Masashi Unoura

Clinical Pilot Study of Intrahepatic Arterial Chemotherapy with Methotrexate, 5-Fluorouracil, Cisplatin and Subcutaneous Interferon-Alpha-2b for Patients with Locally Advanced Hepatocellular Carcinoma

To evaluate the efficacy of methotrexate (MTX)-5-fluorouracil (5-FU), cisplatin (CDDP), and interferon-α-2b(IFNα-2b) combination therapy, we conducted a clinical pilot study in patients with locally advanced hepatocellular carcinoma (HCC). Sixteen patients, who had received no prior treatment for the HCC, with portal tumor thrombosis in the main trunk or in the major branch were enrolled in the study. IFNα-2b (3 × 106 units) was injected subcutaneously 3 times per week. After a bolus administration of MTX (30 mg/m2), CDDP (75 mg/m2) and thereafter 5-FU (750 mg/m2) were given weekly by intrahepatic arterial infusion. In 15 eligible patients, there were 1 complete response (CR) and 6 partial responses (PR) with a response rate of 46.7%. Median survival of the 15 patients was 7 months, and the 2-year survival rate of CR and PR patients was 57.1%. There was severe transient hematologic toxicity. More than grade 2 nausea/vomiting was noted in >50%. In conclusion, the IFNα-2b combination chemotherapy demonstrated good response in patients with locally advanced HCC. This treatment should be tried in a controlled study.

Clinicopathologic study of alcohol-like liver disease in non-alcoholics; non-alcoholic steatohepatitis and fibrosis.

SummaryAlcohol-like liver injury (ALLI) in non-alcoholics has not been elucidated in Japan. The present study attempted to characterize the clinicopathologic features of ALLI in routine liver biopsies. ALLI was found in 1% of 561 biopsy cases obtained from 1988 to May, 1991 at Kanazawa University Hospital. Laboratory data characteristically showed only a mild to moderate degree of dysfunction, and none of the cases exhibited jaundice. Hepatic histology showed a mild to moderate degree of perivenular, pericellular and/or portal stellate fibrosis with a varying degree of fatty change and inflammatory cell infiltration. Portal stellate fibrosis with a varying degree of cell infiltration was more severe than the centrilobular or pericellular fibrosis in all cases. Intralobular inflammatory cell infiltration was associated with spotty or single hepatocyte necrosis, but extensive hepatocyte necrosis was not observed. Neutrophil infiltration was absent or minimal, and lymphocytes predominated in all cases. Mallory bodies were rare and were found in a few hepatocytes of only one of the 7 cases. The above histologic findings in ALLI were very similar to those seen in liver disease in Japanese alcoholics, and were somewhat different from ALLI reported in Western countries. In cases in which hepatic fibrosis, characterized by pericellular, perivenular or portal stellate fibrosis dominated without apparent hepatic necrosis and inflammation, the term “non-alcoholic steatofibrosis” is more suitable to depict its liver histology, being very similar to the alcoholic fibrosis frequently seen in Japanese alcoholics.

Epidemiology of genotypes of hepatitis C virus in Japanese patients with type C chronic liver diseases: A multi-institution analysis

Sixteen medical institutions in Japan collaborated in this study of the epidemiology of hepatitis C virus (HCV) genotypes. A total of 4176 patients with type C chronic liver disease, from the four main islands of Japan, were evaluated. Of those evaluated, 2794 had chronic hepatitis, 727 had liver cirrhosis and 655 had hepatocellular carcinoma. The HCV genotype of the patients was determined by an enzyme‐linked immunosorbent assay based on serological genotype 1‐ and 2‐specific recombinant peptides (SG‐1 and SG‐2, respectively) of the NS4 region. The prevalence of SG‐1 and SG‐2 HCV was similar in the four main islands of Japan. SG‐1 HCV predominated in each disease category (69–76%). The percentage of patients with SG‐1 HCV increased by 7%, while that of patients with SG‐2 HCV decreased by 7%, as liver disease progressed in severity from chronic hepatitis to carcinoma (P < 0.001). Patients with either SG‐1 or SG‐2 had a similar mean age and history of blood transfusion. In conclusion, SG‐1 HCV was found to predominate in Japan, and the HCV genotype was found to be related to the stage of hepatitis C disease.

Hemosiderin deposition in portal endothelial cells: A novel hepatic hemosiderosis frequent in chronic viral hepatitis B and C

We have recently noted a hitherto undescribed hepatic hemosiderosis confined to endothelial cells of the portal tract in chronic viral hepatitis. In this study, this lesion was surveyed in 156 liver biopsy specimens from patients with chronic hepatitis C and in 21 liver biopsy specimens from patients with chronic hepatitis B. As controls, we examined 110 liver biopsy specimens from patients with primary biliary cirrhosis (PBC), 36 from patients with alcoholic liver injury, nine from patients with autoimmune hepatitis (AIH), and five from patients with primary hemochromatosis. Hemosiderin deposition was found in the endothelial cells of venous vessels in portal tracts regardless of the presence or degree of hemosiderin deposition in hepatic parenchyma. This phenomenon was observed in 65 of 156 cases (42%) of chronic hepatitis C and in eight of 21 (38%) cases of chronic hepatitis B. In controls, this lesion was frequent in AIH (78%), but infrequent in PBC (8.1%) and alcoholic liver injury (11%). The incidence of this lesion showed significant differences between chronic hepatitis C, B, and AIH, and between PBC and alcoholic liver injury. There was a positive correlation between the progression of disease and the incidence of this feature in chronic viral hepatitis; the incidence was 18.3% and 11.1% in milder chronic hepatitis C and B, respectively, and 61.2% and 58.3%, respectively, in more severe cases. However, this correlation was not evident in either PBC or alcoholic liver injury. This hemosiderin deposition was positively correlated with the degree of piecemeal necrosis in chronic hepatitis C, and to a lesser degree, the positive correlation was shown in chronic hepatitis B. These findings suggest that the progression of chronic hepatitis and the piecemeal necrosis in chronic hepatitis C and B, followed by the release of hepatocellular iron to portal and periportal areas, are directly or indirectly responsible for endothelial hemosiderosis. Further studies focusing on this peculiar phenomenon in relation to choice of therapy and evaluation of chronicity of viral hepatitis are encouraged.

Sequence comparisons for a hepatitis C virus genome RNA isolated from a patient with liver cirrhosis

The nucleotide (nt) sequence was determined for an isolate of hepatitis C virus (HCV) derived from cirrhotic tissue of a patient with hepatocellular carcinoma. The 9408-nt sequence (EMBL Acq. No. X61596) showed homology of 90.7-91.4% on the nt level, as compared to two Japanese isolates from patients with a high titer of serum transaminase, 78.4-78.8% to those obtained in the United States, and 65.0% to that from an asymptomatic Japanese carrier. The phylogenetic tree of the six isolates classified them into three groups.

Anti-HCV, anti-GOR, and autoimmunity

most were not acidaemic as they had compensated by hyperventilation. A few recruits had no base deficit, and thus no metabolic acidosis, yet were alkalaemic with serum pH values up to 76. These individuals thus had a primary respiratory alkalosis, and had hyperventilated, which, by reducing PaC02, could itself have helped to precipitate their collapse. All biochemical fmdings were normal one week later. Most research on acid-base disturbances in heatstroke has been in laboratory animals. Studies in patients with heatstroke have revealed a mixed picture of metabolic acidosis and respiratory alkalosisl-3 as one might expect. This is the first such study in fit young men undertaking the same strenuous exercise-the others

Primary biliary cirrhosis and chronic pancreatitis in a patient with ulcerative colitis.

A 65-year-old Japanese woman had primary biliary cirrhosis (PBC) and chronic pancreatitis associated with ulcerative colitis. The association of PBC and ulcerative colitis may prove to be valid.

Human chorionic gonadotropin in primary liver carcinoma in adults. An immunohistochemical study.

Production of human chorionic gonadotropin (hCG) by extra-gonadal tumours is not a rare phenomenon. In the liver, similar results have been reported in hepatoblastomas. The present study was attempted to survey hCG level in serum and hCG-immunoreactivity in primary liver carcinoma in adults. Although hCG was elevated in serum in 2 (22.2%) of 9 autopsied cases with hepatocellular carcinoma (HCC), the hCG-reactivity of carcinoma cells was found in 2 (2.1%) of 95 HCC cases. Carcinoma cells positive for immunoreactive hCG was found in 2 (15.4%) of 13 cases with cholangiocarcinoma (CC). The patients with hCG-immunoreactivity in carcinoma and/or elevated serum level of hCG failed to reveal distinct clinical and endocrinological disturbance due to excess hCG. The hCG-positive cells were focal within the carcinoma and showed poor histological differentiation in both HCC and CC, and there were no trophoblastic cells. It is suggested that hCG is one of the hormones produced by primary liver carcinoma in adults and can be localised immunohistochemically in a small number of poorly differentiated carcinoma cells.

The Role of Hepatitis C Virus in Hepatocellular Carcinoma in Japan

Increasing numbers of patients with hepatocellular carcinoma (HCC) have been reported in Japan. In this paper, we investigated the role of hepatitis C virus (HCV) in HCC and the reason for the increase, using patients admitted to our university hospital from 1945 to 1992. 99 (73%) of 135 patients with HCC were positive for anti-HCV. Prospective studies demonstrated that 22 of 158 (14%) patients with chronic hepatitis C, and 31 of 70 (44%) cirrhotic patients with anti-HCV developed to HCC during the follow-up period (10.1 +/- 3.3 and 7.3 +/- 3.5 years, respectively). Prolonged survival of cirrhotic patients during past decades would also contribute to the increasing number of HCC cases as well as the number of HCV infections in Japan.

MR imaging in idiopathic portal hypertension

Magnetic resonance imaging was performed in four patients with biopsy proven idiopathic portal hypertension (IPH). The MR images show proximity of medium-sized intrahepatic vessels to each other and to the liver surface in all patients. Small vessels running parallel to the second order branches of the intrahepatic portal vein are commonly seen as collateral pathways of portal flow in IPH and were seen in two patients. These findings were clearly demonstrated on gradient-recalled echo images. Intrahepatic periportal abnormal high intensity was seen in all patients on T2-weighted images and may reflect abnormalities in the portal tracts such as fibrous enlargement and increase in the number of vascular channels. Tiny low-intensity nodules sometimes observed in liver cirrhosis were not seen in any patient. Magnetic resonance was a useful noninvasive method in the differentiation of IPH from liver cirrhosis.