Prediction Efficacy for Clinical Outcome of Prognostic Nutritional Index in Patients with Resectable Biliary Tract Cancer Depends on Sex and Obstructive Jaundice Status
- 作者列表："Wang, Jie","Bo, Xiaobo","Li, Min","Nan, Lingxi","Wang, Changcheng","Gao, Zhihui","Suo, Tao","Ni, Xiaoling","Liu, Han","Han, Jun","Lu, Pinxiang","Liu, Houbao","Wang, Yueqi
Background The Prognostic Nutritional Index (PNI), a marker of nutritional status and systemic inflammation, is a proven prognostic biomarker in some cancers. The predictive value of PNI in biliary tract cancer (BTC) has not been established. Objective The aim of this study was to determine the relationship between the PNI and outcomes of resectable BTC. Methods In total, 430 patients with stage I–III resectable BTC [gallbladder cancer (GBC), n = 212; cholangiocarcinoma (CHO), n = 218] who had attended Fudan University Zhongshan Hospital were enrolled. The relationship between the PNI and clinical outcomes was evaluated both in the whole cohort and in selected subgroups. Results Eligible patients were classified into PNI-low (PNI < 45) and PNI-high (PNI ≥ 45) groups. The PNI-low group had significantly worse overall survival (OS) in both the whole cohort ( p = 0.002) and in the GBC subgroup ( p = 0.001), but had similar OS as the PNI-high group in the CHO subgroup ( p = 0.328). Multivariate analysis revealed that low PNI is an independent risk factor for worse survival in GBC (hazard ratio 1.623, 95% confidence interval 1.063–2.480, p = 0.026). PNI was found to predict clinical outcome in women ( p < 0.001) and patients without obstructive jaundice ( p = 0.017) with GBC, but was not a prognostic factor in any subgroup with CHO. The estimated area under the time-dependent receiver operating characteristic curve was significantly greater when TNM stage was combined with PNI in women with GBC. Conclusions PNI is an independent predictor of OS in GBC, but not in CHO. It has no prognostic value in men with GBC or patients with obstructive jaundice.
背景预后营养指数 (PNI) 是营养状态和全身炎症的标志物，是一些癌症中已被证实的预后生物标志物。PNI 在胆道癌 (BTC) 中的预测价值尚未确立。目的本研究的目的是确定 PNI 与可切除 BTC 结局之间的关系。方法 430 例 ⅰ-ⅲ 期可切除的 BTC [胆囊癌 (GBC)，n = 212; 胆管癌 (CHO), n = 218] 入选复旦大学附属中山医院。在整个队列和选定的亚组中评价了 PNI 和临床结局之间的关系。结果符合条件的患者分为 PNI-低 (PNI <45) 组和 PNI-高 (PNI ≥ 45) 组。PNI-low 组在整个队列 (p = 0.002) 和 GBC 亚组 (p = 0.001) 中的总生存期 (OS) 均显著较差,但在 CHO 亚组中 OS 与 PNI-high 组相似 (p = 0.328)。多因素分析显示，低 PNI 是 GBC 生存率差的独立危险因素 (风险比 1.623，95% 置信区间 1.063-2.480，p = 0.026)。PNI 可预测女性 (p <0.001) 和无梗阻性黄疸 (p = 0.017) 的 GBC 患者的临床结局,但不是任何 CHO 亚组的预后因素。在 GBC 女性患者中，TNM 分期合并 PNI 时，时间依赖性受试者工作特征曲线下的估计面积显著更大。结论 PNI 是 GBC OS 的独立预测因子，但不是 CHO 的独立预测因子。在男性 GBC 或阻塞性黄疸患者中无预后价值。
METHODS:BACKGROUND & AIMS:Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) exceeds 20% and BTC is currently the leading cause of death in PSC patients. To open new avenues for management, we aimed to delineate novel and clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH & RESULTS:We analysed formalin fixed, paraffin embedded tumor tissue from 186 PSC-BTC patients from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations and copy number variations, along with histomorphological and immunohistochemical characterization. Irrespective of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, e.g. TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g. HER2/ERBB2). We found a high frequency of non-typical/non-ductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%) CONCLUSION: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC show a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.
METHODS:BACKGROUND:The impact of inflammatory bowel disease (IBD) activity on long-term outcomes after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is unknown. We examined the impact of post-LT IBD activity on clinically significant outcomes. METHODS:One hundred twelve patients undergoing LT for PSC from 2 centers were studied for a median of 7 years. Patients were divided into 3 groups according to their IBD activity after LT: no IBD, mild IBD, and moderate to severe IBD. Patients were classified as having moderate to severe IBD if they met at least 1 of 3 criteria: (i) Mayo 2 or 3 colitis or Simple Endoscopic Score-Crohn's Disease ≥7 on endoscopy; (ii) acute flare of IBD necessitating steroid rescue therapy; or (iii) post-LT colectomy for medically refractory IBD. RESULTS:Moderate to severe IBD at any time post-transplant was associated with a higher risk of Clostridium difficile infection (27% vs 8% mild IBD vs 8% no IBD; P = 0.02), colorectal cancer/high-grade dysplasia (21% vs 3% both groups; P = 0.004), post-LT colectomy (33% vs 3% vs 0%) and rPSC (64% vs 18% vs 20%; P < 0.001). Multivariate analysis revealed that moderate to severe IBD increased the risk of both rPSC (relative risk [RR], 8.80; 95% confidence interval [CI], 2.81-27.59; P < 0.001) and colorectal cancer/high-grade dysplasia (RR, 10.45; 95% CI, 3.55-22.74; P < 0.001). CONCLUSIONS:Moderate to severe IBD at any time post-LT is associated with a higher risk of rPSC and colorectal neoplasia compared with mild IBD and no IBD. Patients with no IBD and mild IBD have similar post-LT outcomes. Future prospective studies are needed to determine if more intensive treatment of moderate to severe IBD improves long-term outcomes in patients undergoing LT for PSC.
METHODS::T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant TH17 response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T cell response towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/Ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4+ T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC.