Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet 1 control water (CW group); (2) MCD diet 1 hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nickend labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912-921)

Inhibitory effects of naturally occurring antioxidants on the initiation stage of hepatocarcinogenesis were studied. Group 1 rats were given a diet containing β‐carotene (β8‐CT, 0.02%), α‐tocopherol (α‐TP, 1.5%), glutathione (GLT, 5%), vanillin (VNL, 1%), quercetin (QCT, 1%) or ellagic acid (ELA, 1%), or 3 doses of diallyl sulfide (DAS, 200 mg/kg, i.g) over an 8‐day period. On day 7, the animals received a single dose of 2‐amino‐3‐methylimidazo[4,5‐f]jumoline (IQ, 100 mg/kg, i.g.), 12 h after two‐thirds partial hepatectomy for initiation and 2 weeks thereafter, were placed on promotion regimen comprising phenobarbital (0.05% in diet) and a single dose of D‐galactosamine (100 mg/kg, i.p.). Groups 2 and 3 were treated as described for Group 1, but without test material or IQ, respectively. Survivors were killed at week 11 and antioxidant influence was assessed by comparing values for preneoplastic glutathione S‐transferase placental form‐positive (GST‐P+) foci between Groups 1 and 2. All lesions larger than 70 βm in diameter consisting of approximately 5 cells in cross section were counted. Numbers of GST‐P+ foci/cm2 in Group 1 were: β ‐CT, 7.99; α‐TP, 8.21; GLT, 9.71; DAS, 10.37; VNL, 10.57; QCT, 11.1; ELA, 12.5 (n = 11‐15). All, except ELA, showed a significant decrease as compared with the Group 2 value of 14.54 (n=15). Only β ‐CT showed a significant decrease for the area value. This is the first report to show that β ‐CT, α‐TP, GLT, DAS, VNL, QCT exert inhibitory effects on initiation of hepatocarcinogenesis by the food carcinogen IQ, suggesting that these antioxidants might find application as chemopreventive agents. Furthermore, the current protocol proved practical for the assessment of chemopreventive agents within 11 weeks, a relatively Short period.

BACKGROUND. Pancreaticobiliary maljunction (PBM), an anomalous union of the

Endoscopic pancreatic stenting (EPS) is used for various pancreatic conditions. With the increasing use of pancreatic stents, many complications have been observed. Especially, proximal stent migration presents a more serious condition because of the possibility of pancreatic duct (PD) damage. However, the removal of proximally migrated stents is technically challenging because of the small PD diameter, the bended PD course, the presence of PD strictures, and the lack of suitable devices for stent removal. Thus, few cases of surgical intervention have been encountered. In this study, we review the endoscopic treatment of proximally migrated pancreatic plastic stents. We classify migrated stent conditions into four types according to stent and PD conditions. In Type A, the main pancreatic duct (MPD) has no stricture. In Type B, the stent is positioned across the stricture on the MPD. In Type C, the stent is positioned further away from the stricture on the MPD. The tip of the proximal stent is located in the MPD in types A thru C. In Type D, the tip of the proximal stent is located in a branch duct. We introduced the strategy of endoscopic removal technique of each type of migrated plastic stents.

Background and study aims: Preoperative diagnosis of the pathological grade of intraductal papillary mucinous neoplasms (IPMNs) is difficult. This study aimed to evaluate the accuracy of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) with time???intensity curve analysis in differentiating between low or intermediate grade dysplasia (LGD/IGD) and high grade dysplasia or invasive carcinoma (HGD/invasive carcinoma) in IPMNs and to assess correlation between the time???intensity curve parameters and tumor microvessel density. Patients and methods: Data from 30 patients with resected IPMNs (14 LGD/IGD, 16 HGD/invasive carcinoma) who underwent CH-EUS with time???intensity curve analysis were evaluated retrospectively. Time???intensity curve parameters and the microvessel density of the mural nodule were compared between the HGD/invasive carcinoma and LGD/IGD groups; the diagnostic accuracy of the time???intensity curve parameters was evaluated. Results: The echo intensity change and echo intensity reduction rate of the mural nodule, and the nodule/pancreatic parenchyma contrast ratio were significantly higher in the HGD/invasive carcinoma group than in the LGD/IGD group (P?

Serum and plasma were found to be good materials for detecting cancer-specific DNA in the peripheral blood and the presence of KRAS mutations in blood-derived DNA may be used as a prognostic biomarker for patients with pancreatic cancer.

No abstract

BACKGROUND Pancreaticobiliary maljunction (PBM), an anomalous union of the pancreatic duct with the common bile duct, has frequently been shown to be associated with biliary carcinoma. However, the mechanism of carcinogenesis is unknown. METHODS Mutations of the K‐ras oncogene were examined in cancerous and non‐cancerous biliary tract epithelium of 20 patients with PBM by an extraction of DNA from surgically resected histologic specimens. DNA was analyzed by a polymerase chain reaction single strand conformation polymorphism (PCR‐SSCP) method and direct sequencing. RESULTS An abnormally mobilized DNA band was detected not only in cancerous epithelium but also in hyperplastic, metaplastic, and inflammatory epithelium of the gallbladder and/or common bile duct in patients with PBM. Among the biliary epithelium of patients with PBM, point mutation of K‐ras oncogenes were detected in 4 of 5 (80%) cancerous epithelium, 7 of 12 (58%) hyperplastic and metaplastic epithelium, and 8 of 18 (44%) inflammatory epithelium, whereas no point mutation of the K‐ras oncogene was detected in the gallbladder epithelium in 3 control patients without PBM. Direct sequence analysis of the K‐ras oncogene revealed the mutation at codon 12 substituting the wild‐type glycine (GGT) for aspartic acid (GAT) in all cancerous lesions of patients with PBM. Simultaneous two‐point mutations from the wild‐type glycine (GGC) to arginine (CGC) at codon 13 associated with the mutation at codon 12 were also found in one case of gallbladder carcinoma and one case of bile duct carcinoma. CONCLUSIONS K‐ras gene mutation is involved in the carcinogenesis of biliary tract epithelium in patients with PBM, and appears to be a high risk factor for carcinogenesis of the biliary tract. Cancer 1996;77:1752‐7.