Michio Kogame

Sustained complete response of hepatocellular carcinoma with portal vein tumor thrombus following discontinuation of sorafenib: A case report.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-associated mortality worldwide. No effective treatment has been established for unresectable advanced HCC, and the prognosis is poor. Sorafenib is an oral multi-targeted tyrosine kinase inhibitor for unresectable advanced HCC that significantly improves progression-free and overall survival. However, in the two large phase III clinical trials (the SHARP and Asia-Pacific trials), no cases of complete response (CR) were reported. The present study reports the case of a 68-year-old male with hepatitis C virus-related cirrhosis and multiple recurrent HCCs, with a tumor thrombus of the third portal vein following resection. The patient received 400 mg once daily (half the standard dose) of sorafenib for two years and achieved a CR. At the most recent follow-up examination at one year after the cessation of treatment, the patient was observed to be in remission without clinical or imaging evidence of disease recurrence.

Interferon alpha receptor 2 expression by peripheral blood monocytes in patients with a high viral load of hepatitis C virus genotype 1 showing substitution of amino Acid 70 in the core region.

Background/Aim: When patients with chronic hepatitis C (CHC) are treated with interferon (IFN)-based therapy, achieving serum HCV-RNA negativity by week 12 (early viral response, EVR) is an important predictor of a sustained virologic response. The aim of this study was to clarify whether changes in IFN-α receptor 2 (IFNAR-2) expression by peripheral blood monocytes (Mo) and the EVR rate differed between patients with genotype 1b and a high viral load showing substitution of amino acid 70 in the core region of HCV (mutant, n = 20) and patients without this substitution (wild, n = 23). Patients and Methods: Forty-three CHC patients were studied, and received pegylated IFN plus ribavirin. IFNAR-2 expression by Mo was determined using flow cytometry to measure the mean fluorescence intensity (MFI) before and up to 28 days after starting therapy. Results: The EVR rate of the mutant group was significantly lower than that of the wild group (35 vs.70%). The MFI of Mo was significantly higher in the wild group than in the mutant group before and also 3, 7, and 28 days after starting therapy. Conclusions: Mutation of HCV was related to lower IFNAR-2 expression by Mo before and after starting therapy.

Comparison of percutaneous radiofrequency ablation and CyberKnife® for initial solitary hepatocellular carcinoma: A pilot study

AIM To compare therapeutic outcomes and adverse events in initial solitary hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) and CyberKnife(®). METHODS Seventy three consecutive patients with initial solitary HCC treated with RFA (38 patients; RFA group) and CyberKnife(®) (35 patients; CK group) were enrolled in this study. Background factors were compared between the two groups. Local and intrahepatic distant recurrence control, and cumulative survival rates were compared between the two groups. These were determined using the Kaplan-Meier method, and the significance of differences was analyzed by log-rank test. The presence of more grade 3 on CTCAE ver. 4.0 early and late adverse events was investigated. RESULTS In background factors, age was significantly higher (P = 0.005) and the tumor diameter was significantly larger (P = 0.001) in the CK group. The 1-year local recurrence control rates were 97.4% and 97.1% in the RFA and CK groups, respectively (P = 0.71); the 1-year intrahepatic distant recurrence control rates were 85.6% and 86.1%, respectively (P = 0.91); and the 1-year cumulative survival rates were 100% and 95.2%, respectively (P = 0.075), showing no significant difference in any rate between the two groups. There were no late adverse event in the RFA group, but 11.4% in the CK group had late adverse events. In the CK group, the Child-Pugh score at 12 mo after treatment was significantly higher than that in the RFA group (P = 0.003) and significantly higher than the score before treatment (P = 0.034). CONCLUSION The occurrence of adverse events is a concern, but CyberKnife(®) treatment is likely to become an important option for local treatment of early HCC.

Evaluation of Hemodynamics in Focal Steatosis and Focal Spared Lesion of the Liver Using Contrast-Enhanced Ultrasonography with Sonazoid

We aim to investigate the hemodynamics in focal steatosis and focal spared lesion of the liver using contrast-enhanced ultrasonography (CEUS) with Sonazoid. The subjects were 47 patients with focal steatosis and focal spared lesion. We evaluated enhancement patterns (hyperenhancement, isoenhancement, and hypoenhancement) in the vascular phase and the presence or absence of a hypoechoic area in the postvascular phase for these lesions using CEUS. Of the 24 patients with focal steatosis, the enhancement pattern was isoenhancement in 19 and hypoenhancement in 5. Hypoechoic areas were noted in the postvascular phase in 3 patients. Of the 23 patients with focal spared lesions, the enhancement pattern was isoenhancement in 18 and hyperenhancement in 5. No hypoechoic areas were noted in the postvascular phase in any patient. The hemodynamics in focal steatosis and focal spared lesions in nondiffuse fatty liver can be observed using low-invasive procedures in real-time by CEUS. It was suggested that differences in the dynamics of enhancement in the vascular phase of CEUS were influenced by the fat deposits in the target lesion, the surrounding liver parenchyma, and the third inflow.

Interleukin-28B Genetic Variants and Peripheral Blood Interferon Receptor 2

Background/Aims: Genetic variation in the interleukin 28B (IL-28B) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with pegylatedinterferon (PEG-IFN) and ribavirin (RBV). The aim of this study is to clarify whether changes in type 1 IFN receptor 2 (IFNAR-2) expressions by peripheral blood monocytes (Mo) are related to genetic variation near the IL-28B gene. Patients and Methods: One hundred and forty-eight CHC patients with genotype 1b and high viral load receiving PEG-IFN and RBV were studied. IFNAR-2 expression by peripheral blood Mo was measured as the mean fluorescence intensity (MFI) before and up to 28 days after starting therapy. Eighty-three of 148 patients consented to genetic investigation (IL-28B genetic variants in rs8099917). Results: There were no significant differences in MFI of peripheral blood Mo between SVR and non-SVR patients during the study period in patients with genotype TT in rs8099917; however, MFI of peripheral blood Mo at days 7 and 14 of treatment was significantly higher in SVR patients than in non-SVR patients with genotype TG in rs8099917. Conclusions: IFNAR-2 may be related to efficacy of PEG-IFN and RBV in CHC patients possessing poorresponse IL-28B variants.

Comparison of contrast-enhanced ultrasonograpy with Gd-EOB-DTPA-enhanced MRI in the diagnosis of liver metastasis from colorectal cancer.

To compare contrast‐enhanced ultrasonography (CEUS) using Sonazoid with Gd‐EOB‐DTPA‐enhanced MRI (EOB‐MRI) in the diagnosis of liver metastases in patients with colorectal cancer.

The Importance of Lamivudine Therapy in Liver Cirrhosis Patients Related HBV with Advanced Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy

Purpose: We have previously reported that continuous hepatic arterial infusion chemotherapy (HAIC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with liver cirrhosis (LC) related to HCV infection (C-LC) or alcohol abuse (A-LC) than in patients who had LC related to HBV infection (B-LC). The aim of the present study was to retrospectively assess the efficacy of lamivudine therapy for B-LC patients with aHCC undergoing HAIC. Methods: Seventeen adult Japanese B-LC patients with aHCC were treated by HAIC with or without lamivudine (100 mg/day) between 2002 and 2008 at our hospital. Their tumors were inoperable according to computed tomography findings. HAIC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was given via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. Results: Nine of the 17 patients received lamivudine at a dose of 100 mg/day together with HAIC (LAM group), while 8 patients did not receive lamivudine and only had HAIC (non-LAM group). The response rate was 12.5 in the non-LAM group and 0.0% in the LAM group. However, the survival of the LAM group was better than that of the non-LAM group, although there was no significant difference between them. The median survival time of the LAM and non-LAM groups was 310 and 157 days, respectively. HBV-DNA levels were significantly lower after chemotherapy compared with that before chemotherapy in the LAM group. In the non-LAM group, the percentage of Th2 cells before HAIC and after HAIC was significantly higher than in the control group. However, the percentage of Th2 cells in the LAM group after HAIC was not different from that in the control group, although it was significantly higher in the LAM group than in the control group before chemotherapy. Conclusions: These results indicate that lamivudine therapy may prolong the survival of B-LC patients receiving HAIC for aHCC by reducing HBV-DNA level and inhibiting the increase of Th2 cells in host immunity.

Delayed Intratumoral Hemorrhage after Drug-Eluting Bead Transarterial Chemoembolization for Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) using a drug-eluting bead (DEB-TACE) for hepatocellular carcinoma (HCC) is a new treatment method. We report on a case of delayed intratumoral hemorrhage after DEB-TACE. An 81-year-old male with hepatitis C virus-related cirrhosis was diagnosed with a HCC of 35 mm in diameter in S5 detected by dynamic computed tomography (CT) and contrast-enhanced ultrasonography (CEUS). DEB-TACE with DC Bead® and epirubicin hydrochloride was performed because the patient declined to undergo surgical resection. The treatment was completed, and the course after DEB-TACE was favorable. However, right hypochondriac pain suddenly developed about 1 month after DEB-TACE. Unenhanced CT showed an increase of the tumor diameter and intratumoral high-intensity area, which was not enhanced in the arterial phase. CEUS performed at the time of right hypochondriac pain (5 weeks after DEB-TACE) showed nonenhancement of almost the entire tumor in the vascular phase. The cause of the symptom may have been DEB-TACE-associated intratumoral hemorrhage. Tumor hemorrhage has been reported after DEB-TACE with tumors >5 cm in diameter, and the tumor locations were subcapsular in all previous reports. There has been no case of a tumor with a diameter <5 cm distinct from the subcapsular, as was observed in our patient. Incomplete embolization might be the cause of the intratumoral hemorrhage experienced by this case presenting a few risks. To obtain the therapeutic effect of DEB-TACE while preventing the adverse events, it may be important to understand the characteristics of the beads and to apply the appropriate embolization to each individual case.

726 Type 1 IFN-Alpha Receptor Expression by Peripheral Blood Monocytes During Triple Therapy Influences Rapid Virological Response in Genotype 1b-Infected Patients With Chronic Hepatitis C and High Viral Load

BACKGROUND/AIM: We previously reported that type I IFN receptor alpha-2 (INFAR-2) expression in peripheral blood monocytes (Mo) is related to early virological response (EVR) in patients with chronic hepatitis C (CHC) infected with genotype 1b and having high viral loads (Intervirology 53: 105-110, 2010). The aim of this study was to clarify whether IFNAR2 expression by peripheral blood Mo influences rapid virological response (RVR) in CHC patients infected with genotype 1b, having high viral loads and treated with triple therapy comprising teraprevir (TPV), pegylated (PEG)-interferon (IFN) and ribavirin (RBV). PATIENTS AND METHODS: Twenty-nine adult patients with biopsy-proven CHC were studied. Enrollment criteria included 26 to 82 (median: 58) years of age, baseline serum HCV-RNA quantified by RT-PCR between 5.2 and 7.2 log copies/ml, and infection with HCV genotype 1b. Twenty-four patients (15 males and 9 females) were treated with triple therapy. As a pilot study, TPV alone was administered to 5 patients (4 males and 1 female) for 7 days in order to investigate the effects of TPV for IFNAR-2 expression by peripheral blood Mo. A negative result for serum HCV-RNA on RT-PCR at 4 weeks after starting therapy was defined as RVR. IFNAR-2 expression by peripheral blood Mo was determined using flow cytometry by measuring the mean fluorescence intensity before and up to 14 days after starting triple therapy. IFNAR-2 expression was also determined before and up to 7 days after starting TPV alone. All 29 patients consented to genetic investigation for polymorphisms in the interleukin (IL)-28B gene at rs8099917. Twenty-four patients had genotype TT, 5 patients had genotype TG, and none had genotype GG. RESULTS: RVR was achieved in 19 patients (15 patients with genotype TT and 4 patients with genotype TG) and was not achieved in 5 patients (non-RVR) with genotype TT. Genotype at rs8099917 was not associated with RVR (P=0.65, by χ2 test). IFNAR-2 expression by peripheral blood Mo was not altered at 3 and 7 days after starting therapy, as compared to before therapy in patients receiving TPV alone (4 patients with genotype TT and 1 patient with genotype TG). IFNAR-2 expression by peripheral blood Mo before starting therapy did not differ between RVR patients and non-RVR patients. However, IFNAR-2 expression by peripheral blood Mo after starting therapy was always higher in RVR patients than in non-RVR patients, and IFNAR-2 expression by peripheral bloodMo 3 days after starting therapy was significantly (P , 0.05 on Mann-Whitney test) higher in RVR patients than in non-RVR patients. CONCLUSION: This study showed that IFNAR-2 expression by peripheral blood Mo at day 3 of triple therapy influences RVR in patients infected with genotype 1b and having high viral loads.

Su2039 Changes of Cytokines in Cirrhosis Patients With Advanced Hepatocellular Carcinoma Treated by Sorafenib

PURPOSE:Sorafenib is multi-kinase inhibitor against RAF, involved in the growth of cancer cells and VEGFR(Vascular Endotherial Growth Factor Receptor), involved in angiogenesis around cancer. It is known that tumor stain is reduced by the administration of sorafenib. We retrospectively evaluated whether the decrease of blood flow after the administration of sorafenib affect the overall survival (OS) or not. METHODS:From May 2009 to November 2011, 127 patients out of 201 patients with advanced hepatocellular carcinoma (HCC) were treated with sorafenib and included in the present study. Patients received CE-CT or GdEOB-DTPA-MRI before treatment and every 4~6 weeks were evaluated to find the therapeutic effect. Patients were divided into 3 groups (No change group, partially decrease group, partially disappearance group) of tumor vascularity. We calculated OS of these 3 groups. RESULT:In the decrease group (85 cases, partially decrease group and partially disappearance group), the median OS was 19.6 months (95%C.I. 14.7-24.9). In the no change group (42 cases), the median OS was 8.6 months (95%C.I. 5.6-12.0). There were statistically significant differences between the two groups (p<0.001). In the partially disappearance group (51 cases), the median OS was 19.9 months (95%C.I. 11.3-28.6). In the partially decrease group (34 cases), the median OS was 22.0months (95%C.I. 12.2-32.0). There were no statistically significant differences between the two groups (p=0.59). CONCLUSION:In the treatment of sorafenib for advanced HCC, even if there is no necrosis, decrease of blood flow improves the OS.