co-primary outcomes), comparison by allocation group was performed using generalized linear mixed models for each outcome as a fixed factor and the site(s) as a random factor.</p><p><strong>Findings: </strong>10,069 participants were enrolled (n = 4,549 at intervention sites, n = 5,520 at active control sites), with >95% available for analyses. Initiation of xylitol chewing gum resulted in significant reductions in the co-primary outcomes: preterm birth (12.6% [549/4,349] vs. 16.5% [878/5,321]; relative risk [RR] 0.76, 95% confidence interval [CI] 0.57-0.99) and <2,500-g neonates (8.9% [385/4,305] vs. 12.9% [679/5,260]; RR 0.70, 95% CI 0.49-0.99). Xylitol chewing gum use also led to fewer neonatal demises (0.2% [8/4,305] vs. 0.4% [22/5,260]; RR 0.41, 95% CI 0.19-0.89).</p><p><strong>Conclusions: </strong>Periconception initiation and ongoing use of xylitol chewing gum significantly reduced the occurrence of preterm and low-birthweight deliveries in Malawi.</p><p><strong>Funding: </strong>E.W. Al Thrasher Foundation (to K.A.) and USAID Saving Lives at Birth Grand Challenges Grant AID-OAA-G-11-00062 (to K.A.). Additional financial and in-kind support was graciously provided by Texas Children's Hospital and Baylor Foundation Malawi.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629076","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":"Rising incidence of obesity-related cancers among younger adults in China: A population-based analysis (2007-2021).","authors":"Chang Liu, Ying-Chao Yuan, Mo-Ning Guo, Zhong Xin, Guan-Jie Chen, Nan Ding, Jian-Peng Zheng, Bai Zang, Jin-Kui Yang","doi":"10.1016/j.medj.2024.07.012","DOIUrl":"10.1016/j.medj.2024.07.012","url":null,"abstract":"<p><strong>Background: </strong>Developing countries face an \"obesity epidemic,\" particularly affecting children and younger adults. While obesity is a known risk factor for 12 types of cancer, primarily affecting older populations, its impact on younger generations is understudied.</p><p><strong>Methods: </strong>This study analyzed data from a population-based cancer registry covering 14.14 million individuals in China (2007-2021). We compared the incidence of obesity- and non-obesity-related cancers and applied an age-period-cohort model to estimate their impacts.</p><p><strong>Findings: </strong>Among 651,342 cancer cases, 48.47% were obesity related. The age-standardized incidence rates (ASRs) of the 12 obesity-related cancers increased annually by 3.6% (p < 0.001), while ASRs for non-obesity-related cancers remained stable. Obesity-related cancers surged among younger adults, with rates rising across successive generations. The annual percentage of change decreased with age, from 15.28% for ages 25-29 years to 1.55% for ages 60-64 years. The incidence rate ratio for obesity-related cancer was higher in younger generations compared to those born in 1962-1966. We predict that the ASR for obesity-related cancers will nearly double in the next decade.</p><p><strong>Conclusions: </strong>The rising incidence of obesity-related cancers among young adults poses a significant public health concern. The increasing cancer burden underscores the need for targeted interventions to address the obesity epidemic.</p><p><strong>Funding: </strong>This work was supported by the National Natural Science Foundation of China (81930019, 82341076) to J.-K.Y.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1402-1412.e2"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056682","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":"Patient-derived organoids in precision cancer medicine.","authors":"Le Tong, Weiyingqi Cui, Boya Zhang, Pedro Fonseca, Qian Zhao, Ping Zhang, Beibei Xu, Qisi Zhang, Zhen Li, Brinton Seashore-Ludlow, Ying Yang, Longlong Si, Andreas Lundqvist","doi":"10.1016/j.medj.2024.08.010","DOIUrl":"10.1016/j.medj.2024.08.010","url":null,"abstract":"<p><p>Organoids are three-dimensional (3D) cultures, normally derived from stem cells, that replicate the complex structure and function of human tissues. They offer a physiologically relevant model to address important questions in cancer research. The generation of patient-derived organoids (PDOs) from various human cancers allows for deeper insights into tumor heterogeneity and spatial organization. Additionally, interrogating non-tumor stromal cells increases the relevance in studying the tumor microenvironment, thereby enhancing the relevance of PDOs in personalized medicine. PDOs mark a significant advancement in cancer research and patient care, signifying a shift toward more innovative and patient-centric approaches. This review covers aspects of PDO cultures to address the modeling of the tumor microenvironment, including extracellular matrices, air-liquid interface and microfluidic cultures, and organ-on-chip. Specifically, the role of PDOs as preclinical models in gene editing, molecular profiling, drug testing, and biomarker discovery and their potential for guiding personalized treatment in clinical practice are discussed.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1351-1377"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355447","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":"Dual epigenetic therapy plus chemotherapy in peripheral T cell lymphoma with T follicular helper phenotype.","authors":"Suheil Albert Atallah-Yunes, Yucai Wang","doi":"10.1016/j.medj.2024.07.029","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.029","url":null,"abstract":"<p><p>The nonrandomized phase II study by Ding et al. explored the combination of azacitidine and chidamide with or without GemOx chemotherapy in relapsed/refractory peripheral T cell lymphoma and demonstrated that the dual epigenetic therapy is safe and efficacious, particularly in the angioimmunoblastic T cell lymphoma subset.¹ Further investigation into adding chemotherapy is warranted, building on the promising results seen in this trial.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 11","pages":"1335-1337"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629416","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":"Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease.","authors":"Fangyuan Jiang, Lijuan Wang, Haochao Ying, Jing Sun, Jianhui Zhao, Ying Lu, Zilong Bian, Jie Chen, Aiping Fang, Xuehong Zhang, Susanna C Larsson, Christos S Mantzoros, Weilin Wang, Shuai Yuan, Yuan Ding, Xue Li","doi":"10.1016/j.medj.2024.07.013","DOIUrl":"10.1016/j.medj.2024.07.013","url":null,"abstract":"<p><strong>Background: </strong>The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined.</p><p><strong>Methods: </strong>A phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia.</p><p><strong>Findings: </strong>The observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases.</p><p><strong>Conclusions: </strong>This study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD.</p><p><strong>Funding: </strong>X.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1413-1423.e3"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907819","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":"Preoperative camrelizumab combined with chemotherapy for borderline resectable ESCC: A single-arm, prospective, phase 2 study.","authors":"Guoqing Zhang, Teng Mu, Yan Zhang, Jia Jiao, Zheng Ding, Hang Yang, Dabo Pan, Jia Zhao, Jindong Li, Xiangnan Li","doi":"10.1016/j.medj.2024.07.015","DOIUrl":"10.1016/j.medj.2024.07.015","url":null,"abstract":"<p><strong>Background: </strong>We investigated the safety and efficacy of preoperative camrelizumab combined with chemotherapy for treating thoracic borderline resectable esophageal squamous cell carcinoma (Br-ESCC) (ChiCTR2200056728).</p><p><strong>Methods: </strong>Patients with thoracic Br-ESCC received intravenous camrelizumab plus chemotherapy and underwent esophagectomy. The primary endpoint was the pathologic complete response (pCR) rate. We introduced computed tomography and endoscopic examination into the diagnostic criteria to increase its reproducibility. Additionally, we defined a new resection status, Rbr^+/-, for Br-ESCC.</p><p><strong>Findings: </strong>Thirty-one patients with Br-ESCC were ultimately enrolled in this study. Overall, 71.0% (22/31) of the patients underwent esophagectomy. R0 resection was achieved in 81.8% of patients (18/22). pCR and major pathological response were observed in 40.9% (9/22) and 63.6% (14/22) of the resected patients, respectively. Eighteen R0 resection patients were redefined according to our Rbr definition; 61.1% (11/18) were classified as Rbr⁺ resection, and 38.9% (7/18) were classified as Rbr^- resection. With a median postoperative follow-up of 17.9 months, 4 patients out of 11 who underwent Rbr⁺ resection experienced local recurrence (2 of whom achieved pCR). However, no patients (0/7) who underwent Rbr^- resection experienced local recurrence.</p><p><strong>Conclusions: </strong>Esophagectomy after neoadjuvant immunochemotherapy is a promising radical treatment for Br-ESCC. R0 resection was achieved in 81.8% of patients, and a pCR was observed in 40.9% of resected patients. Even after complete excision, Rbr⁺ resection leads to a higher rate of local recurrence in patients with Br-ESCC.</p><p><strong>Funding: </strong>This study was supported by the Key Scientific Research Projects of the Institutions of Higher Learning in Henan Province (no. 21A320032).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1424-1432.e3"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914183","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":"Lingering impact: Maternal SARS-CoV-2 infection during early pregnancy results in fetal situs inversus.","authors":"Kjersti M Aagaard, Alireza A Shamshirsaz","doi":"10.1016/j.medj.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.010","url":null,"abstract":"<p><p>In this issue of Med, Guo et al.¹ describe their observed association of maternal SARS-CoV-2 infection in early (4-6 weeks) pregnancy with a confirmed fetal diagnosis of situs inversus congenital heart disease. Using sophisticated genomic tools and population-based statistical modeling, the study's authors present a very convincing argument causally linking maternal SARS-CoV-2 infection and resultant fetal situs inversus.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 11","pages":"1338-1339"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629418","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":"Neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma: A multicenter, phase 2 study.","authors":"Bo Long, Huinian Zhou, Zeyuan Yu, Junmin Zhu, Hanteng Yang, Zeping Huang, Dengwen Wei, Shigong Chen, Xiaojun Yang, Xiaoning Zhao, Wenjuan Zhang, Hong Yan, Xiaoying Guan, Long Li, Gengyuan Zhang, Hongwei Yu, Shengfu Che, Zhongti Gao, Xiangyan Jiang, Changjiang Luo, Jie Mao, Da Zhao, Yumin Li, Zebin Jiang, Zuoyi Jiao","doi":"10.1016/j.medj.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.008","url":null,"abstract":"<p><strong>Background: </strong>Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented.</p><p><strong>Methods: </strong>This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety.</p><p><strong>Findings: </strong>Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations were available for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues.</p><p><strong>Conclusions: </strong>Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation.</p><p><strong>Funding: </strong>This study was funded by Akeso Biopharma.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629129","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 prospective phase 2 study of combination epigenetic therapy against relapsed/refractory peripheral T cell lymphoma.","authors":"Kaiyang Ding, Hailing Liu, Haiyan Yang, Huayuan Zhu, Jie Ma, Hongling Peng, Hongming Huang, Wei Shi, Lei Cao, Wei Wu, Xiaoli Zhao, Xiao Shi, Jianyong Li, Xiaohui Zhang, Lei Fan","doi":"10.1016/j.medj.2024.07.007","DOIUrl":"10.1016/j.medj.2024.07.007","url":null,"abstract":"<p><strong>Background: </strong>Peripheral T cell lymphomas (PTCLs) are prototypical epigenetic malignancies with invariably poor prognoses. Novel and effective therapeutic strategies are needed to improve clinical outcomes, particularly in relapsed/refractory patients.</p><p><strong>Methods: </strong>We conducted a multicenter phase 2 study to evaluate the therapeutic efficacy of azacitidine and chidamide, alone or in combination with gemcitabine and oxaliplatin (GemOx), in patients with relapsed/refractory PTCLs (registration number: ChiCTR2000037232). The primary endpoint was the best overall response rate.</p><p><strong>Findings: </strong>As of May 1st, 2024, thirty patients were evaluable for efficacy and toxicity. The best overall response rate was 53.3%, meeting its primary endpoint. Among the patients with angioimmunoblastic T cell lymphoma (AITL; N = 19), a numerically higher response rate was observed, regardless of whether chemotherapy was combined, compared to patients with non-AITL. After a median follow-up of 36.6 months, median progression-free survival and overall survival were 7.1 and 8.7 months, respectively. Patients with AITL who received combination chemotherapy (N = 12) achieved the most promising response rates (overall response rate, 91.7%; complete remission rate, 66.7%) and survival outcomes (median progression-free survival, 17.2 months; median overall survival, 38.8 months). The most common grade 3-4 toxicities were neutropenia (40.0%) and thrombocytopenia (30.0%).</p><p><strong>Conclusions: </strong>The combination of epigenetic therapy with GemOx was well tolerated and highly effective in patients with relapsed/refractory PTCLs. Patients with AITL, in particular, may benefit more from this combination treatment and should be the focus of future studies.</p><p><strong>Funding: </strong>This work was funded by the Natural Science Foundation of Jiangsu Province (BK20232039).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1393-1401.e2"},"PeriodicalIF":12.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861129","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}