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Abstract：
BACKGROUND: Based on previous in vivo studies and human trials, intrathecal cell delivery is a safe and relevant therapeutic tool for improving patient\'s quality of life with neurological conditions. We aimed to characterise the safety profile of intrathecally delivered Mesenchymal stem cells (MSCs).
METHODS: Ovid MEDLINE, Embase, Scopus, Cochrane Library, KCI-Korean Journal Database, and Web of Science. Databases were searched from their inception until April 13, 2023. Randomised Controlled Trials (RCTs) that compared intrathecal delivery of MSCs to controls in adult populations were included. Adverse events (AEs) were pooled and meta-analysed using DerSimonian-Laird random effects models with a correction factor 0.5 added to studies with zero count cells. Pooled AEs were described using Risk ratio (RR) and 95% confidence intervals (95% CI). Then, a random-effects meta-regress model on study-level summary data was performed to explore the relationship between the occurrence of AEs and covariates thought to modify the overall effect estimate. Finally, publication bias was assessed.
RESULTS: 303 records were reviewed, and nine RCTs met the inclusion criteria and were included in the quantitative synthesis (n = 540 patients). MSCs delivered intrathecally, as compared to controls, were associated with an increased probability of AEs of musculoskeletal and connective tissue disorders (categorised by Common Terminology Criteria for Adverse Events-CTCAE version 5.0) (RR: 1.61, 95% CI 1.19-2.19, I2 = 0%). The random-effects meta-regress model suggested that fresh MSCs increased the probability of occurrence of AEs compared to cryopreserved MSCs (RR: 1.554; p-value = 0.048; 95% CI 1.004-2.404), and the multiple-dose, decreased the probability of AEs by 36% compared to single doses (RR: 0.644; p-value = 0.048; 95% CI 0.416-0.996); however, univariate random effects meta-regression models revealed a not significant association between the occurrence of AEs from MSCs intrathecal delivery and each covariate.
CONCLUSIONS: Intrathecal delivery of MSCs was associated with a slight increase in AEs associated with musculoskeletal and connective tissue disorders, albeit without serious AEs. We conclude that intrathecal MSCs delivery is safe for patients with neurological conditions. However, further high-quality, large-scale RCTs are needed to confirm these findings.
METHODS: Ovid MEDLINE, Embase, Scopus, Cochrane Library, KCI-Korean Journal Database, and Web of Science. Databases were searched from their inception until April 13, 2023. Randomised Controlled Trials (RCTs) that compared intrathecal delivery of MSCs to controls in adult populations were included. Adverse events (AEs) were pooled and meta-analysed using DerSimonian-Laird random effects models with a correction factor 0.5 added to studies with zero count cells. Pooled AEs were described using Risk ratio (RR) and 95% confidence intervals (95% CI). Then, a random-effects meta-regress model on study-level summary data was performed to explore the relationship between the occurrence of AEs and covariates thought to modify the overall effect estimate. Finally, publication bias was assessed.
RESULTS: 303 records were reviewed, and nine RCTs met the inclusion criteria and were included in the quantitative synthesis (n = 540 patients). MSCs delivered intrathecally, as compared to controls, were associated with an increased probability of AEs of musculoskeletal and connective tissue disorders (categorised by Common Terminology Criteria for Adverse Events-CTCAE version 5.0) (RR: 1.61, 95% CI 1.19-2.19, I2 = 0%). The random-effects meta-regress model suggested that fresh MSCs increased the probability of occurrence of AEs compared to cryopreserved MSCs (RR: 1.554; p-value = 0.048; 95% CI 1.004-2.404), and the multiple-dose, decreased the probability of AEs by 36% compared to single doses (RR: 0.644; p-value = 0.048; 95% CI 0.416-0.996); however, univariate random effects meta-regression models revealed a not significant association between the occurrence of AEs from MSCs intrathecal delivery and each covariate.
CONCLUSIONS: Intrathecal delivery of MSCs was associated with a slight increase in AEs associated with musculoskeletal and connective tissue disorders, albeit without serious AEs. We conclude that intrathecal MSCs delivery is safe for patients with neurological conditions. However, further high-quality, large-scale RCTs are needed to confirm these findings.
摘要：
背景：基于先前的体内研究和人体试验，鞘内细胞递送是改善患者神经系统疾病生活质量的安全和相关的治疗工具。我们旨在表征鞘内递送的间充质干细胞（MSC）的安全性。
方法：OvidMEDLINE，Embase,Scopus,科克伦图书馆,KCI-韩国期刊数据库，和WebofScience。从数据库开始到2023年4月13日一直进行搜索。包括比较在成人群体中鞘内递送MSC至对照的随机对照试验(RCT)。使用DerSimonian-Laird随机效应模型对不良事件（AE）进行汇总和荟萃分析，其中校正因子为0.5，添加到零计数细胞的研究中。使用风险比(RR)和95%置信区间(95%CI)描述合并的不良事件。然后，本研究对研究水平汇总数据进行了随机效应元回归模型,以探索AE的发生与被认为可修改总体效应估计值的协变量之间的关系.最后,评估发表偏倚.
结果：回顾了303条记录，9个RCT符合纳入标准,并纳入定量综合(n=540例).MSCs鞘内递送,与对照组相比，与肌肉骨骼和结缔组织疾病的AE概率增加相关(按不良事件通用术语标准-CTCAE5.0版分类)(RR:1.61,95%CI1.19-2.19,I2=0%)。随机效应元回归模型表明，与冷冻保存的MSCs相比，新鲜的MSCs增加了AE发生的概率（RR：1.554;p值=0.048;95％CI1.004-2.404），和多剂量，与单剂量相比，AE的概率降低了36%(RR:0.644;p值=0.048;95%CI0.416-0.996);然而，单变量随机效应meta回归模型显示,MSCs鞘内给药产生的AE与各协变量之间无显著关联.
结论：鞘内递送MSCs与肌肉骨骼和结缔组织疾病相关的AEs略有增加有关，尽管没有严重的AE。我们得出的结论是，鞘内注射MSCs对患有神经系统疾病的患者是安全的。然而,进一步高质量，需要大规模的RCT来证实这些发现.
方法：OvidMEDLINE，Embase,Scopus,科克伦图书馆,KCI-韩国期刊数据库，和WebofScience。从数据库开始到2023年4月13日一直进行搜索。包括比较在成人群体中鞘内递送MSC至对照的随机对照试验(RCT)。使用DerSimonian-Laird随机效应模型对不良事件（AE）进行汇总和荟萃分析，其中校正因子为0.5，添加到零计数细胞的研究中。使用风险比(RR)和95%置信区间(95%CI)描述合并的不良事件。然后，本研究对研究水平汇总数据进行了随机效应元回归模型,以探索AE的发生与被认为可修改总体效应估计值的协变量之间的关系.最后,评估发表偏倚.
结果：回顾了303条记录，9个RCT符合纳入标准,并纳入定量综合(n=540例).MSCs鞘内递送,与对照组相比，与肌肉骨骼和结缔组织疾病的AE概率增加相关(按不良事件通用术语标准-CTCAE5.0版分类)(RR:1.61,95%CI1.19-2.19,I2=0%)。随机效应元回归模型表明，与冷冻保存的MSCs相比，新鲜的MSCs增加了AE发生的概率（RR：1.554;p值=0.048;95％CI1.004-2.404），和多剂量，与单剂量相比，AE的概率降低了36%(RR:0.644;p值=0.048;95%CI0.416-0.996);然而，单变量随机效应meta回归模型显示,MSCs鞘内给药产生的AE与各协变量之间无显著关联.
结论：鞘内递送MSCs与肌肉骨骼和结缔组织疾病相关的AEs略有增加有关，尽管没有严重的AE。我们得出的结论是，鞘内注射MSCs对患有神经系统疾病的患者是安全的。然而,进一步高质量，需要大规模的RCT来证实这些发现.
