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Background Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. Methods Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. Results The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. Conclusion Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

Polymorphisms in the inosine triphosphatase (ITPA) gene is associated with anemia induced by peg-interferon (PEG-IFN) plus ribavirin (RBV) treatment for patients with chronic hepatitis C virus (HCV) infection. However, the effect of ITPA polymorphism on sofosbuvir plus RBV treatment is unknown. Two hundred and forty-four patients with chronic HCV genotype 2 infection without decompensated liver cirrhosis were treated with sofosbuvir plus RBV for 12 weeks. The effects of ITPA polymorphism on hemoglobin levels and RBV dose reduction and treatment response were analyzed. ITPA (rs1127354) was genotyped using the Invader assay. Multivariate regression analysis was performed to identify factors associated with sustained virological response (SVR). Overall, SVR12 was achieved in 231 (94.7%) patients, based on intention to treat analysis. During the therapy, reduction of hemoglobin levels was significantly greater in ITPA genotype CC patients than CA/AA patients. Therefore, the cumulative proportion of patients with RBV dose reduction was significantly higher and total dose of RBV was significantly lower in patients with CC genotype compared to CA/AA genotypes. SVR12 rates were similar between ITPA genotypes CC and CA/AA (94.7 and 94.4%, respectively, P = 0.933). Multivariate logistic regression analysis identified FIB4 index

Background: Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC). However, rare but serious complications may occur after RFA. We describe a case of diaphragmatic hernia associated with RFA. Case Presentation: A 68-year-old man with a history of hepatitis C-related liver cirrhosis was admitted to our hospital because of lower abdominal pain. Three years earlier, he underwent RFA for HCC in segment 8. Computed tomography revealed that the intestine was intruding into the right thoracic cavity through a diaphragmatic hernia. On the basis of the diagnosis of right diaphragmatic hernia with a strangulated ileus, an emergency operation was performed. Perforation of the strangulated transverse colon into the right thoracic cavity was suspected, and a combined approach of laparotomy and thoracotomy was utilized. The operative findings showed that the diaphragmatic hernia was 3.5 × 2.0 cm in diameter, and it was simply sutured with a nonabsorbable suture material. Resection of the intruded ischemic transverse colon was completed, and a covering ileostomy was performed. The patient was discharged without any complications. Conclusions: RFA is widely used for the treatment of HCC. Reports of early- and late-phase complications indicate that heat damage contributes to the fragility of neighboring organs. The occurrence of diaphragmatic hernia after RFA is one of the delayed complications. Although it rarely occurs, this complication requires emergency surgery. In conclusion, if perforation of the intestine into the thoracic cavity is suspected, thoracolaparotomy should be considered as a treatment option to prevent postoperative massive empyema.

Background In patients with advanced hepatocellular carcinoma (HCC), evidence is unclear as to whether hepatic arterial infusion chemotherapy (HAIC) or sorafenib is superior. We performed a prospective, open-label, non-comparative phase II study to assess survival with HAIC or HAIC converted to sorafenib. Methods Fifty-five patients were prospectively enrolled. Patients received HAIC as a second course if they had complete response, partial response, or stable disease (SD) with an alpha fetoprotein (AFP) ratio 1 and a DCP ratio > 1 or disease progression. The primary endpoint was the 1-year survival rate. Secondary endpoints were the 2-year survival rate, HAIC response, survival rate among HAIC responders, progression-free survival, and adverse events. Results Of the 55 patients in the intent-to-treat population, the 1-year and 2-year survival rates were 64.0 and 48.3%, respectively. After the first course of HAIC, one (1.8%) patient showed complete response, 13 (23.6%) showed partial response, 30 (54.5%) had SD, and 10 (18.1%) patients had progressive disease. Twenty-three patients (41.8%) had SD with AFP ratios 1 and DCP ratios > 1. Thirty-seven patients (68.5%) were responders and 17 (30.9%) were non-responders to HAIC. In responders, the 1-year and 2-year survival rates were 78 and 62%, respectively. Conclusion Given the results of this study, this protocol deserves consideration for patients with advanced HCC. This trial was registered prospectively from December 12. 2012 to September 1. 2016.

Objectives Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government-sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child–Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis. Methods Altogether 177 patients with advanced HCC at Child–Pugh class A who were free of extrahepatic metastasis were retrospectively enrolled. The patients were divided into the HAIC group (n = 136) and the sorafenib group (n = 41), and were followed up until their death or withdrawal of therapy. Responses to treatment and overall survival were determined and compared between the two groups. Results The proportion of patients with complete response, partial response, stable disease and progressive disease were 5.9%, 25.0%, 40.4% and 21.3% in the HAIC and 2.4%, 2.4%, 43.9% and 41.5% in the sorafenib group, respectively. The response rate was higher in the HAIC group than in the sorafenib group (30.9% vs 4.8%). The median survival time was 10 months in both HAIC and sorafenib groups. In patients with macroscopic vascular invasion (MVI) by the case-control method, the response rate was higher in the HAIC group than in the sorafenib group. Overall survival was longer in the HAIC group than in the sorafenib group (14 months vs 7 months, P = 0.005). Multivariate analysis identified MVI (hazard ratio 2.4, P = 0.018) as an independent prognostic factor of survival in the sorafenib group. Conclusions Response rate to HAIC was higher than that to sorafenib monotherapy. Prognosis was favorable in HAIC responders despite MVI. HAIC might be a potential treatment option for advanced HCC without extrahepatic metastasis.

To compare the outcome of 5-fluorouracil (FU)-based hepatic arterial infusion chemotherapy (HAIC) with sorafenib monotherapy in patients with hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE).In this retrospective cohort study, 123 patients with HCC refractory to TACE, with Child-Pugh A and free of extrahepatic metastasis, were divided into two groups: 65 received HAIC and 58 received sorafenib. Since the size of main tumor and portal vein invasion were significantly different between the HAIC and sorafenib groups, we selected 48 patients from the 65 patients of the HAIC group and 48 from the 58 patients of the sorafenib group. The model used one-to-one matching between the two groups using the case-control method matching method. The clinical characteristics of patients of the case-control HAIC (n=48) and sorafenib groups (n=48) were similar. Overall survival, time to progression and time to treatment failure (TTTF) were compared between the two groups.The median survival time and TTTF were significantly longer in the sorafenib group than in the HAIC group (15 and 12.2 months versus 8 and 4.4 months, respectively; p=0.021 and p=0.002, respectively). Multivariate analysis identified male gender (p=0.008), relative tumor size50% (p=0.012), α-fetoprotein400 ng/ml (p=0.005), and treatment with sorafenib (p=0.001) as significant and independent determinants of better overall survival.In patients with HCC refractory to TACE, overall survival was favorable in those treated with sorafenib rather than HAIC.

Background and Aim We compared the treatment response, survival, and safety to hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) according to Child–Pugh (CP) score. Methods The study subjects were 249 patients with advanced HCC and CP class A and B who had been treated with HAIC. Patients were grouped according to CP score (5/6, 7 and 8/9) and their tumor response, tolerance, and survival were assessed. Results The median survival time (MST) was 8.2, 9.7, 6.3, and 3.9 months for the whole group, patients with CP 5/6, 7 and 8/9, respectively (P

Background and Aim: Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long-term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living-donor liver transplantation (LDLT). Methods: Thirty-five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy. Results: The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG + GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG + GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT : TT (donors' : recipients'), TT : TG + GG, TG + GG : any group were 81%, 50%, and 20%, respectively. The VR rate of TT : TT, TT : TG + GG and TG + GG : any group at 12 weeks were 28%, 0%, and 0%; those at 48 weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors : recipients (TT : TT) as the only independent determinant of SVR (odds ratio 15.0, P = 0.035). Conclusion: Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients.

We report a case in which sustained viral response was achieved after switching treatment from pegylated interferon (PEG-IFN) α-2b to α-2a and ribavirin (RBV) in patients with recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation. The patient was a 62-year-old man with liver cirrhosis due to HCV genotype 1b infection. The patient had 8 amino acid (aa) substitutions in the interferon sensitivity-determining region, and had substitutions for mutant and wild-type at aa70 and aa91, respectively, in the core region. The patient had minor genotype (GG) IL28B single nucleotide polymorphisms (rs8099917). He had initially received interferon α-2b and RBV for 2 years, and later developed hepatocellular carcinoma (HCC). After surgical resection of HCC, he subsequently received PEG-IFN α-2b and RBV for 1.5 years, without undetectable viremia during the treatment course. Due to recurrence of HCC, the patient received a living donor liver transplantation. Later on, hepatitis C relapsed. For the management of relapse, he received another course of PEG-IFN α-2b and RBV. However, breakthrough viremia occurred. PEG-IFN was thus switched from α-2b to α-2a and RBV for another 17 months. The patient eventually achieved a sustained viral response.

Aim: We investigated the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) and systemic interferon (IFN)-α (HAIC-5-FU/IFN) for advanced hepatocellular carcinoma (HCC) with venous tumor thrombosis (VTT) in the hepatic vein trunk (Vv2) or inferior vena cava (Vv3). Methods: Thirty-three patients with HCC/Vv2/3 underwent HAIC with 5-FU (500 mg/body weight/day, into hepatic artery on days 1–5 on the first and second weeks) and IFN-α (recombinant IFN-α-2b 3 000 000 U or natural IFN-α 5 000 000 U, intramuscularly on days 1, 3 and 5 of each week). Three-dimensional conformal radiotherapy (3D-CRT) was used in combination with HAIC-5-FU/IFN in 14 of 33 patients to reduce VTT. Result: The median survival time (MST) was 7.9 months, and 1- and 2-year survival rates were 30% and 20%, respectively. Evaluation of intrahepatic response after two cycles of HAIC-5-FU/IFN showed complete response (CR) in three (9%) and partial response (PR) in seven (21%), with an objective response rate of 30%. Multivariate analysis identified reduction of VTT (P = 0.0006), size of largest tumor (P = 0.013) and intrahepatic response CR/PR (P = 0.030) as determinants of survival. CR/PR correlated significantly with tumor liver occupying rate (P = 0.016) and hepatitis C virus Ab (P = 0.010). Reduction of VTT correlated significantly with radiotherapy (P = 0.021) and platelet count (P = 0.015). Radiotherapy-related reduction in VTT significantly improved survival of 16 patients with Vv3 and non-CR/PR response of HAIC-5-FU/IFN (P = 0.028). Conclusion: As for advanced HCC with VTT of Vv2/3, HAIC-5-FU/IFN responsive patients could obtain favorable survival. Despite ineffective HAIC-5-FU/IFN, the combination with effective radiotherapy to VTT might improve patients' prognosis.

Aim: In this study, we evaluated the clinical characteristics of hepatocellular carcinoma (HCC) because the etiology of HCC has been changing recently. Methods: Consecutive 1374 HCC patients at our institution from 1995 to 2009 were enrolled and clinical characteristics were investigated. Results: Seventeen percent and 67% of HCC were related to hepatitis B virus (HBV-HCC) and hepatitis C virus (HCV-HCC), respectively. Fifteen percent of that was negative for hepatitis B surface antigen (HBsAg) and antibody to hepatitis C virus (HCVAb) (NBNC-HCC). HCV-HCC tended to decrease and NBNC-HCC tended to increase in recent years. Patients with NBNC-HCC and HCV-HCC were significantly older than those with HBV-HCC. The complication rates of diabetes mellitus (DM), heavy alcohol consumption, hypertension, and hyperlipidemia in NBNC-HCC were significantly higher than those in other groups. Furthermore, the platelet counts and body mass index in NBNC-HCC were significantly higher than those of other groups. Among 209 NBNC-HCC patients, 58 patients underwent hepatic resection in which 29%, 36%, and 35% of those were based on non-alcoholic steatohepatitis (NASH), heavy alcohol consumption, and unknown etiology, respectively. DM was prevalent especially in NASH and heavy alcohol consumption. Cirrhosis was detected in 65%, 81%, and 15% in NASH-HCC, heavy alcohol consumption-HCC, and unknown etiology, respectively. Conclusions: NBNC-HCC has gradually been increasing in recent years. The present study elucidated that the presence of NASH and metabolic syndrome were important risk factors for NBNC-HCC and suggests that these patients should receive surveillance for HCC development.

Aim: To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4). Methods: The study subjects were 45 consecutive patients who received HAIC for HCC with Vp3/4 between January 2005 and December 2009. HAIC comprised the combination therapy of intra-arterial 5-FU with interferon-α (5-FU/IFN) in 23 patients and low-dose cisplatin plus 5-FU (FP) in 22. Radiotherapy (RT) was also provided in 19 patients for portal vein tumor thrombosis. Aggravation rate for EV and overall survival rate were analyzed. Results: The aggravation rates for EV were 47% and 64% at 12 and 24 months, respectively. The survival rates were 47% and 33% at 12 and 24 months, respectively. The response rates to 5-FU/IFN and FP were 35% and 41%, while the disease control rates in these two groups were 57% and 50%, respectively. There were no significant differences in the objective response and disease control between 5-FU/IFN and FP. Multivariate analysis identified size of EV (F2/F3) (HR = 7.554, P = 0.006) and HCC disease control (HR = 5.948, P = 0.015) as significant and independent determinants of aggravation of EV, and HCC disease control (HR = 12.233, P

Summary. The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.

We evaluated the clinical features and the prognostic factors of hepatocellular carcinoma (HCC) developed after hepatitis C virus (HCV) eradication with interferon (IFN) therapy. Forty-one consecutive patients who developed HCC after HCV eradication with IFN therapy were enrolled. Clinical features were reviewed, and overall survival and associated factors were analyzed. The recurrence rate in 26 patients receiving radical therapy was also analyzed. Twenty patients developed HCC within 5 years after the end of IFN therapy, 9 patients developed the disease from 5 to 10 years after the end of the therapy, 9 patients developed the disease from 10 to 15 years after the end of the therapy, and 3 patients developed the disease from 15 years after the end of the therapy. Multivariate analysis of independent variables for the development of HCC within 5 years identified age >55 years at HCV eradication (P = 0.007) and heavy alcohol intake (P = 0.009). The 5-year survival rate was 64%. On multivariate analysis of overall survival for the 41 patients, the only risk factor with prognostic influence was radical therapy (P = 0.010), which was associated with a cumulative 5-year survival rate of 91%. The only independent factor for the receipt of radical therapy was regular surveillance for HCC (P = 0.004). Among patients receiving radical therapy, the 3- and 5-year recurrence rates were 18 and 18%, respectively. We found that, despite HCV eradication, patients with the risk factors of high age at HCV eradication and heavy alcohol intake might be at heightened risk for the development of HCC within 5 years after HCV eradication. In contrast, risk factors for the development of HCC more than 10 years after HCV eradication were uncertain. These findings indicate the need for long-term surveillance for HCC after HCV eradication.

症例は72歳，男性．2003年肝細胞癌初発し，RFAを施行．以後，再発癌に対し，TACEやRFAを行ってきたが，2009年1月肺転移，胸壁転移が出現した．全身化学療法を含む集学的治療を行うも奏功せず，2010年4月3日よりsorafenib 800 mg/dayを導入した．副作用として，手足皮膚反応や下痢，倦怠感が出現したため，適宜，減量，休薬にて投与量の調節を行い，11月30日よりsorafenib 400 mg/dayを投与継続中で，副作用も自制内であった．2011年1月4日，急性腹症にて救急外来受診，CTにて骨盤内にfree airを認め，腸管穿孔と診断，S状結腸切除および人工肛門造設術を施行した．術後，合併症無く経過している．肝細胞癌に対するsorafenib内服中に消化管穿孔を合併した症例を経験したので報告する．

AIM We conducted a retrospective cohort study to investigate the efficacy of combination therapy with radiotherapy (RT) and zoledronic acid for bone metastases from hepatocellular carcinoma (HCC). Additionally, we investigated the efficacy of zoledronic acid for non-irradiated bone metastases. METHODS This study consisted of 31 patients who had received RT for bone metastases. Twelve of these patients with 23 sites of bone metastases were also treated with zoledronic acid (Z group). In the Z group, 14 sites received RT and nine sites did not. Nineteen patients with 38 sites of bone metastases were not treated with zoledronic acid (non-Z group). In the non-Z group, 22 sites received RT and 16 did not. We compared survival, pain response, time to pain progression, radiographic response, time to radiographic progression, and safety between groups. RESULTS While pain response rates were similar between the two groups, time to pain progression rates of irradiated and non-irradiated bone metastases was significantly lower in the Z (0% and 20% at 6 months, respectively) than in the non-Z group (34% and 66% at 6 months, respectively) (P = 0.045 and P = 0.005). Further, while radiographic response rates were similar between the two groups, time to radiographic progression rate of non-irradiated bone metastases was significantly lower in the Z (29% at 3 months) than in the non-Z group (91% at 3 months) (P = 0.009). No significant side-effects were documented. CONCLUSION Zoledronic acid delayed the pain progression of both irradiated and non-irradiated bone metastases and the radiographic progression of non-irradiated bone metastases from HCC.

Aim: We compared the ability of five staging system to predict survival in patients with hepatocellular carcinoma (HCC) treated with chemoembolization. Methods: The study subjects were 214 patients with HCC treated with repeated chemoembolization alone using cisplatin and lipiodol. Predictors of survival were assessed by multivariate analysis. Before chemoembolization was carried out, the modified Japan Integrated Staging (m-JIS), Japan Integrated Staging (JIS score), Barcelona (BCLC) stage, Liver Cancer Study Group of Japan/Tumor–Node–Metastasis (LCSGJ/TNM) and Italian score (CLIP score) were checked. To validate the prognostic value of these staging systems, the survival curve was obtained and analyzed by the Kaplan–Meier method. Discriminatory ability and predictive power were compared using Akaike's information criterion (AIC) score and the likelihood ratio (LR) χ2. Results: Overall survival was 1 year in 82.9%, 3 years in 39.9% and 5 years in 15.1%. Multivariate analysis identified more than 90% lipiodol accumulation (grade I) after the first chemoembolization (P = 0.001), absence of portal vein tumor thrombosis (PVTT) (P

Purpose To assess the predictors of hypersensitivity reaction to chemoembolization procedures with cisplatin and Lipiodol suspension for the treatment of hepatocellular carcinoma (HCC). Materials and Methods Between February 2005 and December 2008, 434 patients with HCC were treated with chemoembolization with a cisplatin and Lipiodol suspension. This retrospective cohort study analyzed the incidence of hypersensitivity reactions as an adverse effect and their predictors by multivariate logistic regression analyses. Results In total, 847 chemoembolization procedures were carried out in 434 patients. The median number of procedures per patient was 2 (range, 1–12). Mean dose of cisplatin per chemoembolization session was 27 mg (range, 15.0–80.0 mg), and the median total dose of cisplatin per patient was 55 mg (range, 5.0–560.0 mg). Hypersensitivity reactions occurred in 14 patients (1.7%). The median number of chemoembolization procedures in these patients was 7 (range, 3–10). Mean dose of cisplatin per session was 22 mg (range, 9.2–35.7 mg), and the median total dose of cisplatin was 134 mg (range, 37–286 mg). On multivariate analysis, the only parameter that showed an independent association with hypersensitivity reactions was the performance of 3 or more than three chemoembolization procedures. Conclusions Performance of more than three chemoembolization procedures with a cisplatin and Lipiodol suspension was found to be independently associated with hypersensitivity reactions. Patients undergoing repeated chemoembolization procedures with cisplatin and Lipiodol suspension may experience hypersensitivity reactions as an adverse effect.

The aim of the present retrospective study was to evaluate the therapeutic efficacy and predictive factors of prolongation of treatment with peginterferon (PEGIFN) combined with ribavirin (RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT).Fifty-three patients underwent LDLT due to HCV-related end-stage liver disease. Sixteen patients were removed from the study as a result of early death (n=14), no recurrence of HCV (n=1) and refusal of antiviral therapy (n=1). Therapy is ongoing in another 10 patients. The remaining 27 patients were available to establish the efficacy of IFN therapy. HCV genotype was 1b in 24 patients. All patients with genotype 1b were treated with IFN therapy for at least 48 weeks after HCV RNA levels had become undetectable. Amino acid substitutions in the HCV core region and NS5A region were analyzed by direct sequencing before LDLT.The rate of sustained virological response (SVR) was 37.0% (10/27). SVR rate in patients with genotype 1 was 29.2% (7/24) and 100% (3/3) in patients with genotype 2. Most patients with genotype 1b whose HCV RNA reached undetectable levels achieved SVR (87.5%; 7/8). However, mutation of the HCV core region and number of ISDR mutations were not associated with SVR rate in LDLT in our study.Prolonged IFN therapy for more than 48 weeks after HCV RNA reached undetectable levels might prevent virological relapse of HCV.

Background and Aims: We investigated the efficacy of intra-arterial 5-fluorouracil (5-FU) and systemic interferon (IFN)-α (5-FU-IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. Methods: We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non-meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5-FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. Results: For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non-meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non-meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P

We previously reported that the telomere-targeting drug telomestatin induces apoptosis accompanied by G-tail reduction and dissociation of binding protein TRF2 from telomeres in cancer cell lines but not normal or human telomerase reverse transcriptase (hTERT)-immortalized cells. Because telomere-targeting drugs induce growth arrest in normal cells at higher doses, their development is dependent on the ability to predict toxicity before in vivo use, but no models for this are available. Here, we established two new cell lines, telomerase immortalized human fetal hepatocytes, Hc3716-hTERT, and telomerase immortalized hepatic stellate cells, NPC-hTERT. Examinations showed that Hc3716-hTERT maintained normal mammalian cell morphology, cell growth, albumin expression, and wild-type p53 responsiveness, whereas NPC-hTERT maintained hepatic stellate-like morphology, expression of hepatic stellate markers, alpha-smooth muscle actin, and secretion of type I collagen, an extracellular matrix protein. Given our finding that telomere G-tail length in Hc3716 cells was decreased in senescence and increased by hTERT infection, we next examined the effect of high-dose telomestatin-induced telomere dysfunction and G-tail shortening on cellular functions in Hc3716-hTERT cells. Interestingly, telomestatin decreased expression of cytochrome P450 (CYP) family members CYP3A3/4, CYP3A5, and CYP3A7, mRNA and induced albumin expression at both mRNA and protein levels. These gene expression responses to telomestatin were similar to those of the normal parental cell Hc3716. These established cell lines thus represent the first model for predicting the side-effects of telomere-targeting drugs in normal cells, and should be powerful tools in the development of these drugs.

We evaluate the long-term prognosis and prognostic factors in patients treated with transarterial infusion chemotherapy using cisplatin-lipiodol (CDDP/LPD) suspension with or without embolization for unresectable hepatocellular carcinoma (HCC). Study subjects were 107 patients with HCC treated with repeated transarterial infusion chemotherapy alone using CDDP/LPD (adjusted as CDDP 10mg/LPD 1ml). The median number of transarterial infusion procedures was two (range, one to nine), the mean dose of CDDP per transarterial infusion chemotherapy session was 30 mg (range, 5.0–67.5 mg), and the median total dose of transarterial infusion chemotherapy per patient was 60 mg (range, 10–390 mg). Survival rates were 86-0x1.fc400000008p+0t 1 year, 40 0x1.c617665206557p+855t 3 years, 20 0x1.5687420657461p-505t 5 years, and 16 0x1.5742d676e6f6cp+807t 7 years. For patients with >90% PD accumulation after the first transarterial infusion chemotherapy, rates were 98 0x1.e676f7270206dp+759t 1 year, 60 0x1.46e6120736973p-505t 3 years, and 22 0x1.36f6e676f727p+840t 5 years. Multivariate analysis identified >90% PD accumulation after the first transarterial infusion chemotherapy (p = 0.001), absence of portal vein tumor thrombosis (PVTT; p < 0.001), and Child-Pugh class A (p = 0.012) as independent determinants of survival. Anaphylactic shock was observed in two patients, at the fifth transarterial infusion chemotherapy session in one and the ninth in the other. In conclusion, transarterial infusion chemotherapy with CDDP/LPD appears to be a useful treatment option for patients with unresectable HCC without PVTT and in Child-Pugh class A. LPD accumulation after the first transarterial infusion chemotherapy is an important prognostic factor. Careful consideration should be given to the possibility of anaphylactic shock upon repeat infusion with CDDP/LPD.

We encountered a case with a gastric varix that drained into the gastro-renal shunt, left pericardiacophrenic vein, and several other dilated collateral veins. This patient had a circumaortic venous ring. For this case we successfully performed balloon-occluded retrograde transvenous obliteration in which sclerotic agents were infused from the balloon catheter advanced to the left pre-aortic renal vein and the tip was wedged into the end of the gastro-renal shunt. Before injection of sclerotic agents, collateral veins other than the left pericardiacophrenic vein were embolized with micro-coils. During the injection, the left pericardiacophrenic vein was occluded temporarily with a micro-balloon catheter coaxially advanced from the catheter inserted from the femoral vein to the left pericardiacophrenic vein through the left brachiocephalic vein.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government-sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child-Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis.Altogether 177 patients with advanced HCC at Child-Pugh class A who were free of extrahepatic metastasis were retrospectively enrolled. The patients were divided into the HAIC group (n = 136) and the sorafenib group (n = 41), and were followed up until their death or withdrawal of therapy. Responses to treatment and overall survival were determined and compared between the two groups.The proportion of patients with complete response, partial response, stable disease and progressive disease were 5.9%, 25.0%, 40.4% and 21.3% in the HAIC and 2.4%, 2.4%, 43.9% and 41.5% in the sorafenib group, respectively. The response rate was higher in the HAIC group than in the sorafenib group (30.9% vs 4.8%). The median survival time was 10 months in both HAIC and sorafenib groups. In patients with macroscopic vascular invasion (MVI) by the case-control method, the response rate was higher in the HAIC group than in the sorafenib group. Overall survival was longer in the HAIC group than in the sorafenib group (14 months vs 7 months, P = 0.005). Multivariate analysis identified MVI (hazard ratio 2.4, P = 0.018) as an independent prognostic factor of survival in the sorafenib group.Response rate to HAIC was higher than that to sorafenib monotherapy. Prognosis was favorable in HAIC responders despite MVI. HAIC might be a potential treatment option for advanced HCC without extrahepatic metastasis.

The objectives of this study were to demonstrate the non-inferiority of assist strain ratio (ASR)—a newly developed application tool—to manual strain ratio (MSR)—a currently available standard diagnostic tool—and to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MSR and ASR. Ninety-eight mass lesions in the mammary gland (30 malignant and 68 benign) were included in the study. Skilled physicians performed the elastography scanning by applying minimal vibration. MSRs were obtained and compared with ASRs calculated from the same elastography image to test the correlation between the two groups of data. Diagnostic performance of MSR at a cut-off of 5.0 showed a sensitivity of 84.4 %, a specificity of 80.4 %, an accuracy of 81.6 %, a PPV of 65.5 %, and an NPV of 92.1 %. Diagnostic performance of ASR at a cut-off of 5.0 showed a sensitivity of 74.4 %, a specificity of 84.3 %, an accuracy of 81.3 %, a PPV of 67.7 %, and an NPV of 88.2 %. The areas under the curve (AUCs) for MSR and ASR were found to be 0.885 and 0.875, respectively. ASR demonstrated excellent diagnostic potential and was highly correlated with MSR performed by skilled physicians (r = 0.69, p

We retrospectively evaluated the local tumor control and safety of transcatheter arterial chemoembolization (TACE) followed by stereotactic body radiation therapy (SBRT) for small hepatocellular carcinoma (HCC) in this pilot study.Twenty-eight patients not for the indication of hepatectomy or ablation procedures were enrolled in this study. Eligible criteria was as followed: i) less than 3 hypervascular HCC nodules, each up to 30 mm in diameter; ii) not suitable for the hepatic resection or ablative therapy; iii) Child-Turcotte-Pugh (CTP) scoreor = 7. SBRT was performed within 1-2 months after TACE. Treatment efficacy was evaluated, according to the Response Evaluation Criteria in Cancer of the Liver (RECICL).The median local tumor control time was not reached. The 1-year cumulative local tumor control rate was 96.3%. The median disease-free survival time was 18 months. The 1- year cumulative overall survival rate was 92.6%. One patient (3.6%) died due to intrahepatic ectopic multiple recurrence and systemic metastasis and one (3.6%) due to cerebral hemorrhage. No patients experienced severe acute hematologic or physical toxicity or radiation induced liver damage.Our study demonstrated SBRT combined with TACE is a safe and effective modality of the locoregional therapy for small primary HCC.

A 79-year-old man was diagnosed with hepatocellular carcinoma in 2000 and treated with partial hepatectomy. Intrahepatic carcinoma recurred with lung metastases 7 years later. Several transcatheter arterial chemoembolizations were performed to treat the recurrence, and a right lower lobectomy was performed for lung metastasis. Twelve years after the original carcinoma diagnosis, lip and lung metastases were detected, and he was hospitalized for radiotherapy of the lung metastasis; an oral molecular-targeting drug was initiated. During the therapy, hematochezia was observed, and a colonoscopy was performed. A submucosal lesion with a blood clot measuring approximately 4mm in diameter was found in the sigmoid colon, and endoscopic mucosal resection was performed. Furthermore, an elevated lesion with a 5-mm diameter recess was observed on upper gastrointestinal endoscopy. Both lesions were diagnosed histopathologically as hepatocellular carcinoma metastases.

T22 ([Tyr5,12,Lys7]-polyphemusin II) has been shown to have strong anti-human immunodeficiency virus (HIV) activity comparable to that of 3'-azido-2',3'-dideoxythymidine (AZT). T22, an 18-residue peptide amide, takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Herein we synthesized several shortened analogs of T22 in order to search for a more suitable lead compound. A 14-residue analog having one disulfide bridge, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22), was found to have highly potent activity comparable to that of T22, and to take an antiparallel beta-sheet structure similar to that of T22. This indicates that the molecular size of T22 can be reduced without loss of activity or significant change in the secondary structure, and that TW70 may represent a novel lead compound. Furthermore, modifying the N-terminal alpha-amino group of TW70 with a fluoresceinthiocarbamoyl group, and the epsilon-amino group of D-Lys8 at the turn portion with a 5-aminopentanoyl group remarkably increased the selectivity index (50% cytotoxic concentration/50% effective concentration).

A 30-year-old man underwent a left lobectomy and S5/6 partial hepatectomy in August 2001 for hepatocellular carcinoma (HCC). A lung tumor was detected by positron emission tomography (PET-CT) 8 years after the surgery. In May 2010, he received pulmonary tumor resection and the histopathological findings revealed metastasis of HCC. However a metastatic brain tumor was detected by computed tomography (CT) in September 2010, therefore surgery and radiation therapy were subsequently performed. Thereafter, metastatic hilar lymph node appeared in December 2010, therefore we performed systemic chemotherapy using S-1/cisplatin combined with radiation therapy for the metastatic tumor. The tumor was markedly decreased and no shadow was detected by PET-CT. He has been followed up in the outpatient clinic with no recurrence.

Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long-term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living-donor liver transplantation (LDLT).Thirty-five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy.The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG+GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG+GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT:TT (donors':recipients'), TT:TG+GG, TG+GG:any group were 81%, 50%, and 20%, respectively. The VR rate of TT:TT, TT:TG+GG and TG+GG:any group at 12 weeks were 28%, 0%, and 0%; those at 48weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors:recipients (TT:TT) as the only independent determinant of SVR (odds ratio 15.0, P=0.035).Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients.

Objective: To compare the assessment of response and prognosis of patients to sorafenib treatment by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). Methods: Sixty-six patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib were enrolled in this retrospective study. The response to treatment was evaluated by RECIST, mRECIST and changes in AFP and DCP. Results: The median survival time of all patients was 8.6 months. The median time to radiological progression was 3.3 months. The response rates [complete response (CR) + partial response (PR)] by RECIST and mRECIST were 3.0 and 9.0%, respectively, while the disease control rates [CR + PR + stable disease (SD)] were 50 and 50%, respectively. Assessment by mRECIST of overall survival provided a better stratification of the patients according to the response to treatment (p = 0.009) than RECIST (p = 0.09). Assessment of overall survival by a change in AFP ratio of ≤1 at 8 weeks was better than that of >1 at 8 weeks (p = 0.002). The DCP ratio was not useful for assessment of overall survival. Multivariate analysis identified mRECIST response (CR + PR + SD; p = 0.001), AFP ratio at 8 weeks (≤1; p = 0.046) and Child-Pugh A before treatment (p = 0.012) as significant and independent determinants of survival. The combination of AFP ratio at 8 weeks, assessment by mRECIST and Child-Pugh score before treatment allows stratification of prognosis of patients treated with sorafenib. Conclusion: The combination of mRECIST and AFP ratio is useful for the assessment of prognosis of patients with advanced HCC treated with sorafenib.

A 60 year-old woman was admitted to our hospital because of management of multiple liver tumors. According to image findings and liver biopsy, she was diagnosed as having epithelioid hemangioendothelioma of the liver accompanied by metastases in the spleen, lungs and bones. Based on the spread of the liver tumors and the extensive systemic metastases, she was considered inoperable. Instead, she received hepatic arterial infusion therapy using recombinant interleukin-2. However, she died due to liver failure about two months after admission. Autopsy revealed that the liver tumor was angiosarcoma. It is difficult to differentiate angiosarcoma from epithelioid hemangioendothelioma based on the image findings and pathological findings of percutaneous liver biopsy. Many cases are diagnosed as angiosarcoma at autopsy. There is no established effective treatment for hepatic angiosarcoma, because the tumor stage at the time of diagnosis is often progressive. To date, immunotherapy with recombinant interleukin-2 has been reported to be effective clinically for cutaneous angiosarcoma, such as of the scalp and facial skin. To our knowledge, there have been no reported cases of hepatic angiosarcoma treated with recombinant interleukin-2. Our case is important should recombinant interleukin-2 be considered effective for hepatic angiosarcoma in the future.

A 68-year-old Japanese woman with chronic hepatitis C infection who achieved sustained viral response (SVR) was followed up regularly. Six years after SVR, alpha fetoprotein (AFP) was increased. Hepatocellular carcinoma (HCC) was diagnosed by computed tomography and was excised by hepatic resection. Thirteen years after SVR, AFP increased again, and HCC recurrence was detected, which was excised by hepatic resection. Each HCC was

In this study, we evaluated the clinical characteristics of hepatocellular carcinoma (HCC) because the etiology of HCC has been changing recently. Consecutive 1374 HCC patients at our institution from 1995 to 2009 were enrolled and clinical characteristics were investigated. Seventeen percent and 67% of HCC were related to hepatitis B virus (HBV-HCC) and hepatitis C virus (HCV-HCC), respectively. Fifteen percent of that was negative for hepatitis B surface antigen (HBsAg) and antibody to hepatitis C virus (HCVAb) (NBNC-HCC). HCV-HCC tended to decrease and NBNC-HCC tended to increase in recent years. Patients with NBNC-HCC and HCV-HCC were significantly older than those with HBV-HCC. The complication rates of diabetes mellitus (DM), heavy alcohol consumption, hypertension, and hyperlipidemia in NBNC-HCC were significantly higher than those in other groups. Furthermore, the platelet counts and body mass index in NBNC-HCC were significantly higher than those of other groups. Among 209 NBNC-HCC patients, 58 patients underwent hepatic resection in which 29%, 36%, and 35% of those were based on non-alcoholic steatohepatitis (NASH), heavy alcohol consumption, and unknown etiology, respectively. DM was prevalent especially in NASH and heavy alcohol consumption. Cirrhosis was detected in 65%, 81%, and 15% in NASH-HCC, heavy alcohol consumption-HCC, and unknown etiology, respectively. NBNC-HCC has gradually been increasing in recent years. The present study elucidated that the presence of NASH and metabolic syndrome were important risk factors for NBNC-HCC and suggests that these patients should receive surveillance for HCC development.

To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4). The study subjects were 45 consecutive patients who received HAIC for HCC with Vp3/4 between January 2005 and December 2009. HAIC comprised the combination therapy of intra-arterial 5-FU with interferon-α (5-FU/IFN) in 23 patients and low-dose cisplatin plus 5-FU (FP) in 22. Radiotherapy (RT) was also provided in 19 patients for portal vein tumor thrombosis. Aggravation rate for EV and overall survival rate were analyzed. The aggravation rates for EV were 47% and 64% at 12 and 24 months, respectively. The survival rates were 47% and 33% at 12 and 24 months, respectively. The response rates to 5-FU/IFN and FP were 35% and 41%, while the disease control rates in these two groups were 57% and 50%, respectively. There were no significant differences in the objective response and disease control between 5-FU/IFN and FP. Multivariate analysis identified size of EV (F2/F3) (HR = 7.554, P = 0.006) and HCC disease control (HR = 5.948, P = 0.015) as significant and independent determinants of aggravation of EV, and HCC disease control (HR = 12.233, P 0.001), metastasis from HCC (HR = 11.469, P = 0.001), ascites (HR = 8.825, P = 0.003) and low serum albumin (HR = 4.953, P = 0.026) as determinants of overall survival. RT for portal vein tumor thrombosis tended to reduce the aggravation rate for EV in patients with these risk factors. Hepatocellular carcinoma disease control was the most significant and independent factor for aggravation of EV and overall survival in HCC patients with major portal vein tumor thrombosis treated with HAIC.

The achievement of sustained viral response (SVR) with interferon (IFN) therapy before liver transplantation (LT) is difficult due to liver dysfunction, pancytopenia and frequent side-effects. Here, we report eradication of hepatitis C virus (HCV) genotype 1 after LT in three patients by IFN therapy before surgery. All three patients achieved virological response (VR), namely, fall in serum HCV RNA titer below the detection limit of real-time polymerase chain reaction (PCR) during IFN administration. However, HCV RNA rebound after cessation of treatment in all three patients; namely, they could not achieve SVR despite treatment with pegylated (PEG) IFN plus ribavirin. All three patients had wild-type amino acids (a.a.) at either aa70 or aa91 in the core region. Genotyping of IL-28 single nucleotide polymorphisms (rs8099917) showed TT genotype in two patients and TG genotype in one. All three patients developed multiple hepatocellular carcinomas during the clinical course, and requested living donor LT using liver grafts from their relatives. The patients were treated with IFN to immediately before LT, at which time they remained negative for HCV RNA in serum by real-time PCR. The three patients were followed-up for 14-15 months after LT, during which they remained negative for HCV RNA despite no further IFN therapy. In conclusion, it is possible to eradicate HCV after LT by inducing VR with continuous IFN therapy to before LT in spite of viral and host evidences reflecting low susceptibility to IFN treatment.

Background The preferred choice between surgical treatment and radiofrequency ablation (RFA) for the treatment of small resectable hepatocelluar carcinoma (HCC) has become a subject for debate. Methods We compared the results of hepatic resection (n = 199) with those of RFA (n = 87), of which 69 patients were treated with transcatheter arterial chemoembolization followed by RFA, for 286 patients with 3 or fewer nodules, none of which exceeded 3 cm in diameter at Hiroshima University Hospital. Results In subgroup analysis of single HCC with tumor size exceeding 2 cm in Child-Pugh class A, the disease-free survival time was significantly longer in the surgical resection group than in the RFA group (P = 0.048). In the subgroups of a single and multiple HCC with tumor size ≤2 cm in Child-Pugh class A, the overall and disease-free survival rates were almost the same for the surgical resection and RFA groups (P = 0.46 and 0.58, respectively, in single HCC, and P = 0.98 and 0.98, respectively, in multiple HCC). Conclusion Surgical resection may provide better long-term disease-free survival than RFA in the subgroup of a single HCC exceeding 2 cm of Child-Pugh class A. J. Surg. Oncol. 2011;104:3–9. © 2011 Wiley-Liss, Inc.

A sixties woman was found to have diagnosed by abdominal ultrasonography with a tumor in the left lobe of the liver and was referred to our institution in 1998. Abdominal magnetic resonance imaging (MRI) showed a typical, 70×45 mm cavernous hemangioma, which was followed up by annual MRI. In 2006, 8 years after the initial diagnosis, the MRI showed that the tumor had reduced to 30×15 mm. Although atypical of hemangioma, review of the annual observations indicated a diagnosis of regressive hemangioma, which also accorded with clinical observations. In 2009, a liver biopsy was performed by laparotomy during gastrectomy for gastric cancer. Pathological examination of the biopsy revealed sclerosed hemangioma tissue, confirming the diagnosis of regression of a cavernous hemangioma to a sclerosed hemangioma over 12 years.

The aim of this pilot study was to elucidate the efficacy and safety of systemic combination therapy with S-1 and cisplatin (CDDP) for hepatocellular carcinoma (HCC) patients with extrahepatic metastases.Sixteen patients were enrolled in this pilot study. Two weeks of combination therapy represented one cycle, followed by two-to-four weeks rest. In each cycle, S-1 was administrated orally at 80-120 mg (depending on body surface area) every day and cisplatin was administrated intravenously at 60 mg/m2 on day 8. Response, overall survival and adverse effects were assessed. RESULT. No patient had intrahepatic HCC and all patients had a class A Child-Pugh score. Regarding overall response, 2 (13%), 0 (0%), 5 (31%), and 9 (56%) patients showed complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, giving an overall response rate of 13% (2/16). The overall survival rate at 12 months was 77%. With regard to NCI-CTC grade-3 adverse reactions, 2 (13%), 2 (13%), and 6 (38%) patients developed nausea, anorexia, and neutropenia, respectively. No grade-4 adverse reaction or toxicity-related death occurred. CONCLUSION; S-1/CDDP is a potentially safe and effective combination therapy for HCC patients with extrahepatic metastases.

Two simplified peptides of PA1-14, which corresponds to the N-terminal 1-14 residues of adrenodoxin precursor, were synthesized and examined by circular dichroism and dye leakage measurements. Both peptides showed a tendency to form α-helices and exhibited moderate dye leakage.

We conducted a retrospective cohort study to investigate the efficacy of combination therapy with radiotherapy (RT) and zoledronic acid for bone metastases from hepatocellular carcinoma (HCC). Additionally, we investigated the efficacy of zoledronic acid for non-irradiated bone metastases. This study consisted of 31 patients who had received RT for bone metastases. Twelve of these patients with 23 sites of bone metastases were also treated with zoledronic acid (Z group). In the Z group, 14 sites received RT and nine sites did not. Nineteen patients with 38 sites of bone metastases were not treated with zoledronic acid (non-Z group). In the non-Z group, 22 sites received RT and 16 did not. We compared survival, pain response, time to pain progression, radiographic response, time to radiographic progression, and safety between groups. While pain response rates were similar between the two groups, time to pain progression rates of irradiated and non-irradiated bone metastases was significantly lower in the Z (0% and 20% at 6 months, respectively) than in the non-Z group (34% and 66% at 6 months, respectively) (P = 0.045 and P = 0.005). Further, while radiographic response rates were similar between the two groups, time to radiographic progression rate of non-irradiated bone metastases was significantly lower in the Z (29% at 3 months) than in the non-Z group (91% at 3 months) (P = 0.009). No significant side-effects were documented. Zoledronic acid delayed the pain progression of both irradiated and non-irradiated bone metastases and the radiographic progression of non-irradiated bone metastases from HCC.

We compared the ability of five staging system to predict survival in patients with hepatocellular carcinoma (HCC) treated with chemoembolization.The study subjects were 214 patients with HCC treated with repeated chemoembolization alone using cisplatin and lipiodol. Predictors of survival were assessed by multivariate analysis. Before chemoembolization was carried out, the modified Japan Integrated Staging (m-JIS), Japan Integrated Staging (JIS score), Barcelona (BCLC) stage, Liver Cancer Study Group of Japan/Tumor-Node-Metastasis (LCSGJ/TNM) and Italian score (CLIP score) were checked. To validate the prognostic value of these staging systems, the survival curve was obtained and analyzed by the Kaplan-Meier method. Discriminatory ability and predictive power were compared using Akaike's information criterion (AIC) score and the likelihood ratio (LR) χ(2) . Overall survival was 1 year in 82.9%, 3 years in 39.9% and 5 years in 15.1%. Multivariate analysis identified more than 90% lipiodol accumulation (grade I) after the first chemoembolization (P = 0.001), absence of portal vein tumor thrombosis (PVTT) (P 0.001) and liver damage A (P = 0.012) as independent determinants of survival. AIC score and the LR χ(2) showed superior predictive power of the m-JIS system in 95 patients with grade I accumulation of lipiodol after first chemoembolization.The discriminate ability of the m-JIS score is substantially better than those of other staging systems and has better prognostic predictive power in patients with grade I accumulation of lipiodol after first chemoembolization.

We investigated the efficacy of intra-arterial 5-fluorouracil (5-FU) and systemic interferon (IFN)-alpha (5-FU-IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases.We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non-meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5-FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups.For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non-meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non-meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P0.001) and overall survival (P0.001). No patient died of extrahepatic HCC-related disease.The efficacy of 5-FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited.

We evaluated the prognosis and associated factors in patients with small hepatocellular carcinoma (HCC; up to 3 nodules, each up to 3 cm in diameter) treated with percutaneous radiofrequency ablation (RFA) as first-line treatment.Eighty-eight consecutive patients who underwent percutaneous RFA as first-line treatment were enrolled, among whom 70 who had hypervascular HCC nodules which were treated by a combination of transcatheter arterial chemoembolization and RFA. RFA was repeated until an ablative margin was obtained.The rate of local tumor progression at 1 and 3 years was 4.8% and 4.8%, respectively. The rate of overall survival at 3 and 5 years was 83.0% and 70.0%, and the rate of disease-free survival at 3 and 5 years was 34.0% and 24.0%, respectively. On multivariate analysis, age (70 years; hazard ratio [HR] = 2.341, 95% confidence interval [CI] = 1.101-4.977, P = 0.027) and indocyanine green retention rate at 15 min (15%; HR = 3.621, 95% CI = 1.086-12.079, P = 0.036) were statistically significant determinants of overall survival, while tumor number (solitary, HR = 2.465, 95% CI = 1.170-5.191, P = 0.018) was identified for disease-free survival. Overall survival of patients with early recurrence after RFA was significantly worse than that of patients with late recurrence. Tumor size was the only independent risk factor of early recurrence after RFA of HCC (tumor size2 cm; risk ratio [RR] = 4.629, 95% CI = 1.241-17.241, P = 0.023).Percutaneous RFA under the protocol reported here has the potential to provide local tumor control for small HCC. In addition to host factors, time interval from RFA to recurrence was an important determinant of prognosis.

A 56-year-old man with chronic hepatitis C (HCV) was treated with interferon therapy and achieved sustained virological response (SVR) in 1993. Thirteen years later, in 2006 two liver tumors, 35-mm and 11-mm in diameter respectively, were detected in liver segment 6. Hepatic resection was performed, and pathologically one nodule was diagnosed as cholangiocellular carcinoma (CCC) and the other hepatocellular carcinoma (HCC). Continuity was not recognized between these tumors, thus, we diagnosed this case as double cancer (CCC and HCC). Here, we report a rare case of double cancer (CCC and HCC) that developed 13 years after achieving SVR for HCV infection.

COACH syndrome is a disorder characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis, and 21 cases have been reported to date. Here we describe the first Japanese case of COACH syndrome, who was diagnosed at the age of 37 years and never progressed to liver failure. The patient was found to have delayed developmental milestones at the age of 5 months and mental retardation at the age of 7 years. She had been treated for hepatopathy of unknown origin from the age of 22 years. She was admitted to Hiroshima University Hospital at the age of 37 years after the identification of esophageal varices on a routine upper endoscopy. Computed tomography of the abdomen revealed portal hypertension and splenomegaly, and liver biopsy showed liver fibrosis. In addition, she had coordination disorder and dysarthria. Brain magnetic resonance images revealed hypoplasia of cerebellar vermis. The final diagnosis was COACH syndrome. She underwent endoscopic injection sclerotherapy for esophageal varices. From that point until her death from ovarian cancer at the age of 41 years, the liver function tests were stable without an episode of hematemesis. Physicians should be aware of COACH syndrome when they examine young patients who present with hepatopathy, portal hypertension of unknown origin and cerebellar ataxia.

Objective To study the correlation between changes in portosystemic collaterals, evaluated by multidetector-row computed tomography imaging using multiplanar reconstruction (MDCT-MPR), and prognosis in patients with hemorrhagic esophageal varices (EV) after endoscopic treatment. Methods Forty-nine patients with primary hemostasis for variceal bleeding received radical endoscopic treatment: endoscopic injection sclerotherapy (EIS) or endoscopic variceal ligation (EVL). Patients were classified according to the rate of reduction in feeding vessel diameter on MDCT-MPR images, into the narrowing ( n = 24) and no-change ( n = 25) groups. We evaluated changes in portosystemic collaterals by MDCT-MPR before and after treatment, and determined rebleeding and survival rates. Results The left gastric and paraesophageal (PEV) veins were recognized as portosystemic collaterals in 100 and 80%, respectively, of patients with EV on MDCT-MPR images. The rebleeding rates at 1, 2, 3, and 5 years after endoscopic treatment were 10, 15, 23, and 23%, respectively, for the narrowing group, and 17, 24, 35, and 67%, respectively, for the no-change group ( P = 0.068). Among no-change group, the rebleeding rate in patients with large PEV was significantly lower than that with small PEV ( P = 0.027). The rebleeding rate in patients with small PEV of the no-change group was significantly higher than that in the narrowing group ( P = 0.018). There was no significant difference in rebleeding rates between the no-change group with a large PEV and narrowing group ( P = 0.435). Conclusion Changes in portosystemic collaterals evaluated by MDCT-MPR imaging correlate with rebleeding rate. Evaluation of portosystemic collaterals in this manner would provide useful information for the management of hemorrhagic EV.