First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric,gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.     

多层螺旋CT对腹股沟疝的分型鉴别及应用价值

目的分析多层螺旋CT对腹股沟疝的分型鉴别及应用价值。 方法选择2018年5月至2021年3月于宁国市人民医院外科收治的102例腹股沟疝患者作为研究对象，观察分析多层螺旋CT检查斜疝、直疝、股疝的类型，多层螺旋CT诊断与手术结果对比，多层螺旋CT检查的诊断效能，多层螺旋CT横断位、冠状位及矢状位的诊断符合率，多层螺旋CT检查腹股沟疝的影像学征象。 结果102例患者中单纯性斜疝70例，单纯性直疝20例，单纯性股疝5例，左侧复发性腹股沟直疝2例，右侧嵌顿性腹股沟股疝5例。CT诊断与手术结果相符的斜疝占64.71%（66/102），直疝占16.67%（17/102），股疝占6.86%（7/102）。多层螺旋CT诊断斜疝的特异度、灵敏度、阳性预测值分别为8.33%、91.67%、91.67%；直疝的特异度、灵敏度、阳性预测值分别为15.00%、85.00%、85.00%；股疝的特异度、灵敏度、阳性预测值分别为30.00%、70.00%、70.00%。多层螺旋CT冠状位的诊断符合率为99.02%，稍高于矢状位的98.04%（P>0.05）；冠状位的诊断符合率为99.02%，明显高于横断位的75.49%（P<0.05）；矢状位的诊断符合率为98.04%，明显高于横断位的75.49%（P<0.05）。102例患者共有疝囊105个，斜疝患者有72个疝囊，直疝患者有23个疝囊，股疝患者有10个疝囊。93.06%（67/72）的斜疝疝囊的腹股沟管内环扩大，直疝及股疝疝囊的腹股沟管内环均正常；斜疝及直疝疝囊均无股三角填塞，股疝疝囊均股三角填塞；斜疝及股疝疝囊均无侧新月征，82.61%（19/23）的直疝疝囊具有侧新月征；斜疝及直疝疝囊位于腹股沟韧带的前方，股疝疝囊均位于腹股沟韧带的后方；90.28%（65/72）的斜疝疝囊壁位于腹壁下动脉的外侧，直疝疝囊壁位于腹壁下动脉的内侧，股疝疝囊壁位于腹壁下动脉的后下方。 结论多层螺旋CT检查有助于腹股沟疝的诊断，与临床对腹股沟区解剖结构的了解相结合，对腹股沟直疝、斜疝及股疝的分型具有重要价值。     

近端胃切除人工三角瓣成形抗反流术的力学机理仿真分析

目的:对食管胃结合部腺癌近端胃切除术（PG）人工三角瓣成形后残胃食糜进行流体动力学数值模拟，并计算不同性质胃内食糜的流动特征。方法:构建常规PG和人工三角瓣成形术术后胃仿真模型，运用Fluent软件对不同粘度胃内食糜反流问题进行数值模拟。结果:站立位姿态时，相对常规PG方案，人工三角瓣成形手术方案表现出较好的抗反流作用；卧位姿态时，当胃内食糜粘度大于0.145 2 Pa[?s，且胃内食糜不超过人工三角瓣情况下，人工三角瓣成形抗反流手术表现出较好的抗反流效果；人工三角瓣抗反流成形手术方案数值模拟结果与临床上患者表现一致。结论:本研究仿真分析为人工三角瓣成形抗反流手术方案的有效性机理分析、临床患者术后饮食及手术方案的进一步改进提供理论及数值依据。 【关键词】食管胃结合部腺癌；抗反流；人工三角瓣；计算流体力学     

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.     

基于现代文献的放血疗法疾病谱研究

目的归纳放血疗法近10年的临床研究文献,总结放血疗法疾病谱。方法计算机检索中国知网(CNKI)、维普数据库(VIP)、万方数据库(WANFANG DATA)、PubMed、Cochrane library中有关放血疗法的临床研究文献,各数据库检索时间从2009年1月1日起至2019年2月28日。经阅读筛选后记录每篇文献的病症名,统计各病种文献量,并对各病症系统进行分类总结。结果共纳入文献4288篇,涉及疾病349种,分布于17个系统,其中文献最多的前10种疾病依次是带状疱疹(394)、痤疮(321)、脑血管病(包括出血性、缺血性及其并发症和后遗症,247)、周围性面瘫(218)、痛风性关节炎(183)、带状疱疹后遗神经痛(164)、颈椎病(162)、腰椎间盘突出症(161)、膝骨性关节炎(136)、偏头痛(121)。这些疾病的文献量均≥100,共计2107篇,约占文献总数的49.14%。结论放血疗法的适应症广泛,但优势病种相对集中,主要为神经系统疾病。     

Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Use of Alternative Designs and Data Sources for Pediatric Trials

Abstract

Children are considered a vulnerable group and as such are granted additional protection as research subjects. Research projects using children as research subjects are justifiable if the answer to the scientific question of the study cannot be obtained by enrolling adult subjects (cf. scientific necessity). Thus, there is an ethical obligation to explore innovative analytical strategies that seek balance between the feasibility of conducting a trial and maximizing the utilization of data on efficacy and safety. On this note, there is enthusiasm for implementing some less popular but efficient alternative designs for confirmatory pediatric trials. Within the pediatric extrapolation paradigm, examples of such designs, other than purely based on pharmacokinetic/pharmacodynamic data, are described in this article along with their advantages and disadvantages. This article will also discuss how to incorporate alternative data sources in the analysis of pediatric clinical trials. A discussion of existing approaches and a road-map to their utilization will be provided. Real case examples on the use of the approaches are provided.