Validating Restricted Mean Survival Time Estimates From Reconstructed Kaplan-Meier Data Against Original Trial Individual Patient Data From Trials Conducted by the Canadian Cancer Trials Group

ObjectivesThe development of novel cancer therapies, including immuno-oncology agents, has increased interest in reconstructed individual patient data (IPD) based restricted mean survival time (RMST) analyses. Additionally, reconstructed IPD–based RMST is recommended in cost-effectiveness analyses when original trial IPD are not available. Nevertheless, recently concerns regarding potential bias of reconstructed-IPD RMST have been presented, because reconstructed-IPD RMSTs have not been validated and previous validation endpoints may not capture the entire Kaplan-Meier (KM) curve, especially the “tail.” Our study aims to validate the recommended method of IPD reconstruction by comparing reconstructed IPD– and original trial IPD–based RMST.MethodsCanadian Cancer Trials Group trials from 1990 to 2017 were included. Overall survival and progression-free survival IPD were reconstructed based on published KM curves using the Guyot method. Analysts were blinded to original trial IPD. RMST was calculated at 1 year and over the entire KM curve. Reconstructed-IPD and original trial–IPD (gold-standard) RMSTs were compared for accuracy and predictive error via mean deviation, mean absolute error (MAE), mean percentage bias, and Bland-Altman plots and across KM curve quality (vector traced or bitmapped).ResultsWe identified 39 trials. The mean deviation, MAE, and mean percentage bias of RMST between the reconstructed IPD and original trial IPD were small. In particular, the mean deviation was ?0.01 months and ?0.04 months, MAE was 0.19 months and 0.24 months, and mean percentage bias was 0.82% and 0.84% in overall survival KM curves in control and experimental arms, respectively. Accuracy was generally not associated with KM curve quality.ConclusionsRMST derived from reconstructed IPD displayed excellent accuracy and predictive error compared with the gold standard. Reconstructed IPD could be used to calculate RMST in lieu of original trial IPD, to facilitate decision making for clinicians, researchers, and policy makers.     

Mg2+ Transporters in Digestive Cancers

Despite magnesium (Mg²⁺) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg²⁺ homeostasis is regulated by Mg²⁺ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg²⁺ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg²⁺ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg²⁺ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg²⁺ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.     

How Assessment-Schedule Matching Limits Bias When Comparing Progression-Free Survival in Single-Arm Studies: An Application in Second-Line Urothelial Carcinoma Treatments

ObjectivesPopulation-adjusted comparisons of progression-free survival (PFS) from single-arm trials of cancer treatments can be derived using matching-adjusted indirect comparisons (MAICs); however, results are still susceptible to bias, particularly if the trials had different tumor assessment schedules. This study aims to assess the effects of assessment-schedule matching (ASM) on the relative effectiveness on the PFS of avelumab versus approved comparator immunotherapies or chemotherapy after population matching in the second-line (2L) setting for metastatic urothelial carcinoma.MethodsThe MAIC used patient-level data for avelumab from the JAVELIN Solid Tumor trial (NCT01772004). PFS was compared with published curves for other treatments to obtain population-adjusted hazard ratios (HRs). The MAIC was repeated after conducting ASM for differences in tumor assessment scheduled first at 6 weeks for avelumab and durvalumab and at 8 or 9 weeks for other treatments.ResultsMAIC adjustment alone altered the HR estimates up to 23%, whereas MAIC plus ASM resulted in up to 32.7% reductions from naive comparisons. Even in cases in which MAIC had little effect, ASM brought an additional change of 11.1% to 15.4%. Overall, the HR range of avelumab versus other treatments changed from 0.83 to 1.25 for naive comparisons to 0.76 to 0.99 after ASM plus MAIC, numerically favoring avelumab.ConclusionsSmall variations in assessment schedules can introduce bias in unanchored indirect treatment comparisons of interval-censored time-to-event outcomes. In this study, adjusted PFS was comparable across second-line urothelial carcinoma treatment options, numerically favoring avelumab versus immunotherapies and chemotherapy agents. Correcting this bias is especially important when HRs are applied in cost-effectiveness models to transition patients between states.     

婴儿期生长情况对青春期性发育的影响研究

目的 探讨婴儿期快速生长对青春期性发育的影响,对预防未来青春期提早发育提供依据。方法 选择2004年1月-2005年1月在温州市儿童医院及本院体检的198例生长过快的婴儿为观察组,另选择175名正常婴儿为对照组。根据出现月经初潮/遗精的时间点,把观察组分成性早熟组和正常发育组。采用Spearman相关性分析观察组婴儿1周岁的身高Δ值、体重Δ值与青春期性早熟的相关性。结果 观察组婴儿1周岁的身高Δ值、体重Δ值均显著大于对照组,差异有统计学意义(t＝2.085,2.146,P＜0.05);观察组儿童的身高、体重、体脂、骨龄值均显著大于对照组儿童,观察组儿童的T、E2、FSH、LH水平均显著高于对照组儿童,差异均有统计学意义(P＜0.05)。对照组无性早熟患儿。观察组、早熟组和正常组的男女比例对比,差异无统计学意义(P＞0.05)。早熟组身高、体重、体脂、骨龄值均显著大于正常组,早熟组T、E2、FSH、LH水平均显著高于正常组,差异有统计学意义(P＜0.05)。观察组婴儿1周岁的身高Δ值、体重Δ值与青春期性早熟呈正相关(r=0.816,0.872,P<0.001)。结论 婴儿期快速生长可造成儿童青春期前肥胖和体脂过度,使青春期早发。控制婴儿期过快生长对预防未来青春期提早发育有重要意义。     

妊娠期糖尿病患者产后糖代谢异常转归影响因素分析

目的探讨妊娠期糖尿病(GDM)患者产后糖代谢异常(AGM)转归及其影响因素。方法选择2019年1月至12月,于四川大学华西第二医院孕期被诊断为GDM,并于产后4~12周进行75 g口服葡萄糖耐量试验(OGTT)筛查的1175例单胎妊娠产妇为研究对象。根据其产后糖代谢是否正常,将其分为研究组(n=361,产后AGM者)与对照组(n=814,产后糖代谢正常者)。采用回顾性分析方法,收集受试者一般临床资料及孕期与产后4~12周75 g OGTT结果等,并采用成组t检验或χ^(2)检验进行统计学分析。对GDM患者产后AGM转归相关影响因素进行单因素分析与多因素非条件logistic回归分析,探讨其AGM转归的独立影响因素。本研究遵循的程序符合病例收集医院伦理委员会制定的伦理学标准,得到该伦理委员会批准[审批文号:医学科研2021伦审批第(181)号]。结果①24~28孕周时,1175例GDM患者75 g OGTT结果提示,空腹血糖(FPG)及OGTT 1、2 h血糖指标中,1、2、3项升高者分别为639例(54.4%)、373例(31.7%)与163例(13.9%)。②产后4~12周时,1175例GDM患者75 g OGTT结果提示,产后糖代谢正常者为814例(69.3%),AGM为361例(30.7%),包括空腹血糖受损(IFG)为19例(1.6%),糖耐量受损(IGT)为294例(25.0%),IFG+IGT为23例(2.0%),疑似2型糖尿病(T2DM)患者为25例(2.1%)。③产后AGM转归影响因素的单因素分析结果显示,研究组GDM患者年龄、糖尿病家族史发生率,24~28孕周OGTT 1、2 h血糖值,以及2项血糖指标(OGTT 1、2 h血糖)均升高与3项血糖指标(FPG及OGTT1、2 h血糖)均升高者所占比例,均显著高于对照组,而研究组仅1项血糖指标(FPG或OGTT 1 h血糖)升高者所占比例,则显著低于对照组,2组比较,差异均有统计学意义(P<0.05)。④多因素非条件logistic回归分析结果:模型1将受试者年龄、糖尿病家族史及24~28孕周OGTT 1、2 h血糖值进行多因素logistic回归分析结果显示,糖尿病家族史及24~28孕周OGTT 1、2 h血糖值,均为GDM患者产后AGM转归的独立危险因素(OR=1.693、1.205、1.355,95%CI:1.208~2.373、1.088~1.335、1.204~1.524,P=0.002、<0.001、<0.001)。模型2将受试者年龄、糖尿病家族史、24~28孕周OGTT血糖指标升高项目进行多因素logistic回归分析结果显示,糖尿病家族史及24~28孕周OGTT 2项血糖指标(OGTT 1、2 h血糖)升高与3项血糖指标均升高,均为GDM患者产后AGM转归独立危险因素(OR=1.668、1.421、1.747,95%CI:1.192~2.333、1.035~1.952、1.195~2.553,P=0.003、0.030、0.004);24~28孕周仅FPG或OGTT 1 h血糖升高为其独立保护因素(OR=0.401、0.646,95%CI:0.240~0.670、0.418~0.997,P<0.001、=0.048)。结论对于GDM患者产后AGM转归,临床应关注其年龄、糖尿病家族史、孕期OGTT结果等指标。对GDM高危人群进行上述指标持续监测与规范干预,是健全GDM孕前-孕期-产后全程管理的重要环节。     

心脏瓣膜置换术48例围手术期的处理

目的：总结瓣膜置换术围手术期处理所临床经验。方法：回顾性分析48例瓣膜置换术病人术前、术中、术后处理的临床资料。结果：发生围手术期并发症共14例,其中低心排4例,心律失常4例最多。长期存活47例,死于多器官功能衰竭1例。结论：术前注意纠正心功能不足与合并症的治疗,术中注意心肌保护与三尖瓣关闭不全的矫治,术后强调补足血容量和血清钾后强心利尿。     

生存研究样本量设计表及其使用方法

目的 :本文就两样本生存研究所需样本量用广义渐近正态法设计出 15 30个方案 ,制成设计表供临床使用。方法 :利用C语言编制程序 ,按通用格式打印设计表。结果 :常用方案查表可得。这些与两样本生存率检验相匹配 ,具有还原性 ,摆脱了比例危险的假设 ,在常见临床条件下观测功效符合预定功效。结论 :这些设计表适用于两样本癌症临床研究的设计 ,尤其便于临床医师或有关研究人员使用     

成年起病脊肌萎缩症SMN基因外显子7缺失的初探

目的探讨成年起病的脊肌萎缩症(SMA)患者的运动神经元存活基因SMN的缺失情况。方法用聚合酶链反应-酶切技术对15例SMA病人及33例正常对照的外显子7进行检测,明确有无缺失。结果3例SMA的SMN基因外显子7纯合缺失,其余12例和对照组均阴性。结论SMN基因外显子7缺失可作为成年起病SMA的辅助诊断,以提示SMA遗传的异质性。     

肉苁蓉总苷对~(60)Coγ射线损伤小鼠免疫功能的防护作用

目的　研究肉苁蓉总苷 (GCs)对 6 0 Co损伤小鼠免疫功能及 30 d存活率的影响。方法　小鼠在不同剂量6 0 Coγ射线照射前后 ,均服以 GCs,观察辐射及 GCs对其免疫功能的改变。结果　 6 0 Co照射剂量为 2 ,4及 7Gy时 ,可造成小鼠体液免疫、细胞免疫功能和非特异性免疫功能及 30 d存活率下降 (P<0 .0 5或 P<0 .0 1) ;GCs(31.2 5 ,6 2 .5 ,12 5 m g/ kg)组可促进上述各指标的恢复 ,对 6 0 Co损伤小鼠的抗体产生、外周血 T淋巴细胞数目、迟发型超敏反应、腹腔巨噬细胞的吞噬功能均有明显保护作用 (P<0 .0 1或 P<0 .0 5 ) ;且能提高受照小鼠的脾指数、胸腺指数及 30 d存活率 (P<0 .0 1或 P<0 .0 5 )。结论　 GCs对辐射损伤小鼠的免疫功能具有较强防护作用