Shingo Kinoyama

Interferon Therapy Reduces the Risk for Hepatocellular Carcinoma: National Surveillance Program of Cirrhotic and Noncirrhotic Patients with Chronic Hepatitis C in Japan

Hepatitis C virus (HCV) infection rarely resolves spontaneously once it becomes chronic (1). Most patients remain asymptomatic for a long period, with liver cirrhosis developing after approximately 30 years (2, 3). Chronic hepatitis C with cirrhosis is a major risk factor for hepatocellular carcinoma (4-7). It has been previously shown that the risk increases with the degree of liver fibrosis (5). Interferon is the only agent known to be effective against HCV infection (8-10). It induces a sustained virologic response in 15% to 30% of patients (11-14). Responders usually show biochemical and histologic improvement (9, 11, 15). Recently, interferon therapy in patients with chronic hepatitis C and cirrhosis was shown to be associated with a reduced incidence of hepatocellular carcinoma (16). Because most patients treated with interferon do not have cirrhosis, we included noncirrhotic as well as cirrhotic patients in our analysis of the effect of interferon therapy on the incidence and prevention of hepatocellular carcinoma. A national surveillance program, the Inhibition of Hepatocarcinogenesis by Interferon Therapy (IHIT) Study, was begun in 1994 as a multicenter, large-scale, retrospective cohort study supported by the Japan Ministry of Health and Welfare as one of the Comprehensive 10-Year Strategy for Cancer Control Projects (17). In this program, patients with chronic hepatitis C who have undergone liver biopsy at one of eight participating institutions are enrolled and followed periodically for development of hepatocellular carcinoma by using several imaging techniques. We analyzed the incidence of hepatocellular carcinoma as of February 1998 by using multivariate proportional hazards regression. Methods Patients The IHIT Study Group approved the design of this study on 21 September 1994. All patients who were positive by a second-generation HCV antibody assay and who had undergone liver biopsy since 1986 at one of the eight participating institutions were enrolled. Patients who were participants in interferon trials for non-A, non-B chronic hepatitis (18-21) and in whom anti-HCV seropositivity was confirmed by using stored sera were also included; these patients had undergone liver biopsy in 1986 or later. Patients were excluded if at the time of liver biopsy they presented with hepatocellular carcinoma or other liver diseases, such as chronic hepatitis B, alcoholic liver disease,autoimmune hepatitis, or primary biliary cirrhosis. The minimum follow-up was established as 1 year for two reasons. First, if hepatocellular carcinoma is detected within 1 year after liver biopsy, the possibility that the cancer was present at the time of liver biopsy cannot be ruled out. Second, interferon therapy must be started within 1year after liver biopsy according to Japanese health insurance rules. By February 1998, 3223 patients who fulfilled the inclusion criteria were registered. Of these patients, 333 were excluded from the analysis: 161 patients (5.0%) transferred to other hospitals without follow-up, and the follow-up period after liver biopsy was less than 1 year for172 patients (5.3%). Thus, 2890 patients were included in the present analysis. Figure 1 shows the schema for patient selection. Figure 1. Schema for patient selection. Interferon therapy was given to 2400 patients; 490patients did not receive treatment (control group). Interferon therapy was initiated within 1 year after liver biopsy (within 6 months in 93% of patients); 84% of patients received interferon-, 14% received interferon-, and 2% received a combination of interferon- and interferon-. The median total dose was 480 MU (first quartile, 324 MU; third quartile, 702 MU), and the median duration of administration was 160 days(first quartile, 94 days; third quartile, 168 days). Once interferon therapy was started, a patient was included in the interferon treatment group even if therapy was discontinued because of adverse events or other reasons. The 490patients who did not receive interferon chose this course of action voluntarily on the basis of concerns about adverse effects; lack of time for therapy; or physician recommendation, which took into account depression, severe diabetes mellitus, or other medical conditions. Serum HCV load was quantitatively determined at the timeof liver biopsy by using various commercial and in-house assays. Because it is difficult to correlate the results of different assay methods, only data obtained with two widely used assays, the branched-DNA probe assay (22) and competitive reverse-transcription polymerase chain reaction (RT-PCR) (23), were used. HCV RNA genotype was determined by RT-PCR using genotype-specific primers (24) or by serologic grouping of serum antibody (25), assuming that genotypes 1a and 1b correspond to serologic group 1 (genotype 1) and genotypes 2a and 2b correspond to serologic group 2 (genotype 2) (11). Histologic Evaluation Liver biopsy specimens were evaluated by a representative pathologist at each institution (a total of eight pathologists were involved) and were scored for the stage of liver fibrosis and grade of inflammatory activity according to the classification of Desmet and colleagues (26). Stage of fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis), and grade of inflammatory activity was scored from grade A1 (mild) to grade A3 (severe). To confirm interobserver concordance in scoring, a subsequent blind and independent examination of 350randomly selected liver biopsy specimens was conducted by two of the eight pathologists. Definition of Interferon Response Virologic and biochemical criteria were used to define response to interferon therapy. Hepatitis C virus RNA was used as a marker of virologic response and was determined by RT-PCR. A virologic sustained response was defined as HCV RNA negativity more than 6 months after termination of interferon therapy; positivity at the same time point was considered a nonsustained response (27). Patients with nonsustained response included those who had temporary disappearance of viremia followed by relapse. In patients treated before the availability of RT-PCR, virologicresponse was determined by using sera stored at 30 C or collected afterward. The serum alanine aminotransferase (ALT) level was used as a marker of biochemical response to interferon therapy. Sustained biochemical response was defined as persistently normal serum ALT levels more than 6 months after termination of interferon therapy; nonsustained response was defined as elevated serum ALT levels at the same time point. Nonsustained response was subdivided into two categories: mildly elevated for a serum ALT level less than two times the upper limit of normal and highly elevated for a serum ALT level two or more times the upper limit of normal. Screening for Hepatocellular Carcinoma Patients were examined for hepatocellular carcinoma by abdominal ultrasonography at least every 6 months. If hepatocellular carcinoma was suspected on the basis of ultrasonographic results, additional procedures, such as computed tomography, magnetic resonance imaging, abdominal angiography, and ultrasonography-guided tumor biopsy, were used to confirm the diagnosis. Statistical Analysis Statistical analysis was performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Interobserver concordance of histologic scoring was evaluated by using the Spearman correlation coefficient. Differences between two groups were evaluated by using the unpaired Student t-test or the Mann-Whitney U-test. Categorical data were compared by using the chi-square test or the Fisher exact probability test. Cumulative incidence curves were determined with the Kaplan-Meier method, and the differences between groups were assessed by using the log-rank test. We used the Cox proportional-hazards regression analysis to examine the effect of interferon therapy on the incidence of hepatocellular carcinoma. Because virologic and biochemical responses were mutually dependent, the risk ratio for hepatocellular carcinoma was calculated separately for these factors. The risk ratio attributable to categorical data, such as stage of liver fibrosis and serum ALT level, was calculated by using dummy variables. A P value less than 0.05 was considered statistically significant. Results Patient Characteristics The demographic and clinical features of patients at the time of their enrollment are summarized in Table 1. The frequency distribution of the stages of liver fibrosis differed between interferon-treated patients and untreated patients. Most laboratory values also differed between the two groups. However, differences in laboratory values between treated patients and untreated patients were not significant at the same stage of fibrosis. This indicated the need to adjust for stage of liver fibrosis, which was done in the following analyses. Table 1. Demographic and Clinical Characteristics Histologic Evaluation The concordance in scores for stage of fibrosis and grade of inflammatory activity determined at each institution and by the two representative pathologists was strong, with Spearman coefficients ranging from 0.897 to 0.918 for stage of fibrosis and from 0.878 to 0.849 for grade of inflammatory activity. The original score was sustained by at least one of the two pathologists in 319 of 350 cases for fibrosis staging and in 320 of 350cases for grading inflammatory activity. Response to Interferon Therapy Response to interferon therapy was determined in 2357(98.2%) of the 2400 interferon-treated patients. Response was not determined in43 patients because of insufficient follow-up (<6 months) after termination of therapy. A sustained virologic response was achieved in 789 patients(33.5%). The response rate was similar regardless of the type of interferon used (32.3%, 34.5%, and 25.6% for interferon-, interferon-, and the combination of the two, respectively). A sustained bioch

Effect of a Moderately Energy-Restricted Diet on Obese Patients With Fatty Liver

The effects of a moderately energy-restricted (25 kcal/kg) diet on liver-function tests, anthropometric measurements, mononuclear-cell phospholipid fatty acid, lymphocyte blastogenesis, and plasma prostaglandin E2 and alpha-tocopherol levels were observed at weeks 0, 8, and 24 in 14 obese patients with fatty liver. Serum aminotransferase levels were improved significantly, with decreases in the body mass index and waist circumference. Decreases in energy intake from carbohydrate and increases in intake of vitamin A, vitamin C, and vegetables were observed at week 24. In mononuclear-cell phospholipids, linoleic acid (18:2omega 6), which was significantly lower in patients than in controls at week 0, was increased at week 24. In contrast, arachidonic acid was decreased. Plasma prostaglandin E2 levels were significantly lower in patients than in controls at week 0 and increased at week 24. The mononuclear-cell response for phytohemagglutinin correlated with 18:2omega 6 in mononuclear-cell phospholipids (r = 0.692, P < 0.01). Improvement of the serum alanine-aminotransferase level correlated with an increase in the plasma alpha-tocopherol level (r = -0.667, P < 0.01) and increases in consumption of vitamin A, omega 3 polyunsaturated fatty acids, and vegetables. These findings suggest that a hypoenergetic diet rich in omega 3 polyunsaturated fatty acids and antioxidants might be beneficial for obese patients with fatty liver.

Laparoscopic Microwave Coagulation for the Treatment of Hepatocellular Carcinoma

Abstract: Laparoscopic microwave coagulation (LMC) has recently been indicated for hepatocellular carcinoma (HCC). LMC was performed in 14 patients with a total of 22 HCCs in the 18‐month period from November 1996 to April 1998. The size of HCCs ranged from 10 mm to 100 mm, with an average diameter of 29.3 mm. The duration of microwave emission ranged from 8 min to 54 min; average 26.4 mm. Sufficient microwave emission was possible even in cases of multiple HCC large HCC, and HCC located deep within the liver, with the aid of laparoscopy and intraperitoneal ultrasound. Recurrence was observed in 4 out of 22 HCCs, and was treated by transcatheter arterial embolization (TAE) or percutaneous ethanol injection (PEI). LMC facilitates local control of HCC, and is a promising new therapeutic modality for HCC. (Dig Endosc 1999; 11: 137–143)

Clinical usefulness of the branched DNA assay version 2 in predicting the efficacy of Interferon treatment in a group of chronic HCV patients based on serotype.

Interferon (IFN) response depends upon pretreatment viral loads and viral genotype/serotype. This study investigated the difference in response to IFN in different viral load groups of 96 chronic hepatitis C patients and compared version 1 (bDNA1.0) and version 2 (bDNA2.0) of the branched DNA assay, according to serotype. On univariate analysis, viral load (P=0.0001, by bDNA 1.0; P=0.0020, by bDNA 2.0,), serotype (P=0.0053) and age (P=0.0073) were significant predictors of IFN response. On multivariate analysis, serotype (odds ratio, 5.44; 95% confidence interval, 1.94-15.24; P<0.01) was a stronger predictor of IFN response than age or viral load (by bDNA2.0). In very high (>6.7 log eq/ml), high (6.0 approximately 6.69 log eq/ml) and low (<6 log eq/ml) viral load groups (by bDNA2.0), complete response was 25, 55 and 92.6% in serotype 2 (sero-2), and 10, 20 and 71.4% in serotype 1 (sero-1), respectively. In sero-2, bDNA2.0 can detect high viral loads underestimated by bDNA1.0. In a low viral load group (by bDNA2.0), IFN response is dependent upon serotype; sero-2 responded better than sero-1. However, in high and very high viral load groups, sensitivities of bDNA1.0 and bDNA2.0 are not effective in clinically distinguishing CR from non-response, and aid in patient selection for IFN therapy.

A scanning electron microscopic study of small pathological lesions of human colonic cancer

Sixty-five small colonic lesions, less than 20 mm in diameter, were studied by scanning electron microscopy (SEM). They appeared protruded or depressed colonoscopically and were excised from 35 patients by strip biopsy. As a result, crypt orifices on the mucosal surfaces of the depressed lesions were less than 10 μm in diameter. In the depressed lesions and in the carcinoma, mucosal epithelial cells and goblet cells were displaced, and partial mucosal destruction existed in the carcinoma.