A fatal case of progressive steatohepatitis, possibly chemotherapy- associated steatohepatitis related to gemcitabine

金沢大学医薬保健研究域医学系We report the case of an 80-year-old female suffering from pancreatic cancer who developed severe non-alcoholic steatohepatitis (NASH) resulting in fatal hepatic failure after anti-cancer chemotherapy with gemcitabine. Hepatic encephalopathy appeared 1 year after the chemotherapy, and the patient developed progressive liver failure and eventually died. Radiological examination showed severe fatty liver. Histopathological examination of a liver needle necropsy showed almost panlobular macrovesicular fatty change. Ballooning degeneration and necrosis of hepatocytes accompanying neutrophil infiltration, Mallory bodies, and a few bile plugs were found in zone 3. Marked perivenular and pericellular/perisinusoidal fibrosis and extensive bridging fibrosis were also found. Together, these findings indicated steatohepatitis at a precirrhotic stage. Because the patient had no history of drinking in excess, we made a diagnosis of NASH, in particular, chemotherapy-associated steatohepatitis (CASH). Gemcitabine is a pyrimidine nucleoside antimetabolite with anti-cancer activity. A few reports have mentioned fatal hepatotoxicity caused by gemcitabine, but, to our knowledge, this is the first report of steatohepatitis, possibly associated with gemcitabine. Physicians treating patients with this drug should be aware of the possibility of steatohepatitis. © Springer 2010

Multistep carcinogenesis of perihilar cholangiocarcinoma arising in the intrahepatic large bile ducts

Flat-type “biliary intraepithelial neoplasia (BilIN)” and papillary-type “intraductal papillary neoplasm of the bile duct (IPN-B)” are proposed as precursors of invasive, perihilar intrahepatic cholangiocarcinoma (ICC). Three carcinogenetic pathways are proposed: BilIN progressing to tubular adenocarcinoma, and IPN-B progressing to tubular adenocarcinoma or to colloid carcinoma. Carcinogenesis via BilIN was characterized by mucin core protein 2-/cytokeratin 20-(MUC2-/CK20-) with MUC1 expression, while carcinogenesis via IPN-B leading to tubular adenocarcinoma was associated with MUC1 expression or that to colloid carcinoma with MUC1-negativity. In both the BilIN and IPNB series, the expression of p21, p53, and cyclin D1 was upregulated with histological progression. Interestingly, p53 expression was upregulated at the invasive stage of BilIN, but was low in noninvasive BilIN, while p53 expression was upregulated in IPN-B1 and reached a plateau in IPN-B2 and invasive ICC. Expression of p16INK4a, which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma. EZH2 expression showed a stepwise increase from BilIN to invasive carcinoma. Membranous expression of β-catenin and E-cadherin was more markedly decreased in ICC with BilIN than in ICC with IPNB. Interestingly, disruption of the membranous distribution of β-catenin and E-cadherin seems to result in the invasion and metastasis of carcinoma cells of BilIN and IPN-B expressing MMP-7 and MT1-MMP. Increased expression of cyclin D1 and c-myc was more frequent in the IPNB lineage than BilIN lineage, possibly related to the Wnt signaling pathway associated with the nuclear accumulation of β-catenin. In conclusion, BilIN and IPN-B progress to invasive ICC through characteristic multistep processes

Donkey milk oligosaccharides influence the growth-related characteristics of intestinal cells and induce G2/M growth arrest via the p38 pathway in HT-29 cells

Donkey milk is considered to be a valuable nutritional source. Deeper knowledge of the constituents of donkey milk is necessary. As multifunctional components of milk, oligosaccharides have been reported to have the potential to support intestine development. We studied the composition and content of donkey milk oligosaccharides (DMOs). Sialylated oligosaccharides were found to be the primary oligosaccharides in DMOs, consisting of 3 '-sialyllactose (SL) and 6 '-SL. The amount of 3 '-SL and 6 '-SL in donkey milk was 18.3 +/- 0.7 mg L-1 and 33.1 +/- 0.7 mg L-1, respectively. Moreover, we found that DMOs induced differentiation, promoted apoptosis and inhibited proliferation in HT-29, Caco-2 and HIEC cells in a concentration-dependent manner, suggesting that DMOs promote maturation of intestinal epithelial cells. The mechanism of the DMOs' effects on HT-29 cells was associated with activation of the p38 pathway and cell cycle arrest at the G2/M phase. Our research will help understand the biological functions of DMOs and assess their potential roles in infant nutrition