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Background and study aims A retrospective epidemiological investigation has demonstrated that alcohol abuse is a major risk factor for esophageal cancer. However, prospective endoscopic screening for early detection in heavy drinkers is not available at present. Patients and methods A prospective study was conducted that included 255 alcoholics (aged 52 +/- 9 years). The patients were consecutively screened using esophagoscopy with iodine staining and targeted biopsy. The study also explored whether there was a relationship between the amount of alcohol intake and the detection rate of esophageal cancer. Results Unstained lesions (larger than 5 mm) were observed on the esophageal wall in 55 patients (21.6%). Ten patients (3.9%) with 13 lesions were found to have esophageal cancer of the superficial type, with no symptoms. Cancer invasion was confined to the epithelium in three patients, to the lamina propria in seven, and to the submucosa in three. There was a direct relationship between substantial alcohol intake and the presence of esophageal cancer. Conclusion Screening esophagoscopy with iodine staining is very advantageous in detecting esophageal cancer at an early stage.

To identify injured cells in the liver of patients with primary biliary cirrhosis (PBC) and to determine the effects of ursodeoxycholic acid (UDCA) on these cells, we examined the cellular expression of heat shock proteins (HSPs) in PBC both before and after treatment with UDCA.Expression of HSP70 and ubiquitin in PBC livers (n=34) was evaluated immunohistochemically as well as by immunoblot analysis, and compared with chronic viral hepatitis type C (n= 9), primary sclerosing cholangitis (n=8), and controls (n=7).Immunoblot analysis demonstrated a marked expression of HSP70 and ubiquitin in PBC. Immunohistochemical staining for both HSP70 and ubiquitin was observed to be strong in biliary epithelial cells (BECs) and moderate in both hepatocytes and arteries in PBC. Cellular labelling rates for HSP70 and ubiquitin of bile ducts in PBC were significantly higher (p0.01) than those in chronic viral hepatitis type C, primary sclerosing cholangitis, or controls. The labelling rates for HSP70 and ubiquitin in bile ducts and in hepatocytes were significantly decreased (p0.01) after treatment with UDCA in PBC.The present data suggest that BECs and hepatocytes significantly express HSPs even in the early stages of PBC, and that UDCA treatment significantly improves their condition. The immunohistochemical evaluation of HSPs is a valid and sensitive means to identify injured cells in PBC.

The clinical significance of circulating vascular endothelial growth factor (VEGF) in patients with various liver diseases was investigated. Twenty-one patients with acute hepatitis (AH), 40 with chronic hepatitis (CH), 34 with cirrhosis (LC), 16 with fulminant hepatitis (FH), 10 with primary biliary cirrhosis (PBC), 12 with autoimmune hepatitis (AIH), and 120 healthy individuals were included. Serum VEGF levels were measured by a chemiluminescence enzyme-linked immunosorbent assay. The mean values of serum VEGF levels in the patients with AH, CH, LC, FH, AIH, PBC, and control were 172.7, 58.0, 44.1, 37.3, 49.7, 74.9, and 65.0 pg/ml, respectively. The patients with AH had a level of serum VEGF significantly higher than that of the control group (P0.001). The serum VEGF levels in survivors of FH were significantly increased, but not in the nonsurvivors in the recovery phase compared with the levels on admission (P0.05). In the LC patients, serum VEGF levels were significantly lower than those of the control group (P0.05). These findings suggest that serum VEGF level may be associated with hepatocyte regeneration grade.

To determine whether the initial response to interferon (IFN) therapy predicts the long-term response, monitoring of HCV RNA level in the early phase of IFN therapy was performed.Sixty-seven patients with chronic hepatitis C virus (HCV) infection were investigated. Patients received 6 MU of human lymphoblastoid IFN daily for 2 weeks and then three times weekly for 22 weeks (total dose; 480 U). These were 34 complete responders (CR) and 33 non-responders (NR). Serum levels of HCV RNA were assayed before therapy and at weeks 1 and 2, using the AMPLICOR HCV Monitor kit.Serum levels of HCV RNA were below the detection limit in 33 (97.1%) of 34 CR compared with 13 (39.4%) of 33 NR at week 1, and in 100% of CR compared with 17 (51.5%) of NR at week 2 (PP0.05). These observations were independent with viral genotypes.A complete response to IFN therapy results primarily from a rapid decrease in the serum levels of HCV RNA and a further decrease to below the detection limit by week 2 of the therapy. In spite of a viral genotype, early monitoring of serum levels of HCV RNA during IFN therapy are predictive of a subsequent long-term response to IFN in patients with chronic HCV infection.

We examined the usefulness of imaging portosystemic collaterals accompanying liver cirrhosis by magnetic resonance angiography (MRA), which facilitates imaging of the vascular system without contrast medium.MRA was performed in 30 patients with liver cirrhosis. Of the 30 patients, percutaneous transhepatic portography (PTP) was performed in 10 patients, and conventional arterial portography (CAP) was performed in 20 patients. The three-dimensional (3D) phase contrast method was used for MRA. Study 1: The ability to image portosystemic collaterals was compared between PTP or CAP and MRA. Study 2: The usefulness of MRA for evaluating the effect of treatment on gastric and esophageal varices was examined.Study 1: In comparing PTP and MRA (n = 10), the left gastric vein (n = 10), splenorenal (gastrorenal) shunt (n = 5), and paraumbilical vein (n = 2) were imaged similarly. However, MRA did not reveal any esophageal varices (n = 10). In comparing CAP and MRA (n = 20), the left gastric vein (n = 17), splenorenal (gastrorenal) shunt (n = 10), and paraumbilical vein (n = 4) were imaged similarly. Whereas CAP revealed esophageal varices (n = 4) in four patients, MRA revealed esophageal varices in only one patient. Study 2: When the effect of treatment for varices was evaluated, MRA 3 wk after embolization therapy for gastric varices (n = 4) confirmed the disappearance of gastrorenal shunt. However, it was impossible to evaluate esophageal varices by MRA.It was possible to image portosystemic collaterals accompanying liver cirrhosis by MRA. MRA was useful as a routine examination. Furthermore, it was useful for evaluating the effect of embolization therapy on gastric varices.

Interferon (IFN) therapy is ineffective in about 20-30% of chronic hepatitis C (CH-C) patients who have low HCV RNA levels. Besides the serum HCV RNA level or HCV genotype, hepatic iron concentrations are thought to be correlated with the subsequent response to IFN therapy. Our objective in the present study was to evaluate serum iron, ferritin, and hepatic iron staining in patients with low HCV RNA levels, as predictive markers for IFN therapy.We evaluated 75 CH-C patients whose serum HCV RNA levels were below 1 million genome equivalent (mEq)/ml as shown by a bDNA assay.There were no significant differences in age, sex, serum aminotransferase levels, or serum iron concentrations between responders and nonresponders. The total iron scores (TIS) were significantly higher in responders (p0.01). The TIS was an independent factor relating to the response to IFN therapy by multivariate analysis (p = 0.0062). The TIS significantly correlated with serum ferritin levels (r = 0.637, p0.001), but not with any other parameter. bi]Among CH-C patients within the limits of low HCV RNA levels, TIS of the liver may be used as a predictive marker for IFN therapy.

The aim of this study was to select prognostic factors from information available on admission in order to list patients for liver transplantation before the onset of hepatic encephalopathy in patients with fatal hepatitis type non-A, non-B. Information regarding patient profile and biochemical data obtained on admission was analyzed by multiple stepwise logistic regression, and independent prognostic factors related to death were selected. Four parameters were selected as independent prognostic factors. Patient age (over 50 years), serum total bilirubin level (over 10 mg/dl), peripheral leukocyte count, and prothrombin time were independently related to death. Positive predictive value, negative predictive value, and predictive accuracy were 0.86, 0.79, and 0.84, respectively. Our model is able to predict a patient's fatal outcome much earlier than other currently used models. It will be helpful for early referral to a transplant center.

To investigate correlations between the interval between blood transfusion and the start of IFN therapy, and IFN efficacy, we studied chronic hepatitis C patients with a history of blood transfusion. The subjects were 122 patients with chronic hepatitis C and a history of blood transfusion at 64 institutions. The patients were treated with high or low-dose IFN. High-dose therapy consisted of intramuscular injection of human lymphoblastoid interferon (HLBI), 6 x 10(6) IU daily for 2 weeks, then 3 times a week for 22 weeks, and low-dose interferon therapy of intramuscular injection of HLBI, 6 x 10(6) IU daily for 2 weeks, then 3 x 10(6) IU 3 times a week for 22 weeks. Normal serum ALT levels for 6 months or more after completing IFN (complete response) were found in 44/122 (36.2%) patients and HCV RNA was no longer detectable after completing IFN therapy in 19/68 (27.9%). Patients in whom the interval between blood transfusion and the start of IFN therapy was less than 20 years had significantly higher rates of HCV RNA-negative complete response than those in whom the interval was 20 years or more (p0.039). When chronic HCV infection is caused by blood transfusion, the efficacy of IFN depends on the duration of chronic HCV infection. Since the duration of HCV infection is a factor in predicting efficacy, early IFN therapy may be more effective.

To determine the incidence of hepatocellular carcinoma among patients with chronic hepatitis C who received interferon (IFN) therapy, 63 patients with chronic hepatitis C who underwent IFN therapy (IFN alpha 2a 9 x 10(6) IU daily for 2 weeks and followed 9 x 10(6) IU three times weekly for 14 weeks) from January to December 1992, were studied. Selection criteria were as follows: within six months before IFN therapy patients were diagnosed with chronic active hepatitis without cirrhosis by hepatic histological examination, and were hepatitis C virus antibody positive. Furthermore, patients had records of follow-up liver function tests (once a month) for more than six months after IFN therapy completion, and of ultrasound scanning (once in three to four months) before and for at least more than six months after the therapy completion. An average period of observation was 2.7 years (0.6 to 3.8 years). Twenty five of 63 patients (39.7%) returned to normal values of serum ALT, whereas 38 of 63 (60.3%) still showed abnormal values at six months after IFN therapy completion. Nine of 63 (14.2%) and 6/63 (9.5%) developed cirrhosis and hepatocellular carcinoma, respectively. All patients who developed cirrhosis and hepatocellular carcinoma were from those (n = 38) that showed abnormal ALT values after therapy completion. The five of six patients that progressed to hepatocellular carcinoma were associated with cirrhosis. No patients who returned to normal ALT values developed hepatocellular carcinoma during the period of observation. These results suggest that IFN therapy is effective to prevent the development of hepatocellular carcinoma.

The aim of this study was to examine effects of two H+/K(+)-ATPase antagonists (omeprazole and lansoprazole) on fasting and postprandial serum gastrin and serum pepsinogens A and C.In 8 healthy volunteers, either 20 mg of omeprazole or 30 mg of lansoprazole once daily for 7 days were administered in a double blind and randomized design. After a two-week period to "wash out" the drug, each treatment was then crossed over. Fasting and postprandial serum gastrin and serum pepsinogens A and C levels were measured at baseline and at the end of the treatment.Omeprazole increased fasting levels of serum gastrin and serum pepsinogen A and C. A similar finding was observed after lansoprazole administration. The test meal increased serum gastrin level but did not serum pepsinogens A and C either before or after omeprazole and lansoprazole administration. In addition, the integrated meal stimulated incremental serum gastrin were not modified after omeprazole and lansoprazole administration.This data suggests that both omeprazole and lansoprazole increase fasting serum gastrin and serum pepsinogen A and C levels, but have no effects on postprandial serum gastrin and pepsinogens levels.

The response to interferon therapy for chronic hepatitis is known to decrease with progression of the hepatic fibrosis. On the other hand, serum hyaluronate reflects hepatic sinusoidal capillarization or liver cirrhosis, and also serum type IV collagen, which is one of the main components of the basement membrane, rises with the progression of hepatic fibrosis. In this study, the relationship between the degree of hepatic fibrosis and the response to interferon-alpha was determined retrospectively in patients with chronic hepatitis C. In addition, whether the measurement of serum hyaluronate and type IV collagen before interferon-alpha therapy was useful for predicting the response to interferon-alpha therapy in chronic hepatitis C was determined.Thirty-seven patients with elevated serum ALT levels for at least 6 months and histologically determined chronic hepatitis were studied. All patients were positive for anti-HCV and negative for hepatitis B surface antigen. Twenty-eight healthy adults with normal blood biochemical data, who were negative for hepatitis B antigen and HCV antibody tests, had limited alcohol intake were used as controls. The test group was given IFN-alpha by intramuscular injection for 14 days, and then were treated 3 times per week for 24 weeks.The extent of hepatic fibrosis, particularly, perisinusoidal fibrosis (P0.01) was significantly greater in nonresponders than in responders. The mean serum hyaluronate and type IV collagen levels were more elevated in nonresponders than in responders, especially, the serum hyaluronate level showed a significant difference (P0.01). Most of the patients having a serum hyaluronate level of more than 100 ng/ml were nonresponders who had chronic active hepatitis with bridging necrosis on liver biopsy. Serum hyaluronate and type IV collagen levels showed significant positive correlation with degree of the portal fibrosis (P0.01), perisinusoidal fibrosis (P0.001) and focal necrosis (P0.01) in histological findings of liver biopsy specimens.These results suggest that serum hyaluronate and type IV collagen levels reflect the extent of the hepatic fibrosis in chronic hepatitis C and also that serum hyaluronate level predicts the response to interferon-alpha therapy in patients with chronic hepatitis C.

The aim of this study was to evaluate cardiovascular responsiveness after isotonic exercise in cirrhotic patients.Included were 11 cirrhotic patients and 10 age-matched normal subjects, who served as controls. Hemodynamic data were obtained on each subject before and after muscle exercise on a treadmill (7 metabolic units). Plasma noradrenaline concentration and plasma renin activity also were determined.In both groups, isotonic exercise increased heart rate and systolic arterial pressure, whereas diastolic arterial pressure was not modified. The increase in heart rate and systolic arterial pressure did not differ significantly between the two groups. Plasma noradrenaline concentration and plasma renin activity also were increased. The changes in plasma noradrenaline concentration and plasma renin activity was higher in cirrhotic patients than in controls (p0.05, p0.05), although the differences were not significant when calculated as a percentage.Cardiovascular responsiveness to isotonic exercise is almost intact in cirrhotic patients. However, supernormal activation of the sympathoadrenergic and renin-angiotensin systems is required to maintain cardiovascular homeostasis in these patients.

We investigated the efficacy of retreatment with interferon in patients with chronic hepatitis C who were non responders to the initial interferon treatment. The results were as follows: 1) The effective rate was very low and 2 of the 16 responded to the 2nd treatment. 2) Serum HCV-RNA levels before retreatment with interferon were compared among the 4 responders and the 13 non responders to interferon and it was significantly lower in the 4 responders. 3) HCV-genotypes may be useful to predict the efficacy of interferon readministration.

To determine the risk of death at an early stage of fulminant viral hepatitis, we created severity indexes drawn from clinical data on the day of development of encephalopathy in 128 patients with fulminant hepatitis B and 103 with fulminant hepatitis non-A, non-B. In fulminant hepatitis B, the risk score was 2.75 x BL + 2.75 x BR + 2.7 x AG + 2.3 x WB + 1.67 x CD + 1.56 x AL - 0.098 x PR - 0.88, where BL is 1 if total bilirubin is higher than 20 mg/dl, BR is 1 if the ratio of total to direct bilirubin exceeds 2.2, AG is 1 if age is above 40 yr, WB is 1 if white blood cell count is less than 4,000 cells/mm3 or more than 18,000 cells/mm3, CD is 1 if a hazardous disease coexists and AL is 1 if ALT is less than 100 times the upper limit of normal (otherwise all are 0), and PR is prothrombin time (percentage of normal value). Using a cutoff score of 0, we found the positive predictive value, negative predictive value and predictive accuracy to be 0.90, 0.86 and 0.89, respectively. Sensitivity and specificity were 0.94 and 0.77, respectively. In fulminant non-A, non-B hepatitis, the risk score was 2.66 x BR + 2.25 x BL + 2.24 x DI + 2.05 x AL +/- 1.38 x AG + 0.00021 x WB - 6.33.(ABSTRACT TRUNCATED AT 250 WORDS)

Four patients with acute viral hepatitis complicated by pure red cell aplasia were clinically evaluated. Two patients with hepatitis type A, one with hepatitis type B, and one with posttransfusion non-A non-B hepatitis had pure red cell aplasia. Only the patient with posttransfusion hepatitis was female, and the mean age of the four patients was 37.8 yr (31-51 yr.) The mean interval from the onset of hepatitis to the appearance of pure red cell aplasia was 30.5 days (27-37 days), and the development of hematopoietic disorders coincided with decreases in transaminase levels. Laboratory findings included peak serum glutamate pyruvate transaminase levels of 1305-3160 KU and decreases in the prothrombin time to about 50% in the two patients with hepatitis type A. Pure red cell aplasia was successfully treated by prednisolone or transfusion in all patients.

Among patients with alcoholic hepatitis, three groups were distinguished by histological findings and clinico-pathological features. The aim of this study was to clarify the role of soluble intercellular adhesion molecule-1 (sICAM-1) and interleukin-8 (IL-8) in the development of severe alcoholic hepatitis. The levels of sICAM-1 and IL-8 were well correlated with the severity of liver injuries. The concentrations of serum IL-8 were significantly correlated with the number of polymorphonuclear leukocytes infiltrating the liver. Serial determination of these two markers revealed that IL-8 may be complementary in assessing the severity and prognosis of alcoholic hepatitis.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, we show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. We also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus.

In the present comparative study, we examined an intra-arterial chemotherapy combined with PJ-203 in 60 patients with liver cancer metastasized from gastrointestinal cancer, using an intra-arterial chemotherapy alone as the control. Sixty patients who had been registered by telephone contact were allocated to groups either treated with the intra-arterial chemotherapy alone or with PJ-203 combined, 30 patients each. Mitomycin C was used as the anticancer drug and given at the dose of 8mg/m2 per time. The dose of PJ-203 was 600 +/- 300 mg as degradable starch microspheres. A significantly higher response rate (CR + PR/complete cases) of 54.5% (p = 0.021) was noted in the PJ-203 combined group, as compared to 20.0% for the control group. The 50% survival duration was 282 and 214 days for the PJ-203 combined group and control group, respectively, with no significant difference being noted between the two groups. Principal adverse reactions such as pain, gastrointestinal symptoms and fever were statistically more frequent (p0.01) in the PJ-203 combined group than in the control group. Among the abnormal laboratory values, the incidence of decreased leukocytes was significantly lower (p = 0.022) in the PJ-203 combined group than in the control group. One of the patients concomitantly treated with PJ-203 died of drug-induced hepatitis, which was probably attributed to mitomycin C. However, overall utility assessment was significantly better (p = 0.002) in the PJ-203 combined group.

In the present multi-center cooperative phase II study, in which 16 institutions participated, PJ-203 and mitomycin C were concomitantly infused into the hepatic artery of patients with metastatic liver cancer and the tumor response and safety of the combined therapy were examined. Of 81 patients treated with PJ-203, 52 patients were complete cases in which bidimensionally measurable lesions could be assessed for anticancer effect in accordance with the Direct Evaluation Criteria of Chemotherapy. The number of treatments given to the complete cases until the assessment of therapeutic effect ranged from 1 to 11 times, with the mean of 3.1 times. The overall response rate was 48.1% (25/52). The response rate for each primary lesion was 68.8% (11/16) for stomach cancer, 40.7% (11/27) for colorectal cancer and 33.3% (3/9) for other types of cancer including the gallbladder. The 25 patients with CR or PR, a 50% decrease in tumor size was confirmed after the treatment ranged from 1 to 5 times, with the treatment periods of 2 to 3 weeks. Adverse reactions were found in 56 (69.1%) out of 81 patients assessed for safety. Relatively frequent symptoms were pain in 49.4% (40/81), nausea and vomiting in 33.3% (27/81), fever in 30.9% (25/81) and anorexia in 6.2% (5/81). Principal abnormal laboratory values included a transient elevation of GOT (26.3%), GPT (22.5%), LDH (12.7%) and Al-p (8.8%). Blockade of blood flow could be observed by angiography when the amount of PJ-203 infused was in the range from 180 to 900 mg as degradable starch microspheres. The blood flow blockade could be observed most frequently at the amount of 600 mg (37.7%). The period attaining over 50% of tumor response in 25 complete cases was 42 days as a median. After the treatment was initiated in 81 patients, 50% survival duration and one-year survival rate averaged 277 days and 35.7%, respectively. The corresponding figures for each primary cancer were 419 days and 51.0% for patients with liver cancer metastasized from colorectal cancer, against 239 days and 11.8% for those with liver cancer metastasized from stomach cancer.

Most hepatocellular carcinomas (HCC) in Japan are found in chronic liver diseases with persistent infection of hepatitis B or C virus. Thus, the high risk group for HCC is evident and most small HCC, less than 2 cm in diameter, are detected by a regular follow-up of every three months using ultrasonography (US) in patients with liver cirrhosis or chronic hepatitis over 40 years of age. Approximately half of localized lesions less than 2 cm in diameter found by US are not HCC. Thus, liver biopsy using fine needles is important to make a definite diagnosis in such small lesions. The most important factor in mass survey for HCC is to select people with risk factors for HCC from the whole population. We selected people for a mass survey using US who have risk factors such as 1) abnormal liver function tests, 2) past history of liver diseases, 3) HBV or HCV carrier, 4) past history of blood transfusion, and 5) excessive drinking. About one percent of the people surveyed showed HCC. The detection rate is excellent. In future, serum tumor markers for HCC such as AFP and PIVKA-II will be useful for diagnosis of small HCC because recent studies indicate that such small HCC also produce such tumor markers in about half of the cases.

Changes in serum HBVDNA and their relationship to the prognosis following interferon (IFN) therapy were examined by the polymerase chain reaction (PCR) in 4 patients with chronic hepatitis B infection undergoing IFN therapy. The disappearance of HBVDNA was confirmed by the PCR methods in 3 out of 4 patients who showed favorable subsequent courses. The remaining patient was positive for HBVDNA despite the disappearance of the HBe antigen. In this patient, the hepatitis recurred, and was accompanied by a persistent hepatic disorder. The PCR assay was also carried out to clarify the involvement of the hepatitis B virus in 12 patients who were positive for the HBe antibody and who showed fluctuating transaminase levels. The PCR method revealed that all 12 patients were positive for HBVDNA. These findings indicate the clinical usefulness of the PCR assay for hepatitis B virus infection.

The expression of LeY antigen (Fuc alpha 1--2Gal beta 1--4 [Fuc alpha--3] GlcNAc beta 1--R), recognized by the monoclonal antibody BM-1, was studied in peripheral blood T-lymphocyte subpopulations in patients with viral hepatitis, and in liver tissue of patients with acute viral hepatitis. The relationship between the expression of LeY antigen on peripheral blood T-lymphocytes and the effects of interferon (IFN) therapy for chronic hepatitis type C were also evaluated. LeY antigen is not markedly expressed in B or T-lymphocytes of healthy individuals. However, it was strongly expressed in CD8 and CD4 T-lymphocytes in patients with viral hepatitis. In the acute phase of acute viral hepatitis, the expression of LeY antigen was more markedly expressed on peripheral CD8 T-lymphocytes than on CD4 T-lymphocytes. In chronic hepatitis type B and type C, it was significantly expressed more often on CD4 T-lymphocytes. In the liver tissues of patients with acute viral hepatitis, LeY antigen was expressed on hepatocytes and infiltrating lymphocytes. IFN therapy for chronic active hepatitis type C proved most effective when LeY antigen was more markedly expressed on the patient's CD4 and CD8 peripheral blood T-lymphocytes before treatment. Further studies are needed to clarify the relationship between the mechanisms of hepatic cell injury and LeY antigen.

We investigated the chronic effects of isosorbide dinitrate on systemic and splanchnic hemodynamics and liver function in 13 patients with liver cirrhosis and portal hypertension. Placebo administration for 4 wk (n = 4) had no significant effects on these parameters. In contrast, oral administration of 40 mg/day of isosorbide dinitrate for 4 wk (n = 9) caused a significant fall in portal pressure (-18%, p less than 0.02), as evaluated by measurements of the hepatic venous pressure gradient with no modification in hepatic blood flow (from 0.72 +/- 0.29 to 0.71 +/- 0.34 L/min, NS), suggesting decreased intrahepatic or collateral vascular resistance. On the other hand, there was no significant correlation between the changes in mean arterial pressure and hepatic venous pressure gradient (r = 0.42). Thus, it seems unlikely that a reduction in portal blood inflow by baroreceptor-mediated reflex splanchnic vasoconstriction contributed to the fall in portal pressure. In addition, this drug had no adverse effects on liver function, as evaluated by measurements of the intrinsic clearance. These results suggest that chronic administration of isosorbide dinitrate could be a potentially useful and associated with cirrhosis.

To investigate the infectious situation and causes of hepatitis C virus (HCV) in patients with alcoholism, C100-3 antibody (C100-3) and HCV antibody of the 2nd generation (HCV-2nd) were examined on admission, and the factors that affected the infection of HCV were studied in 226 alcoholics. The positive rate of anti-HCV was as high as 16.4% by C100-3 and much higher by HCV-2nd as 33.2%. The incidence of cases with the history for blood transfusion, drug addict and/or tattoos in alcoholics was as high as 39.4% (89/226). To clarify the influence of the background such as blood transfusion, drug addict and/or tattoos on HCV infection, the positive rate of anti-HCV was compared between those with the background and without the background. In alcoholics without the backgrounds, the positive rate of C100-3 and HCV-2nd were significantly (p less than 0.001) higher than patients without the backgrounds, namely 27.0% vs 9.5%, 56.2% vs 18.2%, respectively. In alcoholics without the backgrounds, the positive rate of anti-HCV became higher in proportion as the age of the patients grows older from 20 to 60 years. These results suggest that a high incidence of HCV infection in alcoholics may resulted from increased the backgrounds that can provide chances of HCV infection and that in those without the backgrounds, alcohol and aging may lead the tolerance to HCV infection.

The localization of substance P (SP) and vasoactive intestinal peptide (VIP) in 12 normal human liver tissues was examined by light and electron immunohistochemistry using immunoperoxidase methods. SP and VIP immunoreactive nerve fibers were observed around portal veins, bile ducts, and hepatic arteries in portal areas, along sinusoids and hepatocytes in hepatic lobules, and around central veins. More SP and VIP immunoreactive nerve fibers were present in the portal areas than in other regions. Moreover, SP and VIP containing nerve endings were localized close to myofibroblasts, Ito cells, fibroblasts and endothelial cells of blood vessels, and sinusoids. The results suggested that part of the innervation of the human liver may be related to the contraction and relaxation of the cells close to nerve endings, and to the regulation of hemodynamic processes by the neurotransmitters such as SP and VIP at the hepatic lobular level.

We developed a new assay method for the evaluation of Le(Y) antigen expression on human peripheral T-lymphocytes using the monoclonal antibodies BM-1, CD4 and CD8 by two-color flow cytometry. Le(Y) antigen expressed on human peripheral T-lymphocytes was stained with fluorescein isothiocyanate (FITC)-labelled BM-1 (anti Le(Y) monoclonal antibody). Le(Y) positive cells were simultaneously stained with phycoerythrin (PE)-labelled CD4 or CD8, then analyzed by flow-cytometer. Coefficients of variations in this double staining assays were 4.2% for BM-1 in CD4 and 5.3% for BM-1 in CD8, respectively. In 124 healthy volunteers 0.2-13.1% of CD4 and 2.5-12.5% of CD8 positive cells were BM-1 positive. Lymphocytes from 200 patients with acute or chronic viral hepatitis showed marked increase in BM-1 expression of CD8 positive cells during the acute phase and exacerbation of the disease. Moreover, BM-1 expression of CD4 cells was positively related with the course of the chronic hepatitis and the prognosis of each patients. Therefore, this new assay using BM-1 and CD4, CD8 monoclonal antibodies would reflect progression of viral hepatitis and its related immunological condition.

In 14 cases of hepatocellular carcinoma with capsule, we studied the mechanism of capsule formation by the immunoperoxidase technique using antibodies to types I, III, and IV collagen, antilaminin antibody, and anti-prolyl hydroxylase antibody. Marked round cell infiltration was observed in the noncancerous side of the capsule and around compressed hepatocytes near the capsule. Thin capsules were composed primarily of type III collagen produced by an increased number of fibroblasts, transitional Ito cells, and hepatocytes near the capsule. In thickened capsules, the noncancerous side consisted primarily of type III collagen and the cancerous side of types I and III collagen. Type I as well as type III collagen was produced by fibroblasts, transitional Ito cells, and hepatocytes. The capsule thus formed is suggested to be part of the defense mechanisms against the growth of hepatocellular carcinoma.

Thirty-eight patients with small hepatocellular carcinomas (HCCs), size less than 20 mm, initially detected by ultrasound (US) and histologically confirmed, were examined by magnetic resonance (MR) imaging, computed tomographic (CT) scan, and angiography. MR imaging demonstrated HCC nodules in nine (75.0%) of 12 patients with tumors less than 10 mm in diameter and in 22 (84.6%) of 26 patients with tumors 10-20 mm in diameter. In total, HCC nodules were detected in 31 of 38 patients (81.6%) by MR imaging. On the other hand, HCC lesions were found on CT scan in 14 of 26 patients (53.8%) and in 27 of 35 patients (77.1%) by angiography. With MR imaging, HCC nodules were demonstrated in 21 of 31 patients on both T1 and T2 weighted images, and 13 of 21 patients (61.9%) were shown to have low intensity areas or iso intensity areas on T1 weighted image, whereas the other eight patients (38.1%) were shown to have high intensity areas. All 21 patients were shown to have high intensity areas on T2 weighted image. Among 15 resected cases, four patients had a high intensity area on T1 weighted image, and a significant fatty change was noted in HCC nodules by histological study of the resected specimen. We suggest that MR imaging is a useful diagnostic imaging modality, even in small HCC of less than 20 mm.

Chemotherapy and chemoembolization using implantable infusion pump were performed in fifteen cases of hepatocellular carcinoma (HCC) and one case of cholangioma. The following results were obtained; (1) Complete response (CR) was obtained in two cases (12.5%) and partial response (PR) in three cases (18.8%) with HCC. (2) Tumor thrombus in the portal vein disappeared in two of four cases with HCC. (3) The followup period ranged from 54 to 768 days and administration from one to 33 times. These results suggest that good therapeutic effects and quality of life can be obtained by implantable drug delivery system.

The survival rate was studied in 218 patients with unresectable hepatocellular carcinoma (HCC) in whom arterial chemotherapy was performed by one-shot injection of anticancer agents (one-shot therapy) was studied. Tumor factors and clinical features of 6 out of 218 cases with more than 3-year survival, were also studied. The following results were obtained; (1) One-year survival rate of the cases which were compatible with criteria for one-shot therapy in our department was 35.6%, and the three-year rate was 7.0%. On the other hand, one-year survival rate of the cases not compatible with same was 1.5%. The latter survival rate was worse than that for conservative care. (2) The longest survival time was 6 years and 5 months after one-shot therapy. (3) The tumor progression rate was above 40% in 4 out of 6 cases which survived more than 3 years, and tumor thrombus in the portal vein was noted in 3 cases. Clinical stage was I-II. (4) One-shot therapy was performed repeatedly after initial treatment in these 6 cases. In 3 of the 6 cases, TAE or percutaneous ethanol injection therapy was performed for recurrence or progression of HCC during observation. The results suggest that criteria for one-shot therapy and multidisciplinary treatment during observation are necessary.

A 42-year-old male was admitted to our Hospital. Diagnosis of invasive bladder cancer was made and a total cystectomy was carried out on September 14, 1982. Histological examination showed transitional cell carcinoma, grade II-III, pT2N0M0. After cystectomy, the patient was treated with a combination chemotherapy of cis-platinum, cyclophosphamide, adriamycin and 5-fluorouracil. After 3 years, he noticed an area of reddish and painless rashes around the urethral meatus. A biopsy of the skin lesion showed a nest formation of transitional cell carcinoma with lymphocyte infiltration under the squamous epithelium. A urethrectomy was carried out on January, 28, 1986. A histologic study established the diagnosis of recurrent transitional cell carcinoma. The pathological process seemed to be a result of hematogenous metastasis rather than multicentricity or implantation.

A case of seminal vesicle cyst associated with ipsilateral renal agenesis was experienced recently in our clinic. A 23-year-old male presented with a complaint of right hemiscrotal pain. Right kidney was not visualized by excretory urography. Cystoscopic examination revealed the absence of the right half of trigone and the right posterolateral wall bulging into the bladder, suggestive of an extrinsic mass displacing the bladder wall. Ultrasonography and computerized tomographic scan showed a large cystic mass in the right side of the retrovesical region. Exploratory operation disclosed that the cystic mass was part of the dilated seminal vesicle. Seminal vesiculectomy was done. Many cases of seminal vesicle cyst are associated with a simple or complex malformation of ipsilateral upper urinary tract (renal agenesis, dysplasia, hypoplasia and ectopic ureter). We speculate that most of the benign seminal vesicle cysts are formed as a congenital anomaly due to defective mesonephric duct development which causes concomitant malformations in the upper urinary tract.

We have undertaken extracorporeal shock wave lithotripsy (ESWL) using the second generation lithotripter, Sonolith 2000. Shock waves are generated by an underwater spark gap discharge and stone localization is performed using an ultrasound scanner. A total of 49 treatments were given to 39 patients with upper urinary tract calculi. Twenty one patients (56.8%, 21/37) were completely free of stones and seven patients (18.9%, 7/37) had residual sandy particles on the 42nd day after ESWL. Seven patients (18.9%, 7/37) had residual fragments less 5 mm in diameter and two patients (5.4%, 2/37) had residual fragments exceeding 6 mm in diameter six weeks after ESWL. Two patients were lost to follow-up. There was a strong correlation between the stone free rate and stone size. Almost all stone of more than 25-30 mm in diameter required more than one session. There were no severe complications during and after ESWL.

We report the case of a 31-year-old female with extrahepatic portal vein obstruction. At the age of 16 she had developed hematemesis from esophageal varices. Trans-splenic portography failed to demonstrate the portal trunk, but showed instead well developed collateral circulation. She suffered from repeated hematemesis and ascites despite mesocaval shunt operation and resection of the esophagus for varices. Death resulted from gastrointestinal hemorrhage. Her family history revealed a 30-year-old sister with Takayasu's disease. On autopsy, the portal trunk and the portal vein at the hilus were indistinguishable due to proliferation of hyalinized connective tissue. Cavernous transformation was observed at the hilus. Histologically the presence of the portal trunk and the portal vein was confirmed, but they showed marked sclerosis, and were almost occluded by possible organized thrombus. The cavernous transformation consisted of numerous thin-walled vessels, which were also observed in the medium-sized portal tracts in the liver. The peripheral portal tracts showed no obvious narrowing nor occlusion of the portal vein branches, which are factors usually considered to play an important role in the genesis of portal hypertension in idiopathic portal hypertension. Even though the etiology is not clear, the portal trunk obstruction is concluded to be a significant factor in this case contributing to the development of protracted portal hypertension.

For the last 6 yr, we had 47 cases of spontaneous rupture of hepatocellular carcinoma causing hemorrhage into the peritoneal cavity. Thirty-three cases were treated by supportive care and 14 cases by emergency transcatheter arterial embolization. Fourteen cases underwent emergency transcatheter arterial embolization and abdominal pain developed in 71.4%, shock in 50.0% and bloody ascites in all cases and the hematocrit of bloody ascites ranged between 1.0% and 40%. On hepatic angiogram, the mean tumor extent rate was 47.9% and the extravasation of the contrast material was noted in 35.7%. The mean survival time of 14 cases that underwent emergency transcatheter arterial embolization was 98.5 days and 13.0 days in 33 cases with supportive care. The former was significantly longer than the latter.