PURPOSEBiliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition.PATIENTS AND METHODSThis randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1,000 mg/m2; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples.RESULTSBetween February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo.CONCLUSIONIn unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.
OBJECTIVE:To determine the interobserver variability for complications of pancreatoduodenectomy as defined by the International Study Group for Pancreatic Surgery (ISGPS) and others. BACKGROUND:Good interobserver variability for the definitions of surgical complications is of major importance in comparing surgical outcomes between and within centers. However, data on interobserver variability for pancreatoduodenectomy-specific complications are lacking. METHODS:International cross-sectional multicenter study including 52 raters from 13 high-volume pancreatic centers in 8 countries on 3 continents. Per center, 4 experienced raters scored 30 randomly selected patients after pancreatoduodenectomy. In addition, all raters scored 6 standardized case vignettes. This variability and the "within centers" variability were calculated for 2-fold scoring (no complication/grade A vs grade B/C) and 3-fold scoring (no complication/grade A vs grade B vs grade C) of postoperative pancreatic fistula, postpancreatoduodenectomy hemorrhage, chyle leak, bile leak, and delayed gastric emptying. Interobserver variability is presented with Gwet AC-1 measure for agreement. RESULTS:Overall, 390 patients after pancreatoduodenectomy were included. The overall agreement rate for the standardized cases vignettes for 2-fold scoring was 68% (95% CI: 55%-81%, AC1 score: moderate agreement), and for 3-fold scoring 55% (49%-62%, AC1 score: fair agreement). The mean "within centers" agreement for 2-fold scoring was 84% (80%-87%, AC1 score; substantial agreement). CONCLUSIONS:The interobserver variability for the ISGPS-defined complications of pancreatoduodenectomy was too high even though the "within centers" agreement was acceptable. Since these findings will decrease the quality and validity of clinical studies, ISGPS has started efforts aimed at reducing the interobserver variability.
BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
胰腺癌是高度恶性的消化系统肿瘤,因其发病隐匿,早期诊断困难,手术切除率低,故预后极差[1].近年来,随着对胰腺癌生物学行为认识的不断深入,以及以外科为基础的综合治疗理念与技术的迅速发展,胰腺癌的五年生存率也有一定提升.
目的 分析急性胰腺炎(AP)患者的血小板数目和凝血指标对急性胰腺炎的病情和预后的意义和诊断价值.方法 回顾性分析我院急诊外科2014年1月～2018年1月收治的部分急性胰腺炎患者,按照胰腺炎分级标准(2013版)将符合纳入标准的71例患者分为轻度胰腺炎组,中度胰腺炎组,重度胰腺炎组,比较三组的PLT、PT、APTT和FIB的差异,并绘制ROC曲线来分析PT、APTT和FIB在诊断中重度急性胰腺炎患者的诊断价值.结果 与MAP组比较,MSAP组的PLT、PT、APTT三项指标差异明显(P＜0.05),FIB差异不明显(P＞0.05),无统计学意义.与MSAP和比较,SAP组的PLT、PT、APTT、FIB四项凝血功能指标有显著差异(P＜0.05),ROC曲线分析结果显示PT在诊断中重度急性胰腺炎的灵敏度为0.741,特异度为0.932,AUC为0.907,APTT在诊断中重度急性胰腺炎的灵敏度为0.889,特异度为0.568,AUC为0.827,FIB在诊断中重度急性胰腺炎的灵敏度为0.889,特异度为0.841,AUC为0.946.FIB的曲线下面积最大,且特异度、灵敏度、Youden指数均较高,提示其诊断准确性最好.结论 随着胰腺炎严重程度的增加,胰腺炎患者存在血浆凝血功能紊乱及微循环障碍,检测血浆凝血指标有助于评估AP患者的病情严重度及预后,及早预防和纠正胰腺炎所致凝血功能障碍提供依据.
