Hiroshi Watanabe

Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C after sustained response to interferon.

BackgroundInterferon (IFN) is expected to prevent the progression of hepatitis C virus infection to cirrhosis and the development of hepatocellular carcinoma (HCC), but there have been several reports of the development of HCC after a sustained response to IFN. Our aim was to elucidate the incidence and clinical features of, and risk factors for, HCC in sustained responders to IFN, taken for the treatment of chronic hepatitis C.MethodsWe designed a retrospective cohort study conducted at 16 major Hospitals. The subjects were a total of 1056 patients showing sustained responses, 29 of whom developed HCC.ResultsThe incidence of HCC per 100 person-years was 0.56 (95% confidence interval, 0.35–0.76) in sustained responders. By the Cox proportional hazard model, we found that older age, higher serum aspartate aminotransferase level, and lower platelet count before IFN therapy were independent risk factors associated with the development of HCC. A risk index of HCC development, based on the coefficients of these risk factors, was used to classify patients into three groups, with low, intermediate, and high risk. The incidence rates of HCC for these three groups were 0.11, 0.44, and 1.98 per 100 person-years, respectively. The median period to the development of HCC was 4.6 years (range, 1.4–9.0 years), and there were no other specific clinical features of the HCC that developed in these patients.ConclusionsThis study suggests that the risk of development of HCC is not completely eliminated in sustained responders to IFN. These findings may be useful in determining a follow-up strategy after a sustained response to IFN.

Immune suppression gene on HLA-Bw54-DR4-DRw53 haplotype controls nonresponsiveness in humans to hepatitis B surface antigen via CD8+ suppressor T cells

The development of antiviral vaccines has been accelerated using monoclonal antibody and/or recombinant DNA techniques, the objective being to prevent grave viral infectious diseases, such as acquired immunodeficiency syndrome (AIDS), adult T-cell leukemia (ATL), and hepatitis B virus (HBV)-associated liver diseases. Certain proportions of individuals in the human population do not have any appreciable immune response to foreign antigens, either in cases of natural exposure or a planned immunization. Here we report that in the nonresponders to HB vaccine, there is an HLA-linked immune suppression gene for hepatitis B surface antigen (Is-HBsAg) controlling the nonresponsiveness to HBsAg through HBsAg-specific suppressor T cells. The Is-HBsAg is in strong linkage disequilibrium with the HLA-Bw54-DR4-DRw53 haplotype.

Lack of association of cytochrome P450 2E1 genetic polymorphisms with the risk of human hepatocellular carcinoma

The iso‐enzyme pattern of cytochrome P450 was shown to be related to the development of chemically induced hepatocellular carcinoma (HCC) in rats, which is accelerated by chronic alcohol ingestion. Our study was designed to investigate the association of cytochrome P450 2E1 (CYP2E1) genetic polymorphisms with the susceptibility to HCC in humans with and without chronic alcohol ingestion. We enrolled 171 male patients (108 Korean and 63 Japanese) with HCC and 31 age‐ and sex‐matched healthy Korean subjects with no evidence of liver disease or cancer in any organ. Genotypes in the 5‐flanking region of the CYP2E1 gene were determined by restriction fragment length polymorphisms using 2 endonucleases: Pst I and Rsa I. Allelic frequencies in the CYP2E1 5‐flanking region in the Korean control population were 83.5% and 16.5% for allele c1 and c2, respectively. The frequencies of genotypes with the c2 allele (c1/c2 and c2/c2) were compared with those of genotypes without c2 (c1/c1) among HCC patients and controls, according to the pattern of alcohol consumption. There was no significant association between HCC risk and genotypes c1/c2 and c2/c2 either in all HCC patients or in HCC patients of different ethnic groups. Habitual drinkers with HCC, especially among Koreans, were more likely to carry genotype c1/c2 and c2/c2 (odds ratio=3.0) than non‐habitual drinkers (odds ratio=1.2); however, the difference was not statistically significant. Even when patients were restricted to those without hepatitis B surface antigen and antibodies against hepatitis C virus but with a history of chronic alcohol ingestion, there was still no increased risk of HCC in those with genotypes c1/c2 and c2/c2. We conclude that there is a lack of association of the polymorphisms of CYP2E1 with the risk of HCC in humans. Int. J. Cancer 71: 737‐740, 1997.

Cholangiocellular carcinoma that produced both granulocyte-colony- stimulating factor and parathyroid hormone-related protein

A 56-year-old man was admitted to our hospital because of consciousness disturbance. Abdominal computed tomography revealed a large low-density tumor in the left lobe of the liver. He presented with marked leukocytosis and hypercalcemia with high levels of serum granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTH-rP). A diagnosis of cholangiocellular carcinoma (CCC) of the liver was confirmed by histological examination of an autopsy specimen. The tumor cells showed positivity for both G-CSF and PTH-rP with immunohistochemical staining. These results suggest that the tumor was producing both G-CSF and PTH-rP. This paraneoplastic G-CSF and PTH-rP production caused by CCC is very rare. Such cases must be followed up carefully, since tumors associated with paraneoplastic syndrome progress rapidly, resulting in a poor prognosis.

Nonalcoholic steatohepatitis associated with psoriasis vulgaris.

A 24-year-old man was admitted to our hospital because of liver dysfunction. He had been diagnosed as having psoriasis vulgaris at 18 years of age. Physical examination demonstrated obesity, general erythema, and hepatomegaly. Laboratory data revealed elevated serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glucose. A histological examination of the liver revealed macrovesicular fatty change and infiltration of inflammatory cells, including lymphocytes and polymorphonuclear cells, within the liver lobules. Pericentral fibrosis and pericellular fibrosis were also recognized. He was diagnosed as having nonalcoholic steatohepatitis (NASH), based on the fact that he had no habit of drinking alcohol, as well as psoriasis vulgaris and diabetes mellitus. We herein report a very rare case of NASH associated with psoriasis vulgaris.

Reduced expression of low-density lipoprotein receptor in hepatocellular carcinoma with paraneoplastic hypercholesterolemia.

Background and Aim:u2002 Hepatocellular carcinoma (HCC) is frequently associated with paraneoplastic hypercholesterolemia. In familial hypercholesterolemia, genetic mutation of the low‐density lipoprotein (LDL) receptor gene has been recognized as being a pathogenesis of the disease. We investigate the expression of a LDL receptor protein and gene abnormalities of a LDL receptor in HCC cells in cases with paraneoplastic hypercholesterolemia.

Hepatic expression of gamma-glutamyltranspeptidase in the human liver of patients with alcoholic liver disease

Background:u2002 Gamma‐glutamyltranspeptidase (GGT) has been recognized as an enzyme that converts glutathione into cysteine, and it is localized predominantly within the liver. Serum GGT is clinically recognized as the most useful marker for diagnosis of alcoholic liver disease (ALD).

Combination therapy of lamivudine and adefovir in Japanese patients with chronic hepatitis B

PurposeThis study aimed to clarify the long-term efficacy of the lamivudine treatment in Japanese patients with chronic hepatitis B either with or without lamivudine resistance or with or without adefovir add-on treatment.MethodsWe followed 110 patients who received lamivudine for more than 12xa0months, including 67 hepatitis B e antigen (HBeAg)-positive and 43 HBeAg-negative patients.ResultsThe median follow-up after the onset of lamivudine was 48 (rangexa0=xa012–86) months. In all the patients with or without lamivudine resistance, the level of alanine aminotransferase (ALT) normalization decreased from 70.0% at 1xa0year to 36.4% at 5xa0years and the loss of serum HBV DNA level decreased from 72.7% at 1xa0year to 31.8% at 5xa0years. Sixty patients (54.6%) developed a lamivudine-resistant mutation, and this occurrence was more frequently observed in those who were HBeAg-positive (Pxa0<xa00.01), those with a low level of ALT (Pxa0<xa00.05), and those with a high level of serum HBV DNA (Pxa0<xa00.01). Thirty-six of 60 patients received adefovir in addition to lamivudine to treat breakthrough hepatitis. A Cox proportional hazards model analysis revealed the level of baseline HBV DNA to be the best predictive factor for the virus recrudescence (risk ratioxa0=xa00.466, 95% confidence interval [CI]: 0.246–0.842, Pxa0=xa00.011) and the breakthrough hepatitis (risk ratioxa0=xa00.444, 95% CI: 0.218–0.879, Pxa0=xa00.019). We carefully monitored the efficacy of this treatment both in patients who received adefovir and in those who did not since the beginning of the lamivudine treatment. The normalization level of ALT was 61.4% at 5xa0years and the loss of serum HBV DNA was 61.4% at 5xa0years since lamivudine was started. A histologic improvement was observed in patients with ALT levels less than two times the upper limit of normal at the time of a second liver biopsy.ConclusionsAlthough the efficacy of lamivudine is limited because of breakthrough hepatitis, adefovir was used as a salvage treatment of patients with lamivudine-resistant chronic hepatitis B. In addition, lamivudine was used for the treatment of Japanese patients with chronic hepatitis B with or without lamivudine resistance, and was found to be useful regarding the long-term virologic and biochemical responses.

Clinical features of hepatocellular carcinoma that occur after sustained virological response to interferon for chronic hepatitis C

Background and Aim:u2002 This study investigated the clinical features of hepatocellular carcinoma in patients with sustained virological response to interferon for hepatitis C viral (HCV) infection.

Selective killing of carcinoembryonic-antigen (CEA)-producing cells in vitro by the immunoconjugate cytorhodin-S and CEA-reactive cytorhodin-S antibody CA208.

SummaryCytorhodin-S, an anthracycline derivative, was covalently coupled to a monoclonal antibody (mAb) CA208, against carcinoembryonic antigen (CEA) in order to achieve selective killing of a CEA-producing colon carcinoma cell line, COLO 205. The conjugate (15 molecules of drugs/antibody) retained substantial antibody activity as well as drug activity as assessed by enzyme-linked immunosorbent assay and 24-h L1210 proliferation assay, respectively. Furthermore, the conjugate inhibited the growth of COLO 205 cells in a short-term cytostatic assay. This cytostatic effect of the immunoconjugate on COLO 205 cells was inhibited in a dose-dependent manner by pretreatment of the cells with unconjugated CA208 mAb. In addition, chloroquine, a lysosomotropic agent, inhibited the cytostatic effect of the immunoconjugate, indicating the involvement of lysosomal enzymes in releasing drugs from the immunoconjugate. The antibody (CA208) was significantly incorporated into the cytoplasm of COLO 205 cells as demonstrated by immuno-electron microscopy. These in vitro results indicate that cytorhodin-S may be a good partner in immunoconjugates. However, in vivo animal experiments with the immunoconjugate revealed that the immunoconjugate was not so effective in prolonging survival. Thus, in vivo efficacy of this immunoconjugate remains to be further improved in application to cancer immunotherapy.