Hisashi Hidaka

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.

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%‐3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico‐pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real‐time polymerase chain reaction–based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico‐pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4‐amplified and three FGFR2‐amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies. (HEPATOLOGY 2013)

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.

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.

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.

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial

Liver cirrhosis represents the end stage of any chronic liver disease, and it is associated with hepatic edema such as ascites. Many patients with ascites do not respond to diuretic therapy or require administration of diuretics at high doses that can cause adverse events. This 7‐day, multicenter, double‐blind trial of tolvaptan was designed to determine the optimal dose of tolvaptan for producing the intended pharmacological effect in hepatic edema.

Entecavir is an optional agent to prevent hepatitis B virus (HBV) reactivation: A review of 16 patients

BACKGROUND Hepatitis B virus (HBV) reactivation is a fatal complication in patients who receive chemotherapy or immunosuppressive therapy. We examined the effect of preventive entecavir (ETV), a new nucleoside analogue on HBV reactivation during chemotherapy or immunosuppressive therapy. METHODS Between February 2007 and September 2009, sixteen nucleoside analogue treatment-naive patients with chronic HBV infection (HB surface antigen [HBsAg] positive) who required chemotherapy or immunosuppressive therapy were enrolled. Referring to some guidelines, the patients received preventive ETV to reduce incidence of HBV reactivation, and were closely monitored for HBV markers. RESULTS HBV reactivation did not occur in any of the 16 patients and the indispensable treatments for their underlying diseases could be continued. However, HBV relapsed after preventive ETV was discontinued in 2 patients. CONCLUSIONS This study suggests that ETV is a useful option for preventing HBV reactivation in patients with chronic HBV infection.

Repeat Radiofrequency Ablation Provides Survival Benefit in Patients With Intrahepatic Distant Recurrence of Hepatocellular Carcinoma

OBJECTIVES:Intrahepatic distant recurrence (IDR) of hepatocellular carcinoma (HCC) after curative treatment occurs frequently and influences the prognoses. The aim of this study was to determine prognostic factors affecting survival after IDR and the optimum therapy for IDR.METHODS:A total of 115 patients with a single small primary HCC who had complete radiofrequency (RF) ablation were enrolled in this study. The prognostic factors and the optimum therapy affecting survival were statistically analyzed among patients with IDRs.RESULTS:IDRs were observed in 59 (51.3%) patients with the median observation period of 19.6 months. The cumulative rates of IDRs were 11.8, 53.9, and 75.8% at 1, 3, and 5 years, respectively. IDR nodules were present as a single nodule in 38 patients and as multiple nodules in 21 patients. In all, 23 patients died during the follow-up. A total of 30 patients were treated with RF ablation, and 27 were treated with transcatheter arterial chemoembolization (TACE). The overall cumulative survival rates after IDRs were 92.7, 55.4, and 43.7% at 1, 3, and 5 years, respectively. A multivariate analysis showed that treatment with RF ablation for IDR was a significant favorable prognostic factor after IDR (hazard ratio: 0.167, 95% confidence interval: 0.048−0.584, P=0.005). In a comparison of survival after IDR between patients treated with RF ablation and TACE, who were comparable with clinical and tumoral characteristics, the cumulative survival rate of patients treated with RF ablation was significantly higher than that of those treated with TACE (77.2 vs 28.5% at 3 years). The cumulative survival rates obtained from the initial RF ablation of the patients with IDRs treated with repeat RF ablation were similar to those of recurrence-free patients.CONCLUSIONS:Repeat RF ablation should be attempted for IDR as much as possible despite tumor multiplicity for survival benefit; by reducing the need, it will help solve the problem of the current shortage of donors for liver transplantations.

Potential Prognostic Benefits of Radiotherapy as an Initial Treatment for Patients with Unresectable Advanced Hepatocellular Carcinoma with Invasion to Intrahepatic Large Vessels

Objectives: To examine the efficacy and prognostic benefits of radiotherapy (RT) in patients who have unresectable advanced hepatocellular carcinoma (HCC) with invasion to intrahepatic large vessels (IHLVs). Methods: Sixty-eight patients who had advanced HCC with invasion to IHLVs were studied. Thirty-two consecutive patients initially received 3-dimensional conformal RT for HCC invasion to IHLVs. Tumor response, prognostic factors, and survival were studied in the patients given RT. Prognostic factors and survival were assessed in the study group as a whole. Data were analyzed using the Kaplan-Meier method, univariate analysis, and a Cox model. Results: The rate of objective response to RT was 48%. Predictors of survival in the patients who received RT were a hepatic function of Child-Pugh class A (p = 0.0263) and a response to RT (p = 0.0121). In the study group as a whole, independent predictors of survival in a Cox model were multinodular HCC (p = 0.007), inferior vena caval invasion (p = 0.001), a serum α-fetoprotein level of >1,000 ng/ml (p = 0.032), and the performance of RT (p < 0.001). Notably, the median survival of the nonresponders to RT (n = 15) was significantly longer than that of the patients who received no treatment for HCC (n = 21; 7.0 vs. 3.4 months, p = 0.0014). Conclusion: RT is considered an effective initial treatment for HCC invasion to IHLVs, and may offer survival benefits, even in nonresponders, because of the induction of stable disease.

Restoration of thrombopoietin production after partial splenic embolization leads to resolution of thrombocytopenia in liver cirrhosis

The aim of this study was to evaluate the relation between thrombopoietin (TPO) and thrombocytopenia in patients with liver cirrhosis and those with idiopathic portal hypertension (IPH) before and after partial splenic embolization (PSE). We examined changes in platelet counts, liver function, megakaryocyte function, and plasma TPO levels after PSE in 30 patients (20 with liver cirrhosis, and 10 with IPH). Platelet counts in both cirrhosis and IPH increased significantly 2 months after PSE (cirrhosis group, 4.0+/-1.9 vs. 7.5+/-4.4x10(4)/&mgr;l: P=0.0002; IPH group, 4.0+/-1.7 vs. 6.5+/-2.3x10(4)/&mgr;l: P=0.0042). Plasma TPO level and prothrombin time increased significantly and alanine aminotransferase level (ALT) and total bilirubin level decreased significantly 2 months after PSE in the cirrhosis group (plasma TPO level, 0.57+/-0.30 vs. 0.72+/-0.27 fmol/ml: P=0.024), but not in the IPH group (0.56+/-0.21 vs. 0.55+/-0.34 fmol/ml: P=0.94). Moreover, the score of megakaryocytes with platelet production, an index of platelet production by megakaryocytes in bone marrow, increased significantly in the cirrhosis group. TPO production in cirrhotic patients is restored after PSE, leading to the resolution of thrombocytopenia. But patients with IPH had no change in liver function, indicating that only decreased spleen volume was responsible for the improvement in platelet count.