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PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.

Background/aims: The prognosis of icteric type hepatocellular carcinoma is extremely poor, not only because of obstructive jaundice, but also because of difficulties for early diagnosis. The aim of this study is to evaluate characteristics of icteric hepatocellular carcinoma for early diagnosis., Methodology: Eight patients with icteric hepatocellular carcinoma among 326 patients with hepatocellular carcinoma in our hospitals were retrospectively examined by laboratory data, image studies and pathology studies., Results: Most cases were already advanced, with a portal tumor thrombus at the time of diagnosis. Imaging studies fail to reveal tumors because this type of hepatocellular carcinoma has an irregular faint margin and has lost the characteristic pattern of hepatocellular carcinoma, such as capsular formation or early enhancement. Pathology observations demonstrated poorly or moderately differentiated hepatocellular carcinoma in all our cases., Conclusions: This type of hepatocellular carcinoma should be considered in cirrhotic patients with obstructive jaundice or in patients with high tumor marker levels even if image studies fail to reveal tumors. For better prognosis, combination therapies such as biliary drainage, support for portal flow as well as treatment for the hepatocellular carcinoma, are necessary.

Background/aims: Esophageal variceal hemorrhage is the most dreaded complication of liver disease. Prevention or emergency therapy of bleeding is important., Methodology: A group of 217 patients underwent endoscopic esophageal variceal therapy including endoscopic ethanol injection, endoscopic esophageal variceal ligation, or a combination of the two., Results: Esophageal varices were eradicated by endoscopic esophageal variceal ligation with the least sessions required, and associated complications with endoscopic esophageal variceal ligation therapy were lower than with the other two approaches. However, the cumulative recurrence-free period of esophageal varices was significantly higher after endoscopic ethanol injection than after endoscopic esophageal variceal ligation and in some cases F3 varices were observed post-endoscopic esophageal variceal ligation hemorrhage. A combined endoscopic esophageal variceal ligation and endoscopic ethanol injection therapy had no advantage with respect to cumulative recurrence-free rate, session number, or complication frequency, relative to either therapy alone., Conclusions: While the combined observations indicate that endoscopic esophageal variceal ligation is safe and simple, we should consider additional therapy to achieve complete mucosal fibrosis of the esophagus after endoscopic esophageal variceal ligation.

Background/aims: Esophageal variceal hemorrhage is a severe complication of liver cirrhosis, and therapy for acute bleeding and prevention of hemorrhage are important. In this study, we evaluated the long-term cumulative survival rate of patients with esophageal varices after treatment with endoscopic ethanol injection sclerotherapy (EIS group) or pharmacological therapy (non-EIS group)., Methodology: All 110 patients were treated for their esophageal varices and their prognosis and complications were analyzed during the follow-up period., Results: The cumulative survival rate in the primary preventive EIS group was superior to that in the non-EIS group. The preventive EIS group had greater long-term survival rate than those treated on an emergency group. With respect to emergency therapy, the EIS group had better survival rates than the non-EIS group during the two-year follow-up period after esophageal variceal therapy., Conclusions: We conclude that primary preventive EIS is an effective therapy for survival of patients with esophageal varices over a long-term period.

Background/aims: In most cases of drug-induced liver injury, it is difficult to diagnose whether these cases would progress to fulminant hepatic failure. We investigated the characteristics of non-viral and suspiciously drug-induced fulminant hepatic failure by comparing clinical data between cases that progressed and those that did not progress to fulminant hepatic failure., Methodology: Ninety-five cases of suspicious drug-induced liver injury including 22 cases that had been treated at our hospital, and subsequently progressed to fulminant hepatic failure were involved in this study. We investigated the characteristics of drug-induced fulminant hepatic failure by a comparison of non-fulminant and fulminant cases, and simultaneously of survivors and fatal cases in the group of fulminant cases., Results: Many of the clinical variables were significantly deteriorated in fulminant cases. The latent period, which means the duration of drug administration, correlated with the severity of drug-induced liver injury including fulminant hepatic failure. Suspicious cases of drug-induced liver injury where the bilirubin level at the time of definite diagnosis stayed over 13 mg/dL for more than one month were likely to progress to fulminant hepatic failure., Conclusions: Our results suggest that the latent period and the peak level of total bilirubin would be prognostic factors for the severity of drug-induced fulminant hepatic failure. Early preparation of liver transplantation should be recommended by referring these characteristics.

Background: The efficacy of continuous arterial infusion chemotherapies via a subcutaneously implanted port has been reported in unresectable HCC cases. However, the regimens for this therapy are still controversial. Among these regimens, cisplatinum (CDDP) + 5-fluorouracil (5-FU) or epirubicin have been reported to have favorable effects., Patients and Methods: The efficacies of these two regimens are compared with regard to size of tumor, a tumor marker and survival rate in patients with unresectable HCC., Results: Treatments with both the epirubicin (epirubicin group) and the CDDP + 5-FU (CDDP group) demonstrated significant tumoricidal effects as compared with conservative therapies (control group). Furthermore, the tumoricidal effects observed in the CDDP group were superior to that in the epirubicin group, despite a higher incidence of portal tumor thrombus in the CDDP group. Additionally, a longer survival was observed in the CDDP group relative to the epirubicin group., Conclusion: Arterial infusion chemotherapy using CDDP + 5-FU may be the superior regimen for advanced HCC, even with portal tumor thrombus complications.

The incidence of hepatocellular carcinoma (HCC) tends to decrease in sustained responders (SR) to interferon (IFN) therapy for chronic hepatitis C rather than in non-responders (NR). However, some SR develop HCC and their details and prognosis are not well-known, so we investigated such cases. Among 462 patients who underwent IFN therapy and were available for follow-up, 142 patients (30.7%) were SR and six of these (4.2%) developed HCCs. The interval between interferon therapy and diagnosis of HCC was 32-99 months (average 59.2 months). Five of the six cases were single HCCs sized 20-125 mm. The remainder was multiple HCCs. After initial treatment, five patients (83.3%) relapsed and three patients (60%) died due to the HCC. The interval between initial treatment and recurrence was 2-14 months (average 5.8 months). Among the three fatal cases, the interval between initial treatment and their death was 11-66 months (average 29.3 months). Though the prognosis of the one patient who did not relapse after initial treatment was good, the other five patients relapsed and three of them died due to the HCC. These results suggest that the prognosis of sustained responders who develop HCC after IFN therapy is not necessarily good, so close follow-up remains necessary, despite their response to IFN therapy.

Currently, pyogenic liver abscess is not frequent, but it is a severe infectious disease. However a strategy for the effective treatment of liver abscess is not established. We analyzed 75 cases of liver abscess over an eight year period and evaluated their prognosis, any associated underlying disease, or the effect of percutaneous transhepatic abscess drainage (PTAD). For all 75 cases, laboratory data were analyzed and imaging studies were performed. Next, PTAD and antibiotic administration were started on these cases as first choice treatments. These treatments were continued until the laboratory data of the patient were restored to within the normal range. Those cases that were PTAD non-effective or required operation for underlying diseases, underwent operations. Of the total 75 cases, 63 survived after treatment and 12 cases died. Bacteria were detected in 50 cases and Klebsiella pneumoniae was detected in 31 of these 50 cases, but 25 out of 75 cases were negative. The biliary system was the main route of infection. PTAD was effective, especially in cases that were complicated with disseminated intravascular coagulation (DIC) or acute renal failure (ARF). PTAD is an effective treatment for liver abscess, it is especially useful in the restoration of severe general conditions as indicated by this study.

Background/aims: Chronic hepatitis C which exhibits a varied natural course, is becoming a major problem worldwide., Methodology: In this study, we investigated 161 patients with chronic hepatitis C by repeated liver biopsies. From initial biopsies, we diagnosed 56 patients with chronic persistent hepatitis, 74 with chronic active hepatitis 2A, and 31 with chronic active hepatitis 2B., Results: During the follow-up period, a progression from chronic hepatitis to liver cirrhosis was recognized among all stages, however the rate of progression to liver cirrhosis was less in chronic persistent hepatitis than in chronic active hepatitis 2A and chronic active hepatitis 2B. Hepatocellular carcinoma was detected in chronic active hepatitis 2A and chronic active hepatitis 2B at the initial stage, however, no tumors developed in chronic persistent hepatitis at the initial stage. Most hepatocellular carcinomas were concomitant with liver cirrhosis., Conclusions: We suggest a close follow-up of patients with chronic hepatitis C, especially those patients with chronic active hepatitis 2A or 2B and exhibiting successive active inflammation of liver.

Proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor, which mainly associates with adipogenesis, but also appears to facilitate cell differentiation or apoptosis in certain malignant cells. This apoptosis induction by PPARgamma is increased by co-stimulation with tumor necrosis factor (TNF)-alpha-related apoptosis-inducing ligand (TRAIL), a member of the TNF family. In this study, we investigated the effect of PPARgamma on Fas-mediated apoptosis in hepatocellular carcinoma (HCC) cell lines. PPARgamma was expressed on all seven HCC cell lines and located in their nuclei. 15-Deoxy-Delta-12,14-prostaglandin J2 (15d- PGJ2), a PPARgamma ligand, inhibited cellular proliferation in HepG2, SK-Hep1 or HLE cells, unlike pioglitazone, another PPARgamma ligand, which did not have a significant influence on proliferation of these cells. However, 15d-PGJ2 facilitated Fas-mediated HCC apoptosis that could not be induced by Fas alone. These results suggest that PPARgamma can augment TNF-family-induced apoptosis.