Yamamoto, Takatsugu M.D.; Takeuchi, Kazuo M.D.; Nagashima, Natsuko M.D.; Honjo, Hajime M.D.; Sakurai, Norio M.D.; Okuda, Chikao M.D.; Koida, Isao M.D.; Kuyama, Yasushi M.D. Author Information

Four hundred and twenty-one patients with hepatocellular carcinoma who firstly underwent transcatheter arterial chemoembolization were divided into three groups as "younger" (32-69yr-old, n = 340), "elderly" (70-79yr-old, n = 74) and "super-elderly" (80-89yr-old, n = 7). Between "younger" and "elderly," clinical stage of underlying liver disease, stage of hepatocellular carcinoma and tumor necrosis rate at first treatment did not differ significantly. In these two groups, the first year survival rates were 83.2, 79.7%, the third year survival rates were 47.2, 36.5% and the fifth year survival rates were 22.9, 14.5% respectively. Cumulative survival rate of the "elderly" was similar to the "younger". Factors significantly affecting the survival period included advanced clinical stage of underlying liver disease and hepatocellular carcinoma, poor tumor necrosis at the first treatment and high serum alpha-fetoprotein level in the "younger" and high alpha-fetoprotein, advanced stage of hepatocellular carcinoma and presence of other than liver disease in "elderly". Transarterial chemoembolization is useful for the treatment of hepatocellular carcinoma in the "elderly" with the attention for their underlying diseases.

Background: To examine the prevalence of TT virus (TTV)? before and after blood transfusion, we retrospectively examined serum samples obtained from 55 patients who received blood transfusions before, during and after resection of hepatocellular carcinoma.Methods: TT virus DNA was extracted from serum samples and detected by nested polymerase chain reaction. Before transfusion, seven (12.7%) were positive for TTV. Patients were transfused whole blood or separated blood components (fresh frozen plasma, platelet and/or red blood cells), the total amount of transfused fresh frozen plasma ranging from 12 to 271 (median 38) units.Results: Seven (14.6%) of the 48 TTV-negative patients became positive for TTV-DNA 1 month after transfusion. Only one of the seven patients, who was already positive for HCV-RNA, exhibited elevation of alanine aminotransferase. Five of the newly infected seven patients become negative for TTV during a 2 year follow up.Conclusions: Our findings suggest that the proportion of patients with TTV was relatively high in this sample, and that the prevalence of TTV transmission by blood components was also relatively high (14.6%). Although TTV persisted for more than 6 months in some patients, infection was not noticeable during the course of chronic liver disease.

OBJECTIVE:Although biochemical and virological responses to corticosteroid withdrawal therapy for chronic hepatitis B have been extensively studied, long term changes in liver histology have not been well documented.METHODS:We retrospectively analyzed 45 paired liver biopsy specimens taken before and after treatment from 40 patients who persistently showed biochemical remission and an absence of HBe antigen (RIA) for up to 20 yr.RESULTS:The grading scores for necroinflammatory and fibrotic activity in the liver specimens decreased significantly after corticosteroid withdrawal therapy. Histological scores graded according to Knodell's components improved significantly in every category after corticosteroid withdrawal therapy. However, inflammatory cell infiltrates remained within the liver for long periods. The disappearance rate of necroinflammation in the periportal, lobular, and portal regions of the liver were 25%, 7.4%, and 7.4%, respectively, at yr 5 after therapy, and were 84.4%, 78.2%, and 58.7%, respectively, at yr 10 after therapy. The cumulative disappearance rate, calculated using the Kaplan-Meier method, was significantly lower for portal inflammation than for periportal necroinflammation.CONCLUSIONS:Our results show that: 1) despite clinical remission of chronic hepatitis B virus infection, long periods are needed for histological resolution of necroinflammation in the liver; and 2) by a Cox proportional hazard analysis of the factors contributing to histopathological disappearance of disease-related inflammation, the degree of fibrosis of liver biopsy specimens from pretherapy patients was the most statistically significant factor (p = 0.049).

Background. Hepatocellular carcinoma often shows a resistance to transcatheter arterial embolization in the course of therapy repetition.

Treatment of hepatitis B virus (HBV) with lamivudine is effective in suppressing virus replication and results in reduced inflammatory activity. However, the emergence of lamivudine-resistant mutant virus, with amino acid substitution in the YMDD motif of DNA polymerase, has been reported. We report the emergence and takeover of YMDD mutant and re-takeover by wild type during and after long-term lamivudine therapy. YMDD mutants were detected in five patients who showed DNA breakthrough (HBV DNA becoming detectable after a period of DNA negativity), which occurred after 9 to 14 months of lamivudine therapy. Four of five mutants had amino acid sequence YIDD, and the remaining mutant had YVDD. Patients with high HBV-DNA titer and/or hepatitis B e antigen tended to develop breakthrough (P = .038). Using a sensitive and specific polymerase chain reaction (PCR)-based method developed in this study, the emergence of YMDD mutants was detected 1 to 4 months before DNA breakthrough, but not detected in any of the pretreatment sera. The mutants were predominant at breakthrough, but were replaced by wild-type virus 3 to 4 months after cessation of therapy in the two patients who discontinued therapy. One of these patients had a relapse of hepatitis. Mutant continued to replicate in the remaining three patients who continued to receive treatment, and relapse occurred in only one of these patients. Our results suggest that the replication of YMDD mutant viruses is less than wild type and is re-overtaken by wild type after cessation of therapy. Re-administration of lamivudine, possibly combined with other antiviral therapy, might be useful in some patients experiencing hepatitis with lamivudine-resistant variants.

In order to elucidate the influence of hepatitis B virus on the hepatocellular carcinogenesis in cirrhotic liver, quantitative analysis of precore region of hepatitis B virus was sequentially carried out. Among 191 patients who were diagnosed with cirrhosis in our hospital between 1974 and 1992 and had received no anti-viral therapy, 52 patients were selected from the following three patient groups: group A, 17 patients with liver cancer development within 5 years after the diagnosis of cirrhosis; group B, 12 patients with cancer development between 5 and 10 years after the diagnosis; and group C, 23 patients without cancer development during the observation period of 10 years or more. In group A, 16 out of 17 patients steadily showed a large amount of precore mutant virus with a high concentration of 104 copy/ml or more throughout the observation period. In group B, precore mutant virus was persistently high in eight of 12 patients. The other four patients showed an increase in mutant virus until the appearance of HCC, from a low concentration of less than 104 copy/ml to a high concentration. Of 23 patients in group C, no mutant virus was detected throughout the 10 year observation period in 11 patients and a complete disappearance of the mutant virus was found during the observation period in seven patients. Mutant virus was detected at least once in the clinical courses in the five remaining of group C. The amount of precore mutant virus at the endpoint of observation was significantly associated with HCC development (28/29 vs. 5/23, P<0.000001). To conclude therefore, appearance or persistence of precore mutant HBV suggested an increased risk of HCC development and its sequential analysis could be very useful in prediction and early detection of small HCC.

Background/Aims/Methods: The aim of this study was to elucidate the rate of development to cirrhosis and the rate of appearance of hepatocellular carcinoma in chronic viral hepatitis and to assess the risk factors for the development of disease in 2215 consecutive patients with viral hepatitis who were prospectively studied for a median observation period of 4.1 years.Results: The rates of development to cirrhosis were 7.6%, 21.7%, and 32.2%, at the 5th, 10th, and 15th year, respectively, The carcinogenesis rates were 3.4%, 10.5%, and 22.4% at the 5th, 10th, and 15th year, respectively The appearance rates of cancer in 645 patients with only hepatitis B surface antigen and in 1500 patients with only anti-hepatitis C virus antibodies were 2.1% and 4.8% at the 5th year, 4.9% and 13.6% at the 10th year, and 18.8% and 26.0% at the 15th year, respectively, The proportional hazard model identified that the amount of alcohol intake (p=0.0002) and the indocyanine green retention rate (p= 0.022) were independently associated with carcinogenesis in hepatitis type B; and stage of hepatitis (p<0.0001), gamma-glutamyl transpeptidase (p=0,0046), history of blood transfusion (p=0.0093), albumin (p=0.012), and amount of alcohol intake (p=0.031) were independently associated with the carcinogenesis rate in hepatitis type C, Although the severity of portal fibrosis was closely correlated with the future disease development and carcinogenesis in chronic hepatitis C, it was not a good predictor in chronic hepatitis B.Conclusion: These epidemiological results suggest that there are some differences in the activity and modes of disease progression and cancer promotion between hepatitis B virus infection and hepatitis C virus infection.

BACKGROUND. To elucidate the influence of long term interferon administration on the rate of occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-related cirrhosis, the authors analyzed 313 consecutive patients with cirrhosis.METHODS. Of the 313 patients, 94 underwent long term intermittent administration of interferon for greater than or equal to 6 months, and the remaining 219 patients received no interferon or other antiviral drug.RESULTS. Cumulative occurrence rates of HCC in the group treated with interferon and the untreated group were 4.5% and 13.3%, respectively, at the end of 3 years; 7.0% and 19.6%, respectively at the end of 5 years; and 17.0% and 30.8%, respectively, at the end of 10 years. The rate of HCC development in the treated group was significantly lower than that of the untreated group (P = 0.0124). The Cox proportional hazard model revealed that interferon treatment was an independent contributing factor in lowering the rate of carcinogenesis (odds ratio = 0.39; P = 0.031) even after correction by significant covariates in multivariate analysis. The virologic study showed that the role of interferon therapy from the viewpoint of cancer prevention was much more significant in patients with a HBV DNA concentration of greater than or equal to 10 milliequivalents.CONCLUSIONS. Interferon therapy for patients with HBV-related cirrhosis significantly decreased the HCC rate, especially in patients with a larger amount of serum HBV DNA. If interferon is administered properly for a selected group of patients, an effective strategy of cancer prevention can be achieved, even in patients with cirrhosis. (C) 1998 American Cancer Society.

To assess the biochemical and histological characteristics of hepatitis G virus (HGV) infection, we examined four patients who were infected with HGV only (HGV group), and compared them with 16 patients infected with both HGV and hepatitis C virus (HCV; HGV + HCV group) and 18 patients infected with HCV only (HCV group). Biochemical examination showed a significantly low level of serum alanine aminotransferase (ALT) in the HGV group, and that the gamma-glutamyl transpeptidase (gamma-GTP)/ALT ratio in the same group was significantly higher than in the other two groups. Although all three patient groups had a similar degree of liver fibrosis, both the degree of periportal inflammation and total histological activity index were significantly lower in the HGV group than in the other two groups. Fibrous enlargement of the portal tract without lymphoid infiltration and thin fibrous septa was characteristically observed in the HGV group. No significant difference was found between the HGV + HCV group and HCV group. Our results suggest that biochemical and histological changes in HGV infection are very mild and quite different from those of HCV infection.

ABSTRACTTo elucidate the relationship between angiographic features and histological findings, an immunohistological study of α‐smooth muscle actin was performed in 106 patients with small hepatocellular carcinoma. Arterial dominance or portal blood paucity were found in 73 patients (68.9%) on digital subtraction angiography, 88 (83.0%) on computerized tomographic arterial portography and 87 (82.1%) on carbon dioxide‐enhanced ultrasonography. Among 73 patients with hypervascularity on angiography, 57 (78.1%) had thick‐walled, nuclei‐rich and slender‐shaped vessels (type II), eight (11, 0%) had thin‐walled, nuclei‐poor and oval‐shaped vessels (type I) and the remaining eight had a mixed type of II and I. Conversely, among 33 patients without hypervascularity, five (15.2%) had a type II, 21 (63.6%) had a type I, five had a mixed type and two had no positive vessel. Tumour size, histological classification and amount of non‐triadal vessels were also associated with the angiographic appearance of the tumours. Among varied aspects of the cancer including tumour size, tumour multiplicity, microscopic portal invasion, histological classification, amount of α‐smooth muscle actin‐positive vessels and shape of α‐smooth muscle actin‐positive vessels, multivariate logistic regression analysis demonstrated that the shape of α‐smooth muscle actin‐positive vessels was solely associated with angiographic hypervascularity independently (P < 0.0001). Although the existence of non‐triadal vessels characterized hepatocellular carcinoma, angiographic hypervascularity was closely associated with the type II vessel. A morphological change of non‐triadal vessel from type I to type II was considered to occur in an early stage of hepatocellular carcinoma.

Detection of hepatitis C virus (HCV) RNA by a second generation (ver 2) HCV bDNA-probe method (bDNA-probe) was compared with detection by the first generation (ver 1) assay. The two assays were performed simultaneously with the same serum samples of HCV genotypes 1b, 2a, 2b, 3a, and 3b. The positive rates with ver 1 were 82% for HCV genotype 1b (type 1b), 57.6% for HCV genotype 2a (type 2a), 75.0% for HCV genotype 2b (type 2b), 55.6% for HCV genotype 3a (type 3a), and 93.8% for HCV genotype 3b (type 3b). The positive rates with ver 2 were 95.0% for type 1b, 93.9% for type 2a, 83.3% for type 2b, 100% for type 3a, and 93.8% for type 3b. With Fisher's exact test, the detection rate for type 2a was significantly higher (P = 0.001) with ver 2 than with ver 1. We obtained regression lines using the HCV counts measured by bDNA-probe on the y axis and the HCV counts obtained by an HCV reverse transcriptase (RT)-competitive polymerase chain reaction method (competitive PCR) on the x axis. The gradients for types 1b, 2a, and 3b were greater with ver 2 compared to ver 1. The gradients for types 2a and 3b were the highest: for type 2a, y = 0.135x + 0.6 with ver 1 and y = 0.248x + 0.1 with ver 2; for type 3b, y = 0.366x + 0.1 with ver 1 and y = 0.727x + 0.3 for ver 2. In addition, HCV-RNA counts for all the genotypes tested in this study were significantly higher with ver 2 than with ver 1. Hence, we conclude that ver 2 of the bDNA-probe measures HCV-RNA counts closer to those obtained with competitive PCR than the ver 1 assay.

Interferon (IFN) can reduce hepatitis C virus load and even eliminate the virus in 30‐40% of patients. Several predictive factors for eradication of the virus have been reported and a higher dose of IFN tends to result in elimination of the virus. However, a small dose of IFN sometimes is as effective as a large dose in eradicating the virus. The predictive factors for such a response are not well established. We retrospectively analysed 50 patients with chronic hepatitis C who were treated with relatively small amounts of IFN (equal or less than 252 million units). Eleven patients were responders (elimination of hepatitis C virus (HCV) and normalization of alanine amino transferase (ALT) for at least 6 months), but the remaining 39 were non‐responders. Multivariate analysis showed that the pretreatment viral load and total dose of IFN per kilogram of bodyweight were significant predictive factors of response to therapy. We also assessed the amino acid substitutions in the IFN sensitivity determining region (ISDR), NS5A codon 2209‐2248, of HCV in serum samples obtained from 31 patients with HCV genotype 1 b. The presence of more than one amino acid substitution in the ISDR tended to correlate with HCV genotype lb elimination. As IFN is expensive and has a number of serious side effects, our study suggests that the optimal dose of IFN may vary from one patient to another and that more stringent criteria should be used to select the optimal dose for therapy.

The glomerular changes of 188 consecutive autopsy cases with hepatitis C virus (HCV) infection were studied. The glomerular changes were classified as follows: Category I: membranoproliferative glomerulonephritis (MPGN; 21 cases, 11.2%), 2) Category II: membranous nephropathy (MN; 5 cases, 2.7 %), 3) Category III: mesangial proliferative glomerulonephritis (MesGN; 33 cases, 17.6%), 4) Category IV: mesangial thickening type without proliferative mesangial cell (MT; 44 cases, 23.4%), and 5) Category V: almost normal glomeruli (85 cases, 45.2%), Glomerulonephritis was defined as glomeruli with an increase in mesangial matrix or a thickening of the capillary walls in the glomeruli; categories I-IV corresponded to glomerulonephritis in this study. Multivariate analysis, using a multiple logistic model, indicated that glomerulonephritis with HCV infection was the most strongly correlated to the existence of esophagogastric varices, Abnormal urinalysis, that is transient or continuous microhematuria or proteinuria, was observed in only 23 (12.2%) cases. These results showed that in HCV-RNA positive patients with esophagogastric varices the possibility of glomerulonephritis should be considered.

A prospective randomized trial was conducted to evaluate the efficacy of long-term oral administration of low-dose 5'-deoxy-5-fluorouridine (5'-DFUR) as an adjuvant chemotherapy, following transcatheter arterial embolization (TAE) in 40 patients with hepatocellular carcinoma (HCC). Forty eligible patients were randomized into two groups: 20 with TAE plus 5'-DFUR (400 mg/day) and 20 with TAE alone. A good necrosis rate or decrease in size of more than 70% of the original tumor mass was attained in 14 by the TAE plus 5'-DFUR arm, and in 12 by the TAE arm at 3 months after the first TAE. Although all five patients with HCC and 70-99% necrosis rate after the first TAE in the TAE alone arm showed a less than 70% necrosis rate at 12 months, four of the seven patients with a 70-99% necrosis in the TAE plus 5'-DFUR arm retained a necrosis of more than 70% at 12 months after the first TAE. The appearance rate of ascites and/or encephalopathy in patients with chemotherapy was not different from that of patients with TAE alone. One-year survival rates in the TAE plus 5'-DFUR arm and the TAE alone arm were 75.0% and 85.0%, 2-year rates were 64.2% and 66.2%, and 3-year rates were 64.6% and 49.7%, respectively. There was no significant difference in the survival curves. In conclusion, adjuvant therapy with 5'-DFUR was well tolerated without significant side effects, and it might maintain a good necrosis state of HCC after TAE. In order to confirm a beneficial effect of the chemotherapy on the survival period, a study using more patients and longer observation periods will be required.