Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini‐infected and N‐nitrosodimethylamine‐treated hamsters

The human liver fluke Opisthorchis viverrini infection and N‐nitrosodimethylamine (NDMA) administration induce cholangiocarcinoma (CCA) and liver injury in hamsters. Melatonin protects against liver injury and reduces the alteration of mitochondrial structure, mitochondrial membrane potential, and mitochondrial pro‐ and anti‐apoptotic pathways in various cancer types. To investigate the chemopreventive effect of melatonin on CCA genesis and liver injury, hamsters were treated with a combination of O. viverrini infection and NDMA concurrently administered with melatonin (10 mg/kg and 50 mg/kg) for 120 days. Melatonin treatment at 50 mg/kg caused a significant reduction in liver/body weight ratios and decreased tumor volumes leading to an increase in the survival of animals. In the tumorous tissues, the high‐dose melatonin reduced DNA fragmentation and mitochondrial apoptosis by inducing anti‐apoptotic protein (Bcl‐2) in the mitochondrial fraction and down‐regulating cytochrome c, pro‐apoptotic protein (Bax), and caspase‐3 in tumor cytosol. Moreover, a high‐dose melatonin treatment significantly increased mitochondrial antioxidant enzymes and prevented mitochondrial ultrastructure changes in the tumor. Overall, melatonin has potent chemopreventive effects in inhibiting CCA genesis and also reduces liver injury in hamster CCA, which, in part, might involve in the suppression of CCA by reducing tumor mitochondria alteration.     

Liver and diabetes. A vicious circle

The complex and bi‐directional relationship linking the liver and diabetes has recently gained intense new interest. This critical review of the published work aims to highlight the most recent basic and clinical data underlying the development of type 2 diabetes, in those with non‐alcoholic fatty liver disease. Moreover, the potentially detrimental effects of type 2 diabetes in liver injury are also discussed in each of the two sections of the present paper. Fatty liver and diabetes share insulin resistance as their chief pathogenic determinant. The roles of the hypothalamus, the intestinal microbiome, white adipose tissue and inflammation are discussed in detail. Molecular insights into hepatocyte insulin resistance as the initiator of systemic insulin resistance are also presented with full coverage of the danger of fatty acids. Lipotoxicity, apoptosis, lipoautophagy, endoplasmic reticular stress response and recent developments in genetics are discussed. Closing the circle, special emphasis is given to biochemical pathways and clinical evidence supporting the role of type 2 diabetes as a risk factor for the development of progressive liver disease, including non‐alcoholic steatohepatitis, cirrhosis and primary liver cancer. In conclusion, data support non‐alcoholic fatty liver disease as a risk factor for the development of type 2 diabetes which is, in turn, a major contributor to progressive liver disease. This pathway leading from fatty liver to type 2 diabetes and back from the latter to the progressive liver disease is a vicious circle.     

512例胆管细胞癌的临床及预后特点

目的： 胆管细胞癌(cholangiocarcinoma，CCA)恶性程度较高，总体预后较差，初诊时分期较晚，治疗手 段有效率欠佳。本研究探索影响CCA发生、发展的临床特点及预后相关因素，以期为CCA的早期诊断及临床治疗提 供潜在的手段。方法： 回顾性分析中南大学湘雅二医院2002 年以来经病理确诊且临床资料完善的512 例CCA患者的 病历资料。利用Kaplan-Meier 法绘制生存曲线、log-rank 进行单因素分析，多元Cox回归法对有意义的变量进行多因 素分析。结果： CCA发病率≤60 岁者高于>60 岁者(61.13% vs 38.87%)，男性略高于女性(52.54% vs 47.46%)，糖类抗 原19-9(carbohydrate antigen 19-9，CA19-9)≥35 μg/L 者占66.21%，病理分期III 和IV 期患者居多(分别占49.22%和 17.58%)。单因素分析发现ALB，ALP，CA19-9 等因素与预后相关，多因素Cox 生存分析发现ALP，CA19-9，肿瘤 最大直径等是CCA预后独立影响因素。结论：CCA发病率≤60 岁人群较高，初诊时分期较晚，CA19-9 是较为敏感的 实验室指标。ALP，CA19-9，肿瘤最大直径，合并子瘤，肝硬化及TNM分期是影响CCA预后的独立因素。     

Multi-Center Analysis of Liver Transplantation for Combined Hepatocellular Carcinoma-Cholangiocarcinoma Liver Tumors

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Major hepatectomy for intrahepatic cholangiocarcinoma or colorectal liver metastases. Are we talking about the same story?

IntroductionMajor hepatectomy (MH) is often needed in the curative management of intrahepatic cholangiocarcinoma (IHCC) and colorectal liver metastases (CRLM). While similar outcomes could be expected after MH for IHCC and CRLM, outcomes seem worse after MH for IHCC. A better understanding of such differences might help improving perioperative outcomes but comprehensive analysis are lacking.MethodsAll patients undergoing curative intent MH for IHCC or CRLM from 2003 to 2009 were included from two dedicated multi-institutional datasets. Preoperative management and short-term outcomes after MH were first compared. Independent predictors of postoperative mortality and morbidity were identified.ResultsAmong 827 patients, 333 and 494 patients underwent MH for IHCC and CRLM, respectively. Preoperative portal vein embolization was more frequently performed in the CRLM group (p < 0.001). MH in the IHCC group required more extended resection (p < 0.001). Postoperative mortality and severe morbidity rates were significantly higher in the IHCC group (7.2% vs. 1.2% and 29.7% vs. 11.1%, p < 0.001, respectively). Main causes for mortality were postoperative liver failure and deep surgical site infection. MH for IHCC was an independent risk factor for mortality (p < 0.001) and severe morbidity (p < 0.001). After propensity score matching (212 patients in each group), the aforementioned differences regarding outcomes remained statistically significant.ConclusionThis study suggests that IHCC patients are inherently more at risk after MH as compared to CRLM patients. Considering that postoperative liver failure was the most frequent cause of death, preoperative planning might have been inadequate in the setting of IHCC while more complex/extended resections should be expected.