Akitaka Shibuya

Radiofrequency ablation of hepatocellular carcinoma: correlation between local tumor progression after ablation and ablative margin.

OBJECTIVE To identify the determinants of tumor progression, we examined the ablation zones and patterns of local progression of small single primary hepatocellular carcinomas after radiofrequency ablation. MATERIALS AND METHODS Eighty-five patients with single primary hepatocellular carcinoma less than 3 cm in diameter underwent complete tumor ablation. Clinical and biochemical features, tumor characteristics, tumor location within 5 mm from intrahepatic vessels, needle biopsy before treatment, and presence of ablative margin of 5 mm or more were statistically analyzed as determinants of local tumor progression. The Kaplan-Meier method and a Cox model were used for the analyses. Patterns of local tumor progression were examined by image analysis. RESULTS During a median observation period of 30.3 months, 14 (16.5%) of the 85 patients had local tumor progression. The results of the log-rank test showed that the presence of vessels contiguous with the tumor (p = 0.0292) and the absence of an ablative margin of at least 5 mm (p = 0.019) significantly correlated with local tumor progression. Cox regression analysis showed that the absence of an ablative margin of at least 5 mm was an independent factor (p = 0.04). The most common pattern of local tumor progression was a single viable outgrowth from the side of the ablated area when the ablative margin was less than 5 mm. Multiple viable outgrowths were observed in one case despite the presence of an ablative margin greater than 5 mm. CONCLUSION An ablation zone with an ablative margin of 5 mm or greater was the most important factor for local control of hepatocellular carcinoma.

An Autopsy Case of Troglitazone-Induced Fulminant Hepatitis

OBJECTIVE To study an autopsy case of troglitazone-induced fulminant hepatitis. CASE REPORT A 58-year-old man contracted severe hepatitis 2 months after administration of troglitazone for the treatment of type 2 diabetes. Liver damage progressed gradually, even after withdrawal of the agent. Despite intensive therapy, the hepatitis became fulminant and the patient died 8 weeks after the onset of liver damage. Autopsy revealed massive hepatic necrosis and cholestasis with inflammatory cell infiltration. The pathological findings and the positive result of the drug-induced lymphocyte stimulation test for troglitazone indicated that the liver damage was mediated by hypersensitivity to troglitazone. CONCLUSIONS One report has attributed troglitazone-induced liver damage in less severe cases to idiosyncratic reactions. However, the present case indicates that troglitazone can induce hypersensitivity resulting in fulminant hepatitis. Careful monitoring of serum liver enzymes during troglitazone therapy is therefore essential.

Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study

Primary biliary cirrhosis (PBC) sera contain antibodies which recognize various nuclear envelope proteins of which antibody against gp210 has been proven to be diagnostic for disease. In contrast, the clinical significance of another nuclear envelope antibody, anti-p62 antibody has not been well investigated. In the present study, we have analyzed anti-nuclear envelope antibodies by indirect immunofluorescence and immunoblot using rat liver nuclear envelope proteins and wheat germ agglutinin-bound fraction. Test sera were obtained from 175 patients with PBC and from 120 controls. Anti-gp210, anti-lamina associated polypeptide 2, anti-lamin B receptor, and anti-p62 complex antibodies were detected with a frequency of 26% (46 of 175), 6% (11 of 175), 9% (16 of 175), and 13% (15 of 115), respectively. The confirmation of Scheuers stage IV was made with a frequency of 27% (4 of 15) in PBC patients with anti-p62 complex antibody, in contrast to only 2% (2 of 100) in PBC patients without anti-p62 complex antibody. This difference was found to be statistically significant. The presence of anti-p62 complex antibody may be related with the progressive or advanced state of PBC.

Intrahepatic distant recurrence after radiofrequency ablation for a single small hepatocellular carcinoma: risk factors and patterns.

Background. The pathogenesis of frequent intrahepatic recurrence of hepatocellular carcinoma (HCC) after surgical resection or local ablation therapy remains uncertain. Risks and patterns of intrahepatic distant recurrence (IDR) of a single, primary HCC lesion after radiofrequency (RF) ablation were examined. Methods. Ninety patients with a single primary HCC lesion of less than 3 cm who had complete RF ablation were enrolled in the study. Risk factors for IDR and the patterns of IDR after RF ablation were analyzed. Results. The median follow-up was 37.4 months. IDR was observed in 44 (48.9%) patients. The cumulative rate of IDR was 10.4%, 52.5%, and 77.0% at 1, 3, and 5 years, respectively. Univariate analysis revealed that a pretreatment serum α-fetoprotein (AFP) level of ≥50 ng/ml (P = 0.0324), a des-γ-carboxy prothrombin (DCP) level of ≥40 mAu/ml (P = 0.006), an ablative margin of <5 mm of the ablation zone (P = 0.0306), and a prothrombin time of <70% (P = 0.0188) were related to IDR. A multivariate stepwise Cox proportional hazards regression model revealed that pretreatment serum AFP and DCP level and the ablative margin were independent risk factors for IDR pretreatment. Serum DCP level ≥ 40 mAu/ml (P = 0.025), local tumor progression (P = 0.011), and ablative margin < 5 mm (P = 0.024) were related to multiple IDR. Conclusions. HCC patients with high serum AFP or DCP before RF ablation should be carefully followed up to monitor any IDR. A suffi cient ablative margin in RF ablation for HCC is required to prevent IDR.

Cellular and stromal characteristics in the scirrhous hepatocellular carcinoma: Comparison with hepatocellular carcinomas and intrahepatic cholangiocarcinomas

Scirrhous hepatocellular carcinoma (SHCC) is a rare variation of HCC, for which characteristics of tumor cells and the fibrotic stroma have not been clarified in detail. The present study was therefore carried out to elucidate cytological features of tumor and stromal cells and components of the stromal extracellular matrix in 15 SHCC patients undergoing hepatectomy without preoperative transarterial embolization. Diagnosis was on the basis of a scirrhous histological pattern exceeding 50% of the tumor area. Expression of cytoplasmic and extracellular matrix proteins was compared among SHCC, HCC and intrahepatic cholangiocarcinoma (ICC) cases with immunohistochemical staining. The lesions could be histologically divided into radiating and sinusoidal types. Common stromal components of SHCC and ICC were collagen types I and III. There was no expression of laminin‐5 in the stroma of SHCC, but it was present in almost all ICC cases. Tenascin‐C expression was significantly lower in the SHCC cases and its distribution differed between SHCC and ICC. Matrix metalloproteinase‐7 (MMP‐7) expression was significantly higher in SHCC compared with HCC. Almost all stromal cells were α‐smooth muscle actin‐positive both in SHCC and ICC, whereas glial fibrillary acid protein (GFAP)‐positive stromal cells were significantly more increased in ICC than in SHCC. SHCC clearly differed from HCC with respect to collagen types I, III and MMP‐7 expression, and from ICC with regard to stromal components including laminin‐5, tenascin‐C and GFAP+ stromal cells.

Higher discontinuation and lower survival rates are likely in elderly Japanese patients with advanced hepatocellular carcinoma receiving sorafenib

Aim:  Sorafenib is approved for the treatment of advanced hepatocellular carcinoma (HCC) in Japan; however, its tolerability and efficacy in elderly patients with HCC have not been clarified. We aimed to evaluate the tolerability and efficacy of sorafenib with increasing age.

Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus.

Objective. Although hepatitis B virus (HBV) DNA can be detected in liver or sera of patients without serum hepatitis B surface antigen (HBsAg), its clinical relevance in hepatocarcinogenesis remains controversial. This observational cohort study was conducted to clarify the risk factors, including the presence of serum HBV DNA and hepatitis B core antibody (anti-HBc), for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). Material and methods. The study comprised 123 patients with LC due to HCV, and negative for HBsAg. The risk factors for HCC development were analyzed by univariate and multivariate analysis. Serum samples were assayed for HBV DNA using real-time polymerase chain reaction. Results. Serum HBV DNA was detectable in 14 patients (11.4%) and serum anti-HBc in 96 (78.0%). During the follow-up period (mean 53.3 months), 80 patients (65.0%) developed HCC. The cumulative HCC development rate was significantly higher in the anti-HBc-positive group than in the anti-HBc-negative group (p=0.0039), but did not differ between the serum HBV DNA-positive and -negative groups (p=0.8570). The multivariate analysis indicated that male gender, alpha-fetoprotein (AFP) 20 ng/ml or greater, average serum alanine aminotransferase (ALAT) 80 IU/l or greater and the presence of anti-HBc were independent risk factors for development of HCC (p=0.038, p=0.013, p=0.020 and p=0.001, respectively). Conclusions. Serum anti-HBc, which indicates a previous HBV infection, has clinical significance in hepatocarcinogenesis in patients with HCV-related LC, but serum HBV DNA does not. Therefore, anti-HBc in serum is a significant predictor for HCC.

Occult hepatitis B virus infection as a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C in whom viral eradication fails.

Aim:  Recent studies have suggested that an occult hepatitis B virus (HBV) infection negative for HBsAg but positive for HBV‐DNA contributes to hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Some follow‐up studies have suggested the clinical importance of occult HBV infections in HCC development even after interferon (IFN) therapy, but a recent study denies the significance of the impact of occult HBV infection. Focusing on HCC development in patients in whom hepatitis C virus (HCV) eradication by interferon (IFN) therapy had failed, we conducted this study in order to assess the impact of occult HBV infections on HCC development in these patients.

Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib.

Background To determine the value of early alterations of the tumor markers &agr;-fetoprotein (AFP) and des-&ggr;-carboxy prothrombin (DCP) for predicting the outcomes of patients with advanced hepatocellular carcinoma (HCC) who receive sorafenib. Materials and methods Tumor response, overall survival (OS), and progression-free survival (PFS) were retrospectively analyzed in 59 patients with advanced HCC. Serum AFP and DCP were examined for early elevation within 4 weeks after the initiation of sorafenib. An increase in AFP was defined as AFP of more than 20%, and an increase in DCP was defined as more than two-fold higher level than the baseline. The relationship of the clinical characteristics, laboratory data at baseline, and early elevations of AFP and DCP with disease progression was analyzed. Results The median OS and PFS were 11 and 3.3 months, respectively. The rate of progressive disease (PD) was 54%, and an early increase in AFP was significantly related to PD (P=0.006) and was a significant independent predictor of both poorer OS and PFS (P<0.001, hazard ratio, 4.14; 95% confidence interval, 1.946–8.811; and P=0.001, hazard ratio, 2.852; 95% confidence interval, 1.524–5.337, respectively). There was no association between early increase in DCP and clinical outcomes. Conclusion Early increase in AFP predicted PD and poorer survival and may thus be a useful biomarker in patients with advanced HCC who receive sorafenib.

Close association between high serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepatocellular carcinoma.

We investigated whether or not a high serum alanine aminotransferase (ALT) level is associated with a more rapid recurrence of hepatocellular carcinoma (HCC) in hepatectomized patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC) (HCV-LC) and HCC. Thirty-three hepatectomized patients with HCV-LC and HCC of a single nodule who had no histologic evidence of portal or hepatic vein invasion and who had been followed up for more than 3 years were included in the study. They were subdivided into two groups according to their serum ALT levels, ALT being a well-known marker of inflammatory necrosis in the liver. Seventeen patients whose serum ALT levels showed several peaks or plateaus above 80 international units (IU) were designated as the high ALT group, and 16 patients whose serum ALT levels showed a sustained low level below 80 IU until the first recurrence were designated as the low ALT group, and the interval between hepatectomy and the first recurrence was observed. In the high ALT group, HCC recurred within 3 years in 70.6% of the patients. In contrast, it recurred in only 18.8% of the low ALT group within the same period (p < 0.05). There was a significant difference (p = 0.0201) between the two groups in the cumulative nonrecurrence rate. The mean interval in recurrent patients between hepatectomy and the first recurrence in the high ALT group (23.6 ± 2.8 months; mean ± SE) was significantly (p < 0.02) shorter than that in the low ALT group (49.3 ± 9.7 months). The expected interval between hepatectomy and recurrence was as short as 2.8 ± 0.5 years (mean ± SE) in the high ALT group, compared with 5.8 ± 0.7 years in the low ALT group (p < 0.05). These results showed that the recurrence of HCC was accelerated in the high ALT group, suggesting that suppression of the rise in ALT level after hepatectomy by treatment with anti-inflammatory drugs may prolong the interval until recurrence by about 2 years in hepatectomized patients with HCC and HCV-LC.