Toyokazu Fukunaga

Low-Dose, Long-Term, Intermittent Interferon-alpha-2b Therapy after Radical Treatment by Radiofrequency Ablation Delays Clinical Recurrence in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma

Objective: To assess whether or not interferon (IFN) therapy prevents recurrence, and eventually improves the prognosis of patients with hepatocellular carcinoma (HCC) after completion of radical radiofrequency ablation (RFA) therapy. Methods: Included as the IFN group in this study were 24 patients in total, who received radical RFA therapy first, followed by medication with IFN-α2b at such a low dose of 3 MIU × 2/week for as long as possible. On the other hand, the control group comprised 33 patients in total, who received radical RFA therapy without subsequent treatment with IFN. The control group was matched to the IFN group in age, platelet counts and size of nodules. Results: Of the 24 patients treated with IFN, only one patient showed sustained virologic response. The median tumor-free period until the first recurrence after radical RFA therapy was 3.4 years in the IFN group and 1.4 years in the control group (p = 0.02). During the first 3 years after commencement of IFN administration, the cumulative recurrence rate in the IFN group was found to be lower than in the control group (p = 0.01); however, with the lapse of time over 3 years, the recurrence rate in the IFN group increased. There was no difference in the cumulative survival rates between the IFN group and the control group (p = 0.25). Conclusion: Subsequently after radical RFA therapy, long-term, low-dose, intermittent IFN therapy successfully delayed clinical recurrence of HCC.

Prognostic factors for portal venous invasion in patients with hepatocellular carcinoma.

BackgroundFactors involved in portal venous invasion (PVI) must be clarified to enable better determination of therapeutic strategies and outcomes in patients with hepatocellular carcinoma (HCC).MethodsOf 365 patients with HCC who consulted our department between January 1999 and January 2003, 53 with PVI at the initial consultation were excluded, and the other 312 without PVI were included in this study. Of these patients, we compared liver function, tumor markers, and initial treatment between 287 patients without PVI during follow-up (until December 2004) and 25 patients who developed PVI, and investigated prognostic factors.ResultsMultivariate analysis using a COX regression model showed that a Lens culinaris A-reactive fraction of α-fetoprotein (AFP-L3) rate of 15% or more, a des-γ-carboxy prothrombin (DCP) level of 100 mAU/ml or more, multiple tumors, and a platelet count of 130 000/mm3 or more were correlated with PVI.ConclusionsHCC frequently infiltrated the portal vein in patients with a high rate of AFP-L3, a high level of DCP, or multiple tumors. Furthermore, the incidence of PVI was significantly higher in patients with a platelet count of 130 000/mm3 or more.

Comparison of three current staging systems for hepatocellular carcinoma : Japan integrated staging score, new Barcelona Clinic Liver Cancer staging classification, and Tokyo score

Background and Aim:  Although various staging systems for hepatocellular carcinoma (HCC) have been developed in recent years, there is no worldwide consensus which staging system is best. The aim of the present study was to compare the performance of the currently developed three staging systems: the Japan integrated staging (JIS) score, new Barcelona Clinic Liver Cancer (BCLC) staging classification, and the Tokyo score.

Percutaneous Radiofrequency Ablation of Sonographically Unidentifiable Liver Tumors

Objective: The purpose of this study was to evaluate the safety and feasibility of a real-time integrated system with computed tomography (CT) and sonographic images for radiofrequency (RF) ablation of hepatic malignancies poorly defined on B-mode sonography, and to clarify the suitable phase of CT images for using this virtual sonography. Methods: Between September 2004 and December 2004, 12 patients with 16 hepatocellular carcinomas and two metastatic lesions arising from colorectal adenocarcinoma (n = 1) and rectal carcinoid (n = 1) were treated. The maximum diameter of nodules ranged from 1.0 to 2.5 cm (mean ± SD; 1.5 ± 0.6 cm) on CT images. Results: Complete tumor necrosis was achieved in a single session in 19 lesions (90%), while a second session was required for the remaining two lesions (10%). Portal phase multi-planar reconstruction images were displayed under a suitable position corresponding to the ultrasound images in 9 patients (HCC = 7, metastasis = 2), and arterial phase multi-planar reconstruction images were displayed in the 3 remaining patients with hepatocellular carcinoma. Conclusion: Percutaneous RF ablation guidance using virtual sonography is an effective treatment for patients with hepatic malignancies. The portal phase of CT images may be the most suitable to indicate the 3-dimensional relationship between the liver vasculature and tumors on virtual sonography.

Clinical characteristics of NonBNonC- HCC: Comparison with HBV and HCV related HCC.

Objective: To clarify the frequency and trends of both HBsAg and HCVAb negative hepatocellular carcinoma (NonBNonC-HCC) in all HCC, to clarify the etiology of NonBNonC-HCC, and to elucidate the clinical characteristics of NonBNonC-HCC compared with those of HBsAg-positive HCC (B-HCC) and HCVAb-positive HCC (C-HCC). Methods: A total of 2,542 patients with HCC examined at three institutions between 1991 and 2004 were categorized based on their serum viral antigen/antibody positivities, and compared between groups for the etiology, annual trend of the incidence, and clinical characteristics. Results: For the etiology, C-HCC was most prevalent, followed by B-HCC, NonBNonC-HCC, and both HBsAg and HCVAb-positive HCC (BC-HCC) in order. For survival, C-HCC had the most favorable prognosis, followed by NonBNonC-HCC, and B-HCC patients had the poorest prognosis in the three groups (C-HCC, B-HCC, and NonBNonC-HCC). In tumor-node metastasis (TNM) stages I+II, however, NonBNonC-HCC patients took the most favorable clinical course. The incidence of NonBNonC-HCC in all HCC was 5–8% from 1991 to 1998, and has increased to 10–12% since 1999. Additionally, the incidence of HBcAb-positive HCC in NonBNonC-HCC declined each year. Among NonBNonC-HCC patients, the morbidity of diabetic complications was significantly higher in HBcAb-negative patients than in HBcAb-positive patients. Conclusion: Although the incidence of NonBNonC-HCC among all HCC has an increasing trend recently, the incidence of HBcAb-positive HCC in NonBNonC-HCC has a tendency of decreasing. This fact suggest its etiology might be changing from occult HBV related HCC to unknown etiology such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) related HCC. The prognosis of NonBNonC-HCC was fairly good if the HCC was found in its early stage.

Outcomes of Nontransplant Potentially Curative Therapy for Early-Stage Hepatocellular Carcinoma in Child-Pugh Stage A Cirrhosis Is Comparable with Liver Transplantation

Background: This study was undertaken to assess the outcome of potentially curative therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis as well as to investigate the impact of low-dose interferon (IFN) therapy after curative therapy on survival. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 224 Child-Pugh stage A cirrhotic patients who received either resection (53 cases) or radiofrequency ablation (RFA: 171 cases) for HCC within Milan criteria. Thirty patients were treated with low-dose maintenance IFN therapy after initial curative therapy. The median follow-up period was 36.7 months. Results: The 5-year survival rate of all patients was 74.9%, with similar rates for the resection and RFA groups (70.4 vs. 76.8%; p = 0.561). The 5-year HCC recurrence rate was higher in the RFA group than the resection group (85.3 vs. 73.2%; p = 0.012). The maintenance IFN-treated group maintained their liver function within Child-Pugh stage A for a significantly longer time (median time 36.9 vs. 32.2 months; p = 0.0025). Conclusion: The 5-year outcomes of resection and RFA in patients with Child-Pugh stage A cirrhosis and early stage HCC were comparable with liver transplantation. Low-dose, long-term maintenance IFN therapy after curative therapy was significantly beneficial on survival.

Differential diagnosis of nodular lesions in cirrhotic liver by post-vascular phase contrast-enhanced US with Levovist: comparison with superparamagnetic iron oxide magnetic resonance images

BackgroundWe investigated the diagnostic utility of post-vascular phase contrast-enhanced ultrasonography (US) and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) as compared to the histological diagnosis of differential grades of hepatocellular carcinomas (HCCs).MethodsForty-nine patients with histologically characterized liver nodules (well-differentiated HCC, n = 20; moderately differentiated HCC, n = 19; poorly differentiated HCC, n = 1; dysplastic nodule, n = 9) received contrast-enhanced US and SPIO-MRI. Subsequently, we quantitatively evaluated the relationships between the images of the nodules and their histological diagnosis and differential grades.ResultsThe ratio of the echogenicity of the tumorous area to that of the nontumorous area with post-vascular phase contrast-enhanced US (post-vascular phase ratio) decreased as nodules became less differentiated (P < 0.05; Kruskal-Wallis test). The ratio of the intensity of the nontumorous area to that of the tumorous area on SPIO-enhanced MR images (SPIO intensity index) also decreased as nodules became less differentiated (P < 0.01). The post-vascular phase ratio correlated with the SPIO intensity index for HCCs and dysplastic nodules (r = 0.76). The conformity of the result from the post-vascular phase contrast-enhanced US and SPIO-MRI was 96%.ConclusionsContrast-enhanced US is a valuable method for predicting the histological grade of HCCs in cirrhotic patients, and may be a good alternative to SPIO-enhanced MRI.

What Is the Best Time to Evaluate Treatment Response after Radiofrequency Ablation of Hepatocellular Carcinoma Using Contrast-Enhanced Sonography?

Purpose: To observe the visibility and changes in the echogenicity of ablated tumor and ablated nontumor areas after radiofrequency ablation (RFA) over time using gray-scale sonography, and, consequently, to decide on the best timing for contrast-enhanced sonography to evaluate the response of hepatocellular carcinoma to RFA. Materials and Methods: Thirty-eight patients with 48 hepatocellular carcinoma nodules underwent RFA. Consecutive gray-scale sonographic observations were made 10 min before RFA and at five points within 4 days after RFA. Two hepatologists blindly reviewed the sonographic images to assess the identifiability of the boundary of the ablated nodules and to semiquantitatively score the echogenicity of the ablated tumor and ablated nontumor regions in 15 hypoechoic nodules with detectable boundaries within 4 days after RFA. Results: The detection rates of the boundaries of ablated tumors were 56.5, 65.2, 54.3, 43.5, and 39.1% at 3–6 h and 15–22 h and on the 3rd, 4th, and 5th days after RFA. There was a significant difference between the detection rate for ablated tumors at 15–22 h and that on the 3rd and 4th days. The difference in echogenicity between ablated tumor and ablated nontumor tissue reached a maximum at 15–22 h after RFA. Conclusion: Ablated tumor can be clearly identified within the ablated area in 65.2% of cases using gray-scale sonography at 15–22 h after RFA. The day following RFA is most appropriate and practical for the performance of contrast-enhanced sonography to evaluate the therapeutic response, including a safety margin.

Review of current staging systems for hepatocellular carcinoma

Several staging systems have been developed to classify patients with hepatocellular carcinoma (HCC), however, there is no consensus on which of these is the most useful and reliable. In this review article, currently available integrated staging systems taking into account both liver function and tumor progression are presented, and their characteristics and applicability for current HCC patients, many of whom are diagnosed in the early stage of the disease and treated by curative therapy, are discussed. Based on the original andsubsequent validation studies of these staging systems, we recommend that further validation studies of staging systems for HCC should focus on the revised Barcelona Clinic Liver Cancer (BCLC) staging classification, Japan Integrated Staging (JIS) score and Tokyo score.

Clinical Significance of the Genotype and Core Promoter/Pre-Core Mutations in Hepatitis B Virus Carriers

It has been shown that clinical and virological characteristics vary among hepatitis B virus (HBV) genotypes. In this study, we measured the virus level, disease severity, and presence or absence of core promoter (CP)/pre-core (PC) mutations in 241 HBV carriers, and investigated the clinical significance of measuring the HBV genotype. In genotype C HBV carriers, the proportion of hepatitis B e antigen (HBeAg)-positive patients was significantly higher than that in genotype B HBV carriers (0 vs. 34.4%, p < 0.05), and the virus level was higher (4.9 vs. 4.05 LGE/ml). In the genotype B HBV carriers, the incidence of PC mutation was significantly higher (69 vs. 34%, p < 0.05). In the genotype C HBV carriers, the incidence of CP mutation was significantly higher (13 vs. 78%, p < 0.05). We compared patients with the wild (W)/mutant (M) pattern in the CP/PC regions to those with the M/W pattern in the CP/PC regions among the genotype C HBV carriers. Both the proportion of HBeAg-positive patients (65.8 vs. 15.4%, p < 0.05) and the alanine aminotransferase (ALT) level (48 vs. 21.5 IU, p < 0.05) were higher in the patients with the M/W pattern in the CP/PC regions, and the disease severity was deteriorated. In conclusion, genotype B HBV may more frequently induce HBe seroconversion via PC mutation compared to genotype C HBV. Among the genotype C HBV carriers, hepatitis activity and the deterioration of the disease severity were significantly inhibited in the group in which PC mutation initially occurred, in comparison to the group in which CP mutation initially occurred.