Background. The development of hepatocellular carcinoma (HCC) is associated closely with cirrhosis. In the present study, the cumulative risk of HCC in patients with cirrhosis was investigated. Methods. A total of 401 patients were registered from April 1977 and followed for a mean of 4.4 years. Of 401 patients, 255 (64%) were tested for hepatitis B surface antigen (HBsAg) and antibody (anti‐) to the hepatitis C virus (HCV); 87 (34%) patients were positive for HBsAg but were negative for anti‐HCV (hepatitis B virus [HBV] group), 126 (49%) were negative for HBsAg but were positive for anti‐HCV (HCV group), 10 (4%) were positive for both and 32 (13%) were negative for both (non‐B non‐C group) Results. By the end of March 1993, HCC was diagnosed in 127 (31.6%) patients. The cumulative risk of HCC in the HCV group was slightly higher than that in HBV group (P = 0.3, 5‐year risk: 36.9 versus 21.2%). In contrast, the rate was significantly lower in the non‐B non‐C group than in the HBV or HCV groups (P < 0.05 and P < 0.01, respectively, 5 year risk: 12.4%). Conclusions. These results suggest that not only HBV infection but also HCV infection increase the risk for HCC in patients with cirrhosis.

In chronic HBV infection, inheritance of the IL-10 gene promoter polymorphisms is involved in a host genetic factor that is relevant to disease progression.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Since interferon-a (IFN-a) is capable of enhancing TNF-ainduced apoptosis in certain cancer cells, we evaluated the effect of IFN-a on TRAIL-induced apoptosis of human hepatoma cells. IFN-a pretreatment enhanced TRAILinduced apoptosis of HuH-7 and Hep3B cells, in which IFN-a upregulated the expression of DR5, a death receptor of TRAIL, and downregulated the expression of survivin, which has an antiapoptotic function. In contrast, IFN-a did not enhance TRAIL-induced apoptosis of HepG2 cells, in which expression of DR5 and survivin was not affected by IFN-a. On the other hand, TRAIL activated NF-jB composed of RelA-p50 heterodimer, a key transcription factor regulating cell survival, in HuH-7 and HepG2 cells. However, IFN-a pretreatment repressed the TRAIL-mediated activation of NF-jB and decreased its transcriptional activity in HuH-7 but not in HepG2 cells. Moreover, IFN-a pretreatment clearly augmented TRAIL-mediated caspase-8 activation in HuH-7 cells. Our results suggest that IFN-a could sensitize certain human hepatoma cells to TRAIL-induced apoptosis by stimulating its death signaling and by repressing the survival function in these cells.

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Transforming growth factor-␤1 (TGF-␤1) has been shown to induce apoptosis in normal or transformed hepatocytes. To elucidate the biochemical pathways leading to apoptosis induced by TGF-␤1 in human hepatoma cells (HuH-7), we examined the expression of Bcl-2-related proteins and X-chromosome-linked inhibitor of apoptosis (XIAP), and activation of the caspase cascade following TGF-␤1 treatment. Bcl-xL expression began to decline at 12 hours after TGF-␤1 treatment and progressively decreased to very low levels in a time-dependent manner. Bax expression showed a little change throughout the experiment. On the other hand, activation of caspase-8 was clearly observed at 36 hours after TGF-␤1 treatment, followed by activation of caspase-9, and caspase-3 was activated at 48 hours after treatment at which time apoptosis of HuH-

Abstract. The biology of the gray-sided vole Clethrionomys rujocanus in Hokkaido, concerning taxonomy, morphology, phylogeny, distribution, and natural history, is reviewed. Applied issues in forest management (damage, control and census) are also mentioned. Although Clethrionomys rujocanus of Hokkaido was originally identified as a distinct species, Evotomys (=now Clethrionomys) bedjordiae Thomas, 1905, current literature generally refers to the gray-sided vole of Hokkaido as Clethrionomys rujocanus or as C. rujocanus bedjordiae (vernacular name, the Bedford's red-backed vole). The gray-sided vole is the most common small mammal in Hokkaido. It inhabits open areas as well as forests, and mainly feeds on green plants. The gray-sided vole has a high reproductive potential; litter size: 4-7; gestation period: 18-19 days; maturation age: 30-60 days old. Although spring-born individuals usually attain sexual maturity in their summer/fall of birth, their maturation is sometimes suppressed under high densities. The breeding season is generally from April to October, but with some regional variation. Clethrionomys rujocanus has a rather specialized diet (folivorous), particularly during winter when it feeds on bamboo grass. Many predators specialize on the grey-sided vole in Hokkaido; even the red fox, which is a typical generalist predator, selectively feeds on this vole. Damage by voles' eating bark used to be sever on forest plantations in Hokkaido. Censuses of small rodents have been carried out for management purpose since 1954.

It is possible that both NDP kinase and the nm23 gene product may be active in the progression and differentiation of tumor cells and that their reduced expression induces a high metastatic potential in tumor cells. Studies using Northern blotting or in situ hybridization should be planned to confirm our findings.

BACKGROUND Hepatitis B virus (HBV) is closely linked to hepatocellular carcinoma (HCC). The objective of the current study was to identify the factors involved in the prognosis of patients with HBV‐associated HCC using multivariate analysis. METHODS The current study included 74 patients with HBV‐associated HCC who were admitted to Nagasaki University Hospital, Nagasaki, Japan, between 1983–1998. Of these, 13 patients underwent surgical tumor resection; 43 patients received nonsurgical treatment with transcatheter arterial embolization, percutaneous ethanol injection, or both; and 18 patients were followed without any active treatment. The significance of the patient's age; gender; history of blood transfusion; alcohol use; serum levels of alanine aminotransferase, α‐fetoprotein, and HBV‐DNA; number and size of liver tumors; clinical stage; and histologic diagnosis of HCC as prognostic factors was evaluated using univariate and multivariate analyses. RESULTS The 3‐year, 5‐year, and 10‐year postdiagnosis cumulative survival rates were 36%, 21%, and 17%, respectively. Multivariate analysis identified the level of serum HBV‐DNA and tumor size at diagnosis as independent and significant prognostic factors (P = 0.0022 and P = 0.0106, respectively). In addition, a low level of viremia was found to be associated with longer survival (P = 0.0057) even in patients who were negative for the hepatitis B e antigen. CONCLUSIONS The results of the current study suggest that viral load is a useful prognostic marker for HBV‐related HCC and that HCC patients with a less favorable course appear either to clear the virus poorly or to have a greater level of virus production. Cancer 2002;94:2663–8. © 2002 American Cancer Society. DOI 10.1002/cncr.10557