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{"title":"Audiological characteristics following gene therapy in patients with autosomal recessive deafness 9.","authors":"Longlong Zhang, Dingding Dong, Yanbo Yin, Honghai Tang, Jun Lv, Qi Cao, Wuqing Wang, Bing Chen, Yunfeng Wang, Huawei Li, Daqi Wang, Yilai Shu","doi":"10.1016/j.medj.2025.100696","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100696","url":null,"abstract":"<p><strong>Background: </strong>Gene therapy shows promising potential for patients with autosomal recessive deafness 9 (DFNB9), with ongoing clinical trials (ChiCTR2200063181). A deeper understanding of changes in audiological characteristics is crucial for optimizing the monitoring and evaluation of patients' recovery post-treatment.</p><p><strong>Methods: </strong>Audiological data were collected from 10 DFNB9 patients who underwent gene therapy, including auditory brain stem response (ABR), auditory steady-state response (ASSR), distortion product otoacoustic emission (DPOAE), and pure-tone audiometry (PTA) tests.</p><p><strong>Findings: </strong>A clear ABR wave V was observed in all participants by 13 weeks. By 52 weeks, distinct ABR waves I and III were visible in some participants. The 1-kHz ABR wave V latency at 85 dB decreased significantly from 9.220 (range 9.015-9.810) ms at 4 weeks to 8.190 (range 7.780-8.530) ms at 52 weeks (p = 0.004), with a trend toward increased wave V amplitude (p = 0.055). Significant correlations were observed between PTA, ABR, and ASSR thresholds at 0.5-4 kHz. The DPOAE signal-to-noise ratio (SNR) at 26 weeks post-treatment showed no significant difference compared with pre-treatment SNR values, nor were there significant correlations between the pre-treatment SNR values and the post-treatment ABR thresholds.</p><p><strong>Conclusions: </strong>The study demonstrates that ABR and ASSR are reliable objective tools for assessing hearing recovery in DFNB9 patients after gene therapy. ABR reveals positive changes in the auditory pathway over time after gene therapy, enhancing our understanding of the impact of gene therapy on auditory pathway recovery.</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":"100696"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133102","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":"Learning from the LEAP trial series: Optimizing clinical trial design for combination therapies.","authors":"Jiatong Ding, Yue Yu, Dandan Cui, Shujun Xing, Dawei Wu, Yuan Fang, Ning Jiang, Peiwen Ma, Yale Jiang, Dongyan Liu, Weijie Yu, Yanjie Han, Jiawei Zhou, Hong Fang, Shuopeng Jia, Qiyu Tang, Shuhang Wang, Ning Li","doi":"10.1016/j.medj.2025.100693","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100693","url":null,"abstract":"<p><p>The LEAP trial series examining the synergy of pembrolizumab and lenvatinib across various cancers has yielded mixed results, highlighting the need for a more detailed understanding of combination therapies. By learning from these trials, we aim to advance the clinical development of more effective combination strategies to improve patient outcomes.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 5","pages":"100693"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036928","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":"Sustained growth-promoting effects of vosoritide in children with achondroplasia from an ongoing phase 3 extension study.","authors":"Ravi Savarirayan, Melita Irving, William R Wilcox, Carlos A Bacino, Julie E Hoover-Fong, Paul Harmatz, Lynda E Polgreen, Katja Palm, Carlos E Prada, Takuo Kubota, Paul Arundel, Yumiko Kotani, Antonio Leiva-Gea, Michael B Bober, Jacqueline T Hecht, Janet M Legare, Sue Lawrinson, Andrea Low, Ian Sabir, Alice Huntsman-Labed, Jonathan R S Day","doi":"10.1016/j.medj.2024.11.019","DOIUrl":"10.1016/j.medj.2024.11.019","url":null,"abstract":"<p><strong>Background: </strong>Vosoritide is a C-type natriuretic peptide analog that addresses an underlying pathway causing reduced bone growth in achondroplasia. Understanding the vosoritide treatment effect requires evaluation over an extended duration and comparison with outcomes in untreated children.</p><p><strong>Methods: </strong>After completing ≥6 months of a baseline observational growth study and 52 weeks in a double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03197766), participants were eligible to continue treatment in an open-label extension (ClinicalTrials.gov: NCT03424018) wherein all received 15 μg/kg vosoritide daily. Data from the CLARITY achondroplasia study provided an external untreated control population and reference data.</p><p><strong>Findings: </strong>The population comprised 119 participants. Annualized growth velocity with vosoritide was similar to the average-stature population before puberty. The mean (SD) differences in annualized growth velocity across each integer age (6-16 years) between treated and untreated children were 1.84 (0.38) cm/year in boys and 1.44 (0.63) cm/year in girls. Three-year comparisons of treated versus untreated children demonstrated an additional height gain of 5.75 cm (95% confidence interval [CI]: 4.93, 6.57) with vosoritide. A significant improvement in upper-to-lower body segment ratio at 3 years of treatment was observed for participants with assessments at age <11 (females) and <12 years (males) versus population-level, age-matched, untreated controls (p = 0.0087). The arm span-to-standing height ratio remained consistent with untreated participants. Vosoritide had a favorable safety profile with continuous treatment for up to 6 years (464.05 person years of exposure). No long-term harms or deaths were observed.</p><p><strong>Conclusions: </strong>Vosoritide treatment was well tolerated and had sustained growth-promoting effects in children with achondroplasia treated for up to 6 years.</p><p><strong>Funding: </strong>This work was funded by BioMarin Pharmaceutical.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100566"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910942","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":"IBI310 plus sintilimab vs. placebo plus sintilimab in recurrent/metastatic cervical cancer: A double-blind, randomized controlled trial.","authors":"Huayi Li, Yu Xu, Xiaofei Jiao, Qin Xu, Zikun Peng, Ying Tang, Jieqing Zhang, Bowen Huang, Yiyang Shen, Baoping Chang, Bairong Xia, Wei Duan, Danbo Wang, Lijing Zhu, Ruifang An, Guonan Zhang, Yaling Tang, Jianli Huang, Hui Qiu, Li Wang, Yi Huang, Guiling Li, Jianhua Qian, Li Sun, Hong Zheng, Ge Lou, Youzhong Zhang, Youguo Chen, Liqin Lu, Yan Cheng, Jihong Liu, Weidong Zhao, Jianghai Ji, Aiqin He, Ke Wang, Guohua Yu, Hong Zhu, Cailing Ma, Jianlin Yuan, Xia Wang, Hongfei Zhang, Xinyan Ma, Chujun Cai, Kang Yin, Han Xie, Ya Wang, Shuyan Wang, Li Li, Hui Zhou, Jing Wang, Jianqing Zhu, Ding Ma, Qinglei Gao","doi":"10.1016/j.medj.2024.100573","DOIUrl":"10.1016/j.medj.2024.100573","url":null,"abstract":"<p><strong>Background: </strong>It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC).</p><p><strong>Methods: </strong>In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3 weeks for 12 weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.</p><p><strong>Findings: </strong>205 patients were randomized to receive IBI310-sintilimab (n = 103) or placebo-sintilimab (n = 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p = 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2 months (95% CI: 2.8-6.2), respectively (hazard ratio [HR] = 0.91, 95% CI: 0.65-1.27; p = 0.58). The median OSs were 13.9 months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2 months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR = 1.12, 95% CI: 0.79-1.58; p = 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%).</p><p><strong>Conclusions: </strong>Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC.</p><p><strong>Funding: </strong>This work was funded by Innovent Biologics (Suzhou).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100573"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013001","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":"Randomized double-blind study on safety and tolerability of TP-102 phage cocktail in patients with infected and non-infected diabetic foot ulcers.","authors":"Ran Nir-Paz, Hadil Onallah, Michal Dekel, Yechiel N Gellman, Amir Haze, Ronen Ben-Ami, Ron Braunstein, Ronen Hazan, Danna Dror, Yonatan Oster, Meir Cherniak, Fabienne Attal, Ana Raquel Barbosa, Helena Dordio, Alexandra Wagner, Daniela Jones-Dias, José Neves, Margarida Barreto, Clara Leandro, Sofia Côrte-Real, Miguel Garcia","doi":"10.1016/j.medj.2024.11.018","DOIUrl":"10.1016/j.medj.2024.11.018","url":null,"abstract":"<p><strong>Background: </strong>Phage therapy offers a promising alternative for treating serious infections, including diabetic foot ulcers (DFUs), through the lytic action of phages. This randomized double-blind study was conducted to evaluate the safety and tolerability of the TP-102 bacteriophage cocktail in patients with DFUs non-infected and infected with Staphylococcus aureus, Pseudomonas aeruginosa, and/or Acinetobacter baumannii.</p><p><strong>Methods: </strong>Nineteen participants with DFUs were randomized after susceptibility testing. TP-102 was applied topically at 10⁹ plaque-forming units (PFUs)/mL/cm³ to the target ulcer: 1 week for non-infected DFUs and 28 days for infected DFUs (PEDIS grade 2/3). The study was conducted in Israel.</p><p><strong>Findings: </strong>Main outcomes included the incidence and severity of TP-102-related adverse events, microbiological data, and ulcer healing. Thirteen patients received TP-102. No treatment-related adverse events were reported. Although the study was underpowered to determine the superiority of TP-102 over placebo, a greater proportion of patients in the TP-102 + standard of care (SOC) group showed microbiological reduction of target bacteria (t = 26) compared to the placebo + SOC group (80% versus 50%, p = 1.000). Additionally, a higher proportion of TP-102 patients reached 50% and 75% wound closure compared to placebo (5/7 [71.4%] versus 1/3 [33.3%], p = 0.500 and 2/7 [28.6%] versus none, p = 1.000, respectively). One patient in the TP-102 group achieved wound closure.</p><p><strong>Conclusions: </strong>TP-102 was well tolerated and safe, showing potential as a groundbreaking treatment in this field. Further studies are needed to confirm its safety and efficacy in larger populations with diabetic foot infections (ClinicalTrials.gov: NCT04803708).</p><p><strong>Funding: </strong>None to declare.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100565"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910941","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":"Immune-cell signatures of persistent inflammation, immunosuppression, and catabolism syndrome after sepsis.","authors":"Xing-Feng Sun, Wen-Chen Luo, Shao-Qiang Huang, Yi-Jun Zheng, Lei Xiao, Zhong-Wei Zhang, Rong-Hua Liu, Zi-Wen Zhong, Jie-Qiong Song, Ke Nan, Zhi-Xin Qiu, Jing Zhong, Chang-Hong Miao","doi":"10.1016/j.medj.2024.12.003","DOIUrl":"10.1016/j.medj.2024.12.003","url":null,"abstract":"<p><strong>Background: </strong>Management of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) after sepsis remains challenging for patients in the intensive care unit, experiencing poor quality of life and death. However, immune-cell signatures in patients with PICS after sepsis remain unclear.</p><p><strong>Methods: </strong>We determined immune-cell signatures of PICS after sepsis at single-cell resolution. Murine cecal ligation and puncture models of PICS were applied for validation.</p><p><strong>Findings: </strong>Immune functions of two enriched monocyte subpopulations, Mono1 and Mono4, were suppressed substantially in patients with sepsis and were partially restored in patients with PICS after sepsis and exhibited immunosuppressive and pro-apoptotic effects on B and CD8T cells. Patients with PICS and sepsis had reduced naive and memory B cells and proliferated plasma cells. Besides, naive and memory B cells in patients with PICS showed an active antigen processing and presentation gene signature compared to those with sepsis. PICS patients with better prognoses exhibited more active memory B cells and IGHA1-plasma cells. CD8TEMRA displayed signs of proliferation and immune dysfunction in the PICS-death group in contrast with the PICS-alive group. Megakaryocytes proliferation was more pronounced in patients with PICS and sepsis than in healthy controls, with notable changes in the anti-inflammatory and immunomodulatory effects observed in patients with PICS and verified in mice models.</p><p><strong>Conclusions: </strong>Our study evaluated PICS after sepsis at the single-cell level, identifying the heterogeneity present within immune-cell subsets, facilitating the prediction of disease progression and the development of effective intervention.</p><p><strong>Funding: </strong>This work was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission \"Yiyuan New Star\" Youth Medical Talent Cultivating Program, and Shanghai Clinical Research Center for Anesthesiology.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100569"},"PeriodicalIF":12.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012955","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":"Emerging trends in clinical allogeneic CAR cell therapy.","authors":"Yan-Ruide Li, Yichen Zhu, Ying Fang, Zibai Lyu, Lili Yang","doi":"10.1016/j.medj.2025.100677","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100677","url":null,"abstract":"<p><p>There has been significant progress in the clinical development of allogeneic off-the-shelf chimeric antigen receptor (CAR)-engineered cell therapies for the treatment of cancer and autoimmune diseases. Unlike autologous CAR cell therapies, allogeneic approaches overcome challenges such as high costs, labor-intensive manufacturing, and stringent patient selection. This makes allogeneic therapies a more universally applicable option for a diverse patient population. In this review, we examine recent clinical advancements in allogeneic CAR cell therapies, including CAR-T cell therapy derived from healthy donor peripheral blood mononuclear cells, as well as CAR-NK cell therapy from cord blood or induced pluripotent stem cells. We provide an overview of their genetic engineering strategies, clinical designs, and outcomes, highlighting their promising efficacy and safety. Additionally, we summarize key preclinical developments, address key challenges, and explore future directions to provide insights into emerging trends in the field.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100677"},"PeriodicalIF":12.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080957","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":"Burden of neurological disorders in China and its provinces, 1990-2021: Findings from the global burden of disease study 2021.","authors":"Chen Zhang, Xuan Yang, Dongshan Wan, Qingfeng Ma, Peng Yin, Maigeng Zhou, Junwei Hao","doi":"10.1016/j.medj.2025.100692","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100692","url":null,"abstract":"<p><strong>Background: </strong>The burden of neurological disorders in China has not been systematically analyzed. We aim to provide a comprehensive estimation of the national and subnational neurological burden across China from the Global Burden of Disease Study (GBD) 2021.</p><p><strong>Methods: </strong>We assessed burden estimates for 16 neurological disorders by age, sex, and province from 1990 to 2021, with prevalence, death, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs). We performed decomposition analysis to determine contributing factors for DALYs and used the socio-demographic index (SDI) to assess relations with development level.</p><p><strong>Findings: </strong>In 2021, there were 468.29 million prevalent cases of neurological disorders in China, corresponding to 78.10 million DALYs. Intracerebral hemorrhage was the leading cause of DALYs, followed by ischemic stroke, dementias, and migraine. DALYs of neurological disorders were higher in males than females, peaking at 70-74 years. From 1990 to 2021, the number and age-standardized rate of DALYs significantly decreased for idiopathic epilepsy and subarachnoid hemorrhage, primarily attributed to the reduction in YLLs, while the number of DALYs disproportionately increased for dementias, Parkinson's disease, and ischemic stroke contributed by population aging. The age-standardized DALY rates of seven neurological disorders had more than 5-fold variation between western and eastern provinces, despite reduced burdens with rising SDI.</p><p><strong>Conclusions: </strong>Neurological disorders pose a large and growing burden on public health, primarily driven by population aging. Our findings could inform priority setting and targeted strategies to optimize neurological service delivery.</p><p><strong>Funding: </strong>The funding information is presented in the acknowledgments.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100692"},"PeriodicalIF":12.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055808","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":"CD19 CAR-T cell therapy in a pediatric patient with MDA5⁺ dermatomyositis and rapidly progressive interstitial lung disease.","authors":"Andrés París-Muñoz, Rosa M Alcobendas-Rueda, Cristina Verdú-Sánchez, Clara Udaondo, Víctor Galán-Gómez, Berta González-Martínez, Juan J Menéndez, Isabel Martínez-Romera, Jordi Minguillón, Lidia Pertíñez, Cristina de Manuel-Gómez, Ana de la Cruz-Benito, Alejandro Sanz-Rupérez, Agustín Remesal, Carmen Cámara, Elena Sánchez-Zapardiel, Lucía Del Pino-Molina, Ana Gómez-Zamora, María G Serrano-Olmedo, Marta Español-Rego, Marta Ruiz de Valbuena, Francisco Climent, Paloma Dorao, Juan J Ríos-Blanco, José D Andrade, Gonzalo Ruiz-Zurita, Miguel A Fernández-García, Antonio Pérez-Martínez","doi":"10.1016/j.medj.2025.100676","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100676","url":null,"abstract":"<p><strong>Background: </strong>Anti-melanoma differentiation-associated protein 5 dermatomyositis (MDA5⁺DM) is a potentially fatal subtype of dermatomyositis. The most severe cases are characterized by rapidly progressive interstitial lung disease (RPILD), the leading cause of death in these patients. There is currently no curative treatment for these patients, and indeed, MDA5⁺DM-RPILD is considered one of the most challenging pathologies in medicine. Nevertheless, the recent introduction of CD19 chimeric antigen receptor (CAR)-T cell therapies appears to offer a serious opportunity to develop solutions for complex autoimmune diseases refractory to multiple immunosuppressant treatments, mainly rheumatic diseases such as rheumatoid arthritis, dermatomyositis, and systemic lupus erythematosus.</p><p><strong>Methods: </strong>In this report, we describe the first use of a second-generation CD19 CAR-T cell therapy (ARI-0001) in a pediatric patient with severe MDA5⁺DM-RPILD.</p><p><strong>Findings: </strong>Conventional treatments stabilized MDA5⁺DM-RPILD before CAR-T cell inoculation (-34 days). The presence of CD19⁺ B lymphocytes that might serve as target cells in deeper tissues was suspected due to CAR-T cell expansion in a context of B cell aplasia. No fever or cytokine release syndrome/cell-associated neurotoxicity syndrome was evident. In global terms, B cell reconstitution and cutaneous, motor, respiratory, and neurological improvements were observed gradually in the patient in an immunosuppressant-free context (-7 to +325 days).</p><p><strong>Conclusions: </strong>A pediatric patient with aggressive MDA5⁺DM-RPILD achieved progressive long-term improvement and immunosuppressant-free remission over 11 months after compassionate use of a CD19 CAR-T cell therapy (ARI-0001).</p><p><strong>Funding: </strong>This work was supported by the Programa Investigo (PI_SEPE_APM) and grants from the ISC-III (PI22/01226) from the Comunidad de Madrid (S2022/BMD-7225) and from the CRIS Cancer Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100676"},"PeriodicalIF":12.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988983","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":"Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression.","authors":"Benjamin J Murdock, Bangyao Zhao, Ian F Webber-Davis, Samuel J Teener, Kristen D Pawlowski, Joshua P Famie, Caroline E Piecuch, Dae Gyu Jang, Eva L Feldman, Lili Zhao, Stephen A Goutman","doi":"10.1016/j.medj.2025.100673","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100673","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure and limited treatment options. The immune system is implicated in disease pathology, unlocking a potential therapeutic avenue. However, it is unclear whether immune changes are a cause or consequence of disease progression.</p><p><strong>Methods: </strong>Peripheral immune cells were longitudinally measured at monthly intervals in 55 ALS and 50 control participants. 22 peripheral immune markers in the blood were assessed using flow cytometry, and clinical progression was assessed using the revised ALS functional rating scale (ALSFRS-R). Individual immune markers, their trajectories, and overall variability were compared in ALS versus control participants; ALS participants were also stratified by clinical progression rates and assessed similarly across progression groups. Finally, a novel, lagged linear regression model correlated the rate of immune changes to subsequent downstream ALSFRS-R changes.</p><p><strong>Findings: </strong>Numerous immune markers were dysregulated in ALS versus control participants, with altered levels, trajectories, or variability in immune populations and surface markers. ALS participants had increased immune variability relative to control participants; within ALS participants, faster progressors overall had decreased marker variability. Finally, natural killer (NK) cell numbers, NK cell subpopulations, and NK cell surface markers were significantly associated with downstream ALS progression.</p><p><strong>Conclusions: </strong>The immune system is dysregulated in ALS and more consistently dysregulated in faster ALS progression, and immune dysregulation occurs upstream of clinical changes. These findings suggest that the immune system is a causal factor of ALS progression in human patients.</p><p><strong>Funding: </strong>CReATe Consortium, NIH, Target ALS, DoD, ALSA.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100673"},"PeriodicalIF":12.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989004","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}