Relationship between Meat/Fish Consumption and Biliary Tract Cancer: The Japan Public Health Center-Based Prospective Study.
- 作者列表："Makiuchi T","Sobue T","Kitamura T","Ishihara J","Sawada N","Iwasaki M","Yamaji T","Shimazu T","Tsugane S
BACKGROUND:The effect of meat and fish consumption on cancer risk has been well studied in humans. However, studies related to biliary tract cancer (BTC) are scarce. METHODS:We examined the association between meat and fish consumption and the risk of BTC in a population-based prospective cohort study in Japan. HRs and 95% confidence intervals (CI) were estimated using the Cox proportional hazard model. RESULTS:During 1995 and 1999, 43,177 men and 49,323 women ages 45 to 74 years were enrolled and followed up for 607,757.0 person-years (men) and 728,820.3 person-years (women) until 2012, during which time 217 male and 162 female BTC cases were identified. Higher total meat consumption was significantly associated with a decreased BTC risk in men (HR for the highest vs. lowest quartiles = 0.66; 95% CI, 0.44-0.98; Ptrend = 0.011) but not in women. Similar association was observed with red meat, but no association was observed with poultry. Fish was not associated with BTC risk. We further analyzed each BTC subtype to confirm the observed association with BTC. However, significant association with each BTC subtype was not observed, although a trend of decreased extrahepatic bile duct cancer risk was observed. CONCLUSIONS:BTC risk was lower among men who consumed more meat, particularly red meat, in Japan. IMPACT:This is the first prospective study that evaluated the relationship between meat and BTC. This may provide important suggestions to elucidate the etiology of BTC.
背景: 肉类和鱼类消费对癌症风险的影响已经在人类中得到很好的研究。然而，与胆道癌 (BTC) 相关的研究很少。 方法: 我们在日本一项基于人群的前瞻性队列研究中检测了肉类和鱼类消费与 BTC 风险之间的相关性。使用 Cox 比例风险模型估计 HRs 和 95% 置信区间 (CI)。 结果: 在 1995 和 1999 期间，43,177 名男性和 49,323 名女性 (年龄 45 至 74 岁) 被纳入并随访了 607,757.0 人年 (男性) 和 728,820.3 人年 (女性) 2012年, 在此期间，确定了 217 例男性和 162 例女性 BTC 病例。较高的总肉类消费量与男性 BTC 风险降低显著相关 (最高与最低四分位数的 HR = 0.66; 95% CI，0.44-0.98; Ptrend = 0.011) 但在女人身上不是。与红肉观察到类似的关联，但与家禽没有观察到关联。Fish 与 BTC 风险无关。我们进一步分析了每个 BTC 亚型，以确认观察到的与 BTC 的关联。然而，未观察到与每个 BTC 亚型的显著相关性，尽管观察到肝外胆管癌风险降低的趋势。 结论: 在日本，摄入更多肉类，特别是红肉的男性 BTC 风险较低。 影响: 这是第一个评估肉类和 BTC 之间关系的前瞻性研究。这可能为阐明 BTC 的病因提供重要建议。
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.