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Aim: The aim of this study was to evaluate the use of a new classification for safer transradial access hepatic interventional radiology, based on preoperative evaluation of the location of the left subclavian artery bifurcation in the aortic arch. Methods: A total of 38 consecutive patients with hepatocellular carcinoma and 74 sessions of radial access for visceral intervention (R.A.V.I.) were reviewed. We classified the location of the left subclavian artery bifurcation in the aortic arch in three areas using an oblique view computed tomography image matched with the curve of the aortic arches according to a new criteria Three Areas Criteria For R.A.V.I. (named "TAC‐F‐R"), and measured the required time from initial left radial artery arteriography to celiac artery or superior mesenteric artery arteriography. Results: The median time required for left radial artery arteriography to the celiac artery or superior mesenteric artery arteriography in each of the three areas were: area A, 0:11:10 (h, min, s); area B, 0:14:44; and area C, 0:31:51. There were significant differences between each area after Bonferroni correction (p < 0.01; A vs. B, p = 0.086; A vs. C, p = 0.001; and B vs. C, p = 0.045), with areas A and B requiring a significantly shorter time. Finally, no patients showed neurogenic disfunction within 1 week after the R.A.V.I. procedure. Conclusions: The new classification, "TAC‐F‐R," for safer transradial access hepatic interventional radiology is effective for avoiding difficult cases, and selects more suitable patients with hepatocellular carcinoma for the R.A.V.I. procedure. [ABSTRACT FROM AUTHOR]

Simple Summary: The Barcelona clinic liver cancer (BCLC) system is used widely for staging hepatocellular carcinomas (HCCs). However, it is questionable that for patients classified as BCLC stage C, control of intrahepatic targets using various treatment procedures is not the main topic of discussion, whereas the importance of intrahepatic tumor control in patients with extrahepatic tumor spread is reviewed. Therefore, this study analyzed the data of 64 consecutive BCLC stage C patients with intrahepatic target nodules who received systemic therapy and evaluated the efficacy of the combined use of systemic sequential therapy, including more than two agents, and locoregional treatment administered after initiation of systemic therapy. We showed that the combined use of systemic sequential therapy of more than two agents and locoregional-treatment improved overall survival in BCLC stage C HCC patients with intrahepatic target nodules who had previously received systemic therapy-based treatment. Background: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). Methods: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP). Results: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003). Conclusions: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment. [ABSTRACT FROM AUTHOR]

Introduction: When lenvatinib is administered to people with hepatocellular carcinoma (HCC), tumor blood flow is reduced due to the inhibition of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). Few studies have examined the decrease in tumor blood flow with respect to changes in tumor blood vessels (TBVs) in clinical practice. We investigated the mechanism of tumor blood flow control by investigating changes in the diameter of relatively large TBVs in large-sized lesions with high blood flow. Methods: From January 2011 to October 2021, patients receiving lenvatinib for unresectable intrahepatic HCC at Toranomon Hospital, Tokyo, Japan, were considered for inclusion. We investigated the TBV diameter in the arterial phase of dynamic computed tomography before treatment and its change over time (2–12 weeks after lenvatinib initiation). The relationship between changes in TBV diameter and prognosis was also examined. Results: Of 114 patients treated with lenvatinib for HCC, 26 patients who had intrahepatic lesions with a tumor diameter of 30 mm or more enrolled in the study. The median tumor and TBV diameters before treatment were 58 mm and 2.55 mm, respectively. Twenty-five patients (96%) had a shrinkage in TBV diameter 2–12 weeks after lenvatinib administration. The maximum TBV diameter shrinkage of 20% or more was observed in 19 patients (73%), and progression-free survival was prolonged in these patients compared to the group with less than 20% TBV diameter shrinkage (p = 0.039). Discussion/Conclusion: Due to the antiangiogenic effect of lenvatinib, a shrinkage in the TBV diameter of HCC was observed. The shrinkage of TBV may be regarded as a process of normalization of TBVs. The shrinkage of TBVs in imaging analysis may be associated with improved prognosis; however, additional studies are still required. [ABSTRACT FROM AUTHOR]

Background and Aims: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of early progressive disease (e-PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). Methods: Twenty consecutive patients with measurable intrahepatic target nodules who received Atezo/Bev treatment were reviewed. The oncological aggressiveness of tumors estimated by 18F-FDG-PET/CT was analyzed using the rate of e-PD within 12 weeks and early progression-free survival (e-PFS) and overall survival (OS). Multivariate analysis was used to identify potential confounders for PD during Atezo/Bev therapy. Results: Using the Response Evaluation Criteria in Solid Tumors version 1.1, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with lower objective response rates compared with TLR values <2 (18% vs. 33%, respectively). Moreover, TLR values ≥2 were significantly associated with higher e-PD rates compared with TLR values <2 (64% vs. 11%, respectively) and worse e-PFS (p = 0.021). In multivariate analysis, TLR ≥2 showed marginal significance as a predictor of e-PD (p = 0.053), and utility as a predictor for worse e-PFS (hazard ratio, 7.153; 95% confidence interval, 1.258–40.689; p = 0.027). In contrast, no significant differences in OS with/without e-PD were observed during the treatment course. In this study, 8 patients experienced e-PD and almost 40% of patients experienced acceptable disease control following subsequent lenvatinib treatment. Conclusion: Pretreatment 18F-FDG-PET/CT may be a useful new predictor of e-PD and may enable early decision-making based on early treatment changes following Atezo/Bev treatment of HCC. [ABSTRACT FROM AUTHOR]

Serum hepatitis B core‐related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e‐antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow‐up of 11.0 years, 22 patients developed HCC (11.8/1,000 person‐years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log‐rank test; P < 0.001). In 110 patients (61.1%) with ≥4.0 log U/mL at baseline (high HBcrAg cohort), HBcrAg declined to ≤2.9 log U/mL at year 1 in 25 patients (22.7%). The adjusted hazard ratio for HCC incidence was significantly lower in patients with HBcrAg ≤2.9 log U/mL at year 1 than in those in the high HBcrAg cohort. Conclusion: Measurement of HBcrAg by ultrasensitive assay has better potential for predicting HCC during antiviral treatment than the current HBcrAg assay. [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of overall prognosis in patients with hepatocellular carcinoma treated with lenvatinib. Methods: Forty-eight consecutive patients who received lenvatinib treatment were reviewed. The oncological aggressiveness of tumors estimated using 18F-FDG-PET/CT was investigated by the analysis of progression-free survival (PFS), post-progression survival (PPS), and overall survival (OS). Multivariate analysis was used to identify potential confounders for OS during lenvatinib therapy. Results: Using the Modified Response Evaluation Criteria in Solid Tumors, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with a better objective response to lenvatinib than a TLR <2 (78 vs. 62%), resulting in a similar PFS (p = 0.751). Because of a significantly worse PPS, OS with a TLR ≥2 was poor compared to a TLR < 2 (p = 0.012). Multivariate analysis confirmed that a TLR ≥ 2 was associated with poor OS (hazard ratio, 2.709; 95% CI, 1.140–6.436; p = 0.024). Analysis of 24 patients who received a repeat 18F-FDG-PET/CT showed that daily changes expressed as ΔTLR × 103/day over the treatment course tended to be different among the types of subsequent treatment. A R0 resection and lenvatinib-TACE sequential therapy provided good disease control (median, −4.593 and −0.024, respectively) compared with other treatments (median, 5.278) (p = 0.075). Conclusion: Lenvatinib has acceptable disease control regardless of estimated tumor differentiation. A high TLR (≥2) is a poor prognostic factor of OS following lenvatinib treatment, while ΔTLR × 103/day provides useful information of disease control status. [ABSTRACT FROM AUTHOR]

Aims: Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core‐related antigen (HBcrAg), measured by the ultra‐highly sensitive assays, in cases with HCC development after HBsAg seroclearance. Methods: We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non‐HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra‐highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology. Results: All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT‐HBsAg or iTACT‐HBcrAg at all follow‐up points. HBcrAg levels in the HCC group, using iTACT‐HBcrAg, were significantly higher than those in the non‐HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8–4.2) versus 2.6 (<2.1–3.8), p = 0.020). The best cutoff value of iTACT‐HBcrAg for predicting HCC development was 2.7 LogU/ml by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non‐HCC group (100% [5/5] versus 33% [4/12], p = 0.029). Conclusions: Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients. [ABSTRACT FROM AUTHOR]

Background: The sensitivity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in hepatocellular carcinoma (HCC) is low; however, clinical evidence demonstrating its prognostic value in patients with HCC has recently been reported. This study aimed to assess the value of 18F-FDG-PET/CT as a tool for evaluating the response of HCC to lenvatinib treatment. Methods: We evaluated 11 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18F-FDG-PET/CT from April 2018 to December 2019. The tumor-to-normal liver ratio (TLR) of the target tumor was measured before and during the course of lenvatinib treatment with 18F-FDG-PET/CT (pre and post analysis, respectively), with a TLR ≥2 classified as PET-positive HCC. At the time of each evaluation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the modified RECIST (mRECIST), and the tumor marker alfa-fetoprotein (AFP). Results: Of 11 patients, 3 (27%) and 8 (73%) had an objective response to lenvatinib treatment at the time of post-analysis by RECIST 1.1 and mRECIST, respectively. There were 3 (27%) and 7 (64%) patients with PET-positive HCC at the time of pre- and post-analysis, respectively. There was a significant correlation between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019). Based on these results, we were able to perform liver resection on 4 patients with PET-positive HCC as conversion therapy. Three samples from these patients showed poorly differentiated tumors. Conclusion: 18F-FDG-PET/CT has potential as an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality may provide useful information for considering prognosis and subsequent therapy. [ABSTRACT FROM AUTHOR]

Introduction: It remains unclear whether TERT promoter mutation (TERT C228T) in serum cell-free DNA (cfDNA) is useful for the diagnosis of hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Methods: In this retrospective study, we analyzed the relationships between TERT C228T in serum cfDNA and levels of AFP and PIVKAII in 57 Japanese patients with histopathologically confirmed NAFLD background, consisting of 36 patients with HCC and 21 without HCC. We also examined the liver-related survival rate and HCC recurrence rate after the initial treatment for HCC. TERT C228T was detected using a highly sensitive method based on wild-type blocking PCR (detection limit in excess of 0.7% mutant-type DNA). Results: In all of the 57 patients, multivariate analysis identified TERT C228T positive as significant determinant of primary HCC. In the 36 patients with HCC, the percentage of patients positive for TERT C228T was 63.9%. The percentage of patients positive for TERT C228T with normal AFP and PIVKAII was 35.3%. The positive predictive value and specificity for prediction of BCLC stage 0 or A were both high. In 6 patients, TERT C228T was repeatedly negative during follow-up but became positive at the time of HCC diagnosis. Four patients who underwent HCC surgical resection had well-differentiated solitary HCC measuring <30 mm, and all were TERT C228T positive with normal AFP and PIVKAII. TERT C228T status had no influence on the cumulative liver-related survival rate and HCC recurrence rate. Conclusions: Our results highlight the superiority of TERT C228T in serum cfDNA compared with AFP and PIVKAII in the early diagnosis of primary HCC in NAFLD patients. [ABSTRACT FROM AUTHOR]

Aim: The number of patients with fatty liver disease (FLD) is increasing globally. Ethanol consumption in FLD is known to be associated with an increased risk of hepatocellular carcinoma (HCC), but the effects of alcohol consumption on the occurrence of multiple HCCs remain unclear. We explored the relationship between the daily ethanol intake and the HCC number. Methods: This single‐center retrospective study enrolled 114 patients without viral or immune hepatitis undergoing first‐line HCC treatment who had been diagnosed with FLD by abdominal ultrasonography or a liver biopsy at the same time as or before HCC detection. We categorized patients into four groups according to the daily alcohol consumption (<20 g: non‐alcoholic fatty liver disease, n = 45; 20–39 g: low‐intermediate ethanol intake with FLD, n = 13; 40–69 g: high‐intermediate ethanol intake with FLD, n = 31; ≥70 g: alcoholic fatty liver disease, n = 25). The relationship between the daily ethanol consumption and the number of HCCs (single or multiple) was examined. Results: The risk of multiple HCCs was significantly higher in the high‐intermediate ethanol intake with FLD (HR 2.89, 95% CI 1.04–8.02, P = 0.042) and alcoholic fatty liver disease (HR 3.14, 95% CI 1.07–9.22, P = 0.037) groups than in the others. A multivariate analysis showed that a daily ethanol intake ≥40 g was associated with a significantly increased risk of multiple HCCs (HR 2.82, 95% CI 1.16–6.88, P = 0.023). Conclusions: Our findings suggest that a high daily ethanol intake might lead to multiple hepatocarcinogenesis in patients with FLD. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC). Methods: Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy. Results: Heterogeneous enhancement patterns (Type-3 and -4), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern (Type-2) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS (p = 0.313). Because of significantly worse PPS, overall survival of Type-4 tumor was poor compared to Type-2 or -3 tumors (p = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01–0.71; p = 0.023), while Type-4 enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06–8.05; p = 0.039). Conclusion: Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) promoter mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). However, there is currently no suitable highly sensitive method that can detect such mutation using serum cell‐free DNA (cfDNA). We analyzed somatic point mutations that substitute cytosine for thymidine at position 228 (C228T), as one of the hotspots of TERT promoter mutations, in serum cfDNA using a highly sensitive detection method of wild‐type blocking polymerase chain reaction (WTB‐PCR) combined with Sanger sequencing. In TERT promoter mutation sensitivity study, synthetic oligonucleotides were prepared to determine the lowest detection limit of the WTB‐PCR, using serial dilutions of mutant‐type (MT) DNA in the background of wild‐type (WT) DNA. Using this technique, we conducted a longitudinal study in one patient who developed HCC during the follow‐up and determined the relationship between HCC and TERT C228T in serum cfDNA. In the sensitivity study, the mutant peak at position 228 was detected at 0.7% or higher but was not detected at 0.6%. Thus, sequencing analysis of WTB‐PCR product demonstrated the limit of detection in excess of 0.7% MT DNA in the background of WT DNA. One male patient with HCV‐related cirrhosis developed HCC during the follow‐up. TERT C228T was negative before the diagnosis of HCC, positive at the diagnosis of HCC and did not increase with advancement of malignancy. We developed a highly sensitive method for detection of TERT promoter mutation using WTB‐PCR combined with Sanger sequencing and demonstrated its clinical usefulness in the measurement of TERT C228T in serum cfDNA. Larger studies are needed to confirm these results and establish the clinical utility of this new method. Research Highlights: We developed a highly sensitive method for detection of TERT promoter mutation using WTB‐PCR combined with Sanger sequencing and demonstrated its clinical usefulness in the measurement of TERT C228T in serum cfDNA. [ABSTRACT FROM AUTHOR]

Aim: The risk of development of hepatocellular carcinoma (HCC) persisted in patients with advanced fibrosis, even after achieving sustained virologic response (SVR). This study aimed to show the advantage of liver stiffness measurement (LSM) at baseline and after SVR to predict HCC occurrence and esophageal varices (EV) exacerbation. Methods: These risks were evaluated in 398 chronic hepatitis C patients without a history of HCC who achieved SVR after direct‐acting antiviral agent and evaluated LSM at least twice during follow up. We defined liver cirrhosis and chronic hepatitis as LSM of ≥12 kPa and <12 kPa, respectively. Results: LSM was significantly correlated with serum fibrosis markers, such as Fib‐4 index and Wisteria floribunda agglutinin‐positive Mac‐2 binding protein, at baseline and SVR at 24 weeks after treatment (SVR24). Five patients received preventive treatment of EV, but no EV bleeding occurred after SVR, and their LSM at baseline and SVR24 was significantly higher than that of other cirrhosis patients. The annual rate of HCC during the first 4 years was 1.5%. LSM in HCC patients tended to decrease after direct‐acting antiviral agent therapies, but significantly higher than that of cirrhosis patients without HCC before and after treatment. Multivariate analysis identified LSM and alpha‐fetoprotein at baseline and LSM at SVR24 as significant independent predictors of HCC. Conclusions: Evaluating LSM not only at baseline, but also SVR24, was found to be useful for the detection of advanced fibrosis patients at high risk of HCC occurrence and EV exacerbation. We recommend focused surveillance of HCC and EV for these patients. [ABSTRACT FROM AUTHOR]

Aim: The long‐term effects of sustained virologic response (SVR) to antiviral therapy on the risk of liver complications, such as exacerbation of esophageal varices (EV), hepatocellular carcinoma (HCC), malignant lymphoma, and liver‐related and overall death in hepatitis C virus (HCV)‐infected patients with liver cirrhosis are not fully known. Methods: These risks were evaluated during long‐term follow up of 457 patients with HCV‐related Child–Pugh Class A liver cirrhosis without history of HCC. Results: The respective cumulative 5‐ and 10‐year rates of EV exacerbation were 2.0% and 3.1%. Multivariate analysis identified the presence of EVs, thrombocytopenia at baseline. and alcohol intake as significant independent predictors of EV exacerbation before and after SVR. The cumulative 5‐ and 10‐year rates of HCC were 6.8% and 10.2%, respectively. Male sex and the presence of EV were significant independent determinants of HCC before and after SVR. Although the cumulative 5‐year HCC recurrence rate was 49.4%, the overall survival rate since HCC was 73.6% at 5 years. The overall survival rates since SVR were 98.7% and 93.6% at 5 and 10 years, respectively. Progression of HCC was the most frequent all‐cause mortality, but none of the patients died of liver decompensation. Male sex and Fibrosis‐4 index of ≥3.0 after SVR were significant and independent predictors of mortality. Conclusion: Patients with HCV remain at risk of HCC for >10 years after achieving SVR, and HCC is the most common cause of mortality. We recommend long‐term surveillance of cirrhotic patients with HCV, even after achieving SVR. [ABSTRACT FROM AUTHOR]

Background: We determined the antiviral potency and viral breakthrough rate after 10 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection.Methods: The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1 log copies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10 years were calculated.Results: The median age was 50 years and follow-up period was 5.5 years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10 years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was - 0.08 log IU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan-Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment.Conclusions: Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10 years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to clarify the utility of a no‐touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC) compared to surgical resection. Methods: We evaluated 175 consecutive patients with HCC (single nodule, tumor diameter ≤ 30 mm) who underwent surgical resection (146 received partial resection) and 313 patients who received RFA; 277 patients received touch ablation using a monopolar or bipolar RFA device, and 36 received no‐touch ablation using a bipolar RFA device. Pretreatment arterial and portal phase dynamic computed tomography (CT) or magnetic resonance imaging (MRI) images were classified into four enhancement patterns: Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively; Type 3 is a heterogeneous enhancement pattern with a septum‐like structure; and Type 4 is an irregularly shaped ring structure enhancement pattern. Results: Cumulative recurrence rates significantly differed between procedures (surgical resection, 7.5%; no‐touch ablation, 2.9%; and touch ablation, 17.7% at the third year; P = 0.005). Multivariate Cox proportional hazards analysis revealed that enhancement pattern type (Type 3: hazard ratio [HR], 2.95; P = 0.002; and Type 4: HR, 3.88, P = 0.002), treatment procedure (touch ablation: HR, 3.36; P < 0.001), and serum α‐fetoprotein level (≥30 μg/L: HR, 1.87; P = 0.009) were significant predictors of intrasubsegmental recurrence. No significant differences between no‐touch ablation and surgical resection were observed. Conclusion: The no‐touch pincer ablation procedure has the potential to prevent intrasubsegmental recurrence after RFA for patients with HCC to the same degree as partial resection. [ABSTRACT FROM AUTHOR]

Impact of substitution of aa70 in the core region (Core aa70) in HCV genotype 1b (HCV‐1b) on hepatocarcinogenesis following eradication of HCV RNA by direct‐acting antiviral therapy is not clear. In a retrospective study, 533 patients with HCV‐related chronic liver disease, with sustained virological response defined as negative HCV RNA at 12 weeks after cessation of direct‐acting antiviral therapy, were examined to evaluate the relationship between Core aa70 substitution and hepatocarcinogenesis. Twelve patients developed hepatocellular carcinoma during the follow‐up period. The cumulative hepatocarcinogenesis rates were 1.7% and 2.4% at the end of 1 and 2 years, respectively. Overall, multivariate analysis identified HCV subgroup (HCV‐1b with Gln70(His70); P = 0.003) and age (>65 years; P = 0.049), as pretreatment predictors of hepatocarcinogenesis. In HCV‐1b patients, multivariate analysis identified post‐treatment Wisteria floribunda agglutinin positive Mac‐2 binding protein (>1.8 COI; P = 0.042) and HCV subgroup (HCV‐1b with Gln70(His70); P = 0.071), as predictors of hepatocarcinogenesis, including post‐treatment parameter. In conclusion, Core aa70 substitution in HCV‐1b at the start of direct‐acting antiviral therapy is an important predictor of hepatocarcinogenesis following eradication of HCV RNA. This study emphasizes the importance of detection of Core aa70 substitution before initiating antiviral therapy. [ABSTRACT FROM AUTHOR]

Aim Pruritus is one of the complications of chronic liver disease, and it is important to investigate the predictors. Methods Six hundred and seventy-three consecutive Japanese patients with chronic liver disease were retrospectively investigated for itch severity. Furthermore, 138 of all 673 patients were introduced to nalfurafine hydrochloride, and the improvement of itch severity was evaluated. The itch severity was self-assessed using the pruritus scores by Kawashima's criteria and visual analog scale. Results Two hundred and twenty-nine of the 673 patients (34.0%) were evaluated as 1 point or more of pruritus severity of Kawashima's criteria, and 46 patients (6.8 %) as 3 points or more. Multivariate analysis established that being negative for hepatitis B surface antigen (HBsAg) and presence of hepatocellular carcinoma (HCC) were significant determinants of pruritus (≥1 point of Kawashima's criteria), and being negative for HBsAg and having lower levels of platelet count were significant determinants of severe pruritus (≥3 points). Ninety-three of the 138 patients (67.4%) with nalfurafine hydrochloride indicated improvement of itch, defined as a decrease in VAS of 50 mm or more. There were no significant differences in treatment efficacy of nalfurafine hydrochloride, regardless of the three predictors of pruritus (HBsAg, HCC and platelet count). Conclusion The present retrospective study indicated the predictors for pruritus, based on the large number of patients with chronic liver disease. Furthermore, this study demonstrated that nalfurafine hydrochloride may be useful for pruritus, regardless of the predictors. [ABSTRACT FROM AUTHOR]

With rapidly aging population in the world, many elderly patients present with hepatitis B virus (HBV) infection. We conducted a retrospective cohort study involving 359 untreated HBV patients aged 60 and older who were free of hepatocellular carcinoma (HCC) and acute hepatitis at the initial visit, and examined the incidence of HCC and liver-related mortality rate. During the follow-up period of 7.9 years (range, 0-25 years), 26 patients (7.2% of patients) developed HCC, 20 patients died from liver-related diseases (61% of total deaths), including HCC, liver failure, and gastrointestinal bleeding. The cumulative rates of HCC at years 5, 10, and 15 were 6.5%, 15.6%, and 15.6%, respectively. The cumulative rates of mortality from liver-related diseases at years 5, 10, 15 were 3.3%, 12.3%, and 15.7%, respectively. Multivariate analysis identified HBV DNA (≥5.0 Log IU/mL), male gender, and FIB4-Index (≥3.6) as significant independent risk factors for HCC, and alpha-fetoprotein (≥10 ng/mL) as significant independent predictors of liver-related mortality. We conclude that high levels of HBV DNA, progression of liver fibrosis, and male gender are independent risk factors of HCC in untreated patients infected with HBV aged 60 and older. [ABSTRACT FROM AUTHOR]

Background: Suppressive activity of recurrence by interferon-free direct-acting antivirals (DAA) is not elucidated after curative treatment of hepatocellular carcinoma (HCC).Patients and Methods: A total of 177 patients received DAA after curative manners of HCC: 89 patients underwent DAA therapy after initial HCC treatment, and the other 88 patients after repeated therapy of 2-10 times. Among a cohort of HCC patients with surgery and radiofrequency ablation, 89 patients were chosen adjusting age, gender, and Barcelona Clinic Liver Cancer (BCLC) staging with 89 patients with initial HCC therapy.Results: HCC recurrence rates at the end of first and second year were 18.1 and 22.1% in patients with once of HCC therapy, 28.2 and 41.6% in those with 2-3 times of therapy, and 60.2 and 74.5% in those with 4 or more times of therapy, respectively (P < 0.0001). Recurrence rates were compared between 89 patients with DAA therapy after initial HCC therapy and 89 age-, gender-, and BCLC staging-matched patients without antiviral therapy after initial HCC therapy. HCC recurrence rates at first and second year were 18.1 and 25.0% in patients with DAA therapy and 21.8 and 46.5% in those without DAA therapy, respectively (P = 0.003). Multivariate analysis showed DAA therapy significantly decreased recurrence rate with a hazard ratio of 0.353 (confidence interval: 0.191-0.651) after adjustment with covariates of tumor multiplicity, alpha-fetoprotein value, and prothrombin time.Conclusions: DAA therapy significantly decreased recurrence rate when it was performed after initial HCC therapy. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to clarify the usefulness of a no-touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC). Methods We studied 303 consecutive patients with HCC (single nodule and tumor diameter ≤30 mm) who received RFA between January 2005 and April 2015; 268 patients received touch ablation using a monopolar or bipolar RFA device, and 35 received no-touch ablation using a bipolar RFA device. The pretreatment arterial and portal phase dynamic computed tomography or magnetic resonance images were classified into four enhancement patterns. Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively. Type 3 is a heterogeneous enhancement pattern with a septum-like structure, and Type 4 is an irregularly shaped ring structure enhancement pattern. Results With regard to intrasubsegmental tumor recurrence, among the 268 patients who underwent the touch ablation procedure, tumors recurred in 52 (19.4%) patients, and among the 35 patients who underwent the no-touch ablation procedure, tumors recurred in one (2.9%) patient. Cumulative intrasubsegmental tumor recurrence rates tended to be higher with touch ablation ( P = 0.083). Multivariate Cox proportional hazards analysis revealed that ablation procedure (touch ablation, hazard ratio [HR] 10.32, P = 0.032), type of enhancement pattern (Type 3, HR 3.05, P = 0.006; and Type 4, HR 8.87, P < 0.001) and serum des-γ-carboxyprothrombin level (≥100 AU/L; HR 2.73, P = 0.035) were significant predictors for intrasubsegmental recurrence. Conclusion The no-touch pincer ablation procedure has the potential to prevent intrasubsegmental recurrence after RFA for patients with HCC. [ABSTRACT FROM AUTHOR]

Objectives: There is little information on the risk factors for hepatocellular carcinoma (HCC) and outcome of treatment with an all-oral combination of direct-acting antiviral regimens following eradication of hepatitis C virus (HCV) RNA. Methods: The study subjects were 1,170 patients with HCV genotype 1-related chronic liver disease treated with either NS5A inhibitor plus NS3/4A protease inhibitor (n = 707), NS5A inhibitor plus NS5B polymerase inhibitor (n = 345), or NS5A inhibitor, NS3/4A protease inhibitor plus ritonavir (n = 118), for 12-24 weeks. All patients were free of HCC before and during therapy. Results: In this retrospective study, 22 patients developed HCC during the follow-up (time from the end of antiviral therapy until the last visit: 1.3 years). At 1 and 2 years after completion of the treatment, the cumulative HCC rates for the whole group were 1.8 and 2.3%, respectively, and 1.4 and 1.8%, respectively, for 1,065 patients who showed sustained virological response (SVR). The risk factors for HCC identified by multivariate analysis were hypoalbuminemia, thrombocytopenia, a high α-fetoprotein level, and non-SVR for all patients, and hypoalbuminemia and a high α-fetoprotein level for patients with SVR. Conclusion: Eradication of HCV RNA by direct-acting antiviral regimens might reduce the risk of HCC. Albumin and α-fetoprotein levels are significant risk factors for HCC. [ABSTRACT FROM AUTHOR]

Aim The effect of transcatheter arterial chemoembolization (TACE) is not necessarily sufficient in patients with multiple hepatocellular carcinoma (HCC). We evaluated the antitumor activity and adverse events of TACE using warmed miriplatin suspension for multiple HCC. Methods Seventy patients with multiple HCC received TACE using warmed miriplatin/lipiodol suspension, including patients who were TACE-naïve (group A, n = 5), those undergoing initial TACE after radical therapies (group B, n = 31), and those with a history of repeated TACE (group C, n = 34). Median tumor size was 19.5 mm and a median of four nodules. Results Complete necrosis (TE 4) and partial necrosis (TE 3) of 50% or more were attained in 24 and 19 patients at 3 months after TACE, respectively. Response rates (TE 4 + TE 3) were 60.0% in group A, 83.9% in group B, and 41.2% in group C ( P = 0.038). Survival rates of all patients after TACE were 82.6% after 1 year, 65.6% after 2 years, and 47.7% after 3 years. Three-year survival rates of patients in groups A, B, and C were 53.3%, 78.8%, and 29.7%, respectively ( P = 0.0029). Conclusion Transcatheter arterial chemoembolization using warmed miriplatin induced high response rate in multiple HCC, and the rate was significantly high in those patients with recurrent multiple HCCs after curative therapies. [ABSTRACT FROM AUTHOR]

Aim The aim of this study is to clarify the usefulness and limitations of balloon-occluded transcatheter arterial chemoembolization (B-TACE) using miriplatin for patients with four or fewer hepatocellular carcinoma (HCC) nodules. Methods We studied 47 nodules in 30 consecutive patients who received miriplatin by B-TACE to treat HCC with four or fewer nodules per patient. The treatment effect was evaluated using the Response Evaluation Criteria in Cancer of the Liver. Results Nodules were divided according to the presence or absence of portal vein visualization during B-TACE. In the presence group, dynamic computed tomography at 3 months post-therapy showed Response Evaluation Criteria in Cancer of the Liver treatment effect (TE) 4 in 88% (14/16), TE3 in 0% (0/16), TE2 in 0% (0/16), TE1 in 12% (2/16), and objective response in 88% of nodules. In the absence group, the results were TE4 in 35% (11/31), TE3 in 13% (4/31), TE2 in 26% (8/31), TE1 in 26% (8/31), and objective response decreased to 48% of nodules. In addition to typical hypervascular nodules, we treated three nodules with irregular ring enhancement that predicted poorly differentiated HCC and four nodules that included a hypoenhancement area that predicted well to moderately differentiated HCC. All irregular ring enhancement nodules achieved TE4. Other nodules that were predicted to be well to moderately differentiated HCC did not have portal vein visualization during B-TACE and could not achieve TE4. Conclusion Balloon-occluded transcatheter arterial chemoembolization is a useful technique for treatment of classical hypervascular HCC, and portal vein visualization during the B-TACE procedure may provide more favorable local control. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the rate of development of hepatocellular carcinoma (HCC) in patients who achieved sustained virologic response (SVR) by direct antiviral agents (DAA). We retrospectively evaluated patients who achieved SVR by oral DAA interferon-free regimens (n = 77) (daclatasvir/asunaprevir [n = 67], ombitasvir/paritaprevir/ritonavir [n = 9], and telaprevir [n = 1]) and by pegylated-interferon plus ribavirin (Peg-IFN/RBV, n = 528). In all patients, the background was chronic hepatitis or cirrhosis caused by HCV genotype 1b. During a median follow-up period of 4.0 years, two (2.6%) of DAA-treated patients developed HCC. The 3- and 5-year cumulative HCC development rates were 1.30% and 3.03%, respectively, in the DAA group, and 1.02% and 2.19 % in the Peg-IFN/RBV group ( P not significant). In patients with Fib-4 score of >3.25, the 3-year HCC development rates were 4.35% and 3.95%, whereas those of the 5 year were 9.66% and 8.37%, in the DAA and Peg-IFN/RBV group, respectively. In patients with Fib-4 score of ≤3.25, none of the DAA group developed HCC, whereas 0.48% at 3-year and 1.05% at 5-year of patients of the Peg-IFN/RBV group did. Propensity score analysis using the inverse probability of treatment weights (IPTW) also showed no significant difference in HCC development rate between the two groups. Serum AFP gradually and similarly decreased after initiation of antiviral therapy in both groups. Our data indicate that the HCC risk rate after SVR is similar regardless of whether the latter was achieved by DAA or IFN-based regimens. J. Med. Virol. 89:476-483, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background and Aims: Predictive factors for hepatocarcinogenesis following eradication of hepatitis C virus (HCV) RNA by antiviral therapy with direct-acting antivirals are unknown. Especially the impact of treatment with or without interferon on hepatocarcinogenesis is not clear. Methods: A total of 958 patients with HCV genotype 1-related chronic liver disease and a sustained virological response defined as negative HCV RNA 24 weeks after cessation of antiviral therapy with direct-acting antivirals (triple therapy of NS3/4A protease inhibitor/peginterferon/ribavirin or all-oral combination therapy with NS3/4A protease inhibitor plus NS5A inhibitor) were included in a retrospective study. None of the patients had hepatocellular carcinoma before and during antiviral therapy. Results: In all, 14 patients developed hepatocellular carcinoma during follow-up, and the development rate per 1,000 person-years was 7.35. The cumulative hepatocarcinogenesis rates were 4.2 and 4.2% at the end of 5 and 7 years, respectively. Multivariate analysis identified fibrosis 4 (FIB4) index (= 2.7) and body mass index (= 23.0) as determinants of hepatocarcinogenesis, but they did not identify the treatment regimen. In patients with a FIB4 index = 2.7, the hepatocarcinogenesis rates with the interferon regimen were not different from those for the regimen without interferon, regardless of gender. Conclusion: Liver fibrosis and body mass index, but not treatment regimen, are important predictors of hepatocarcinogenesis following eradication of HCV RNA by direct-acting antivirals. [ABSTRACT FROM AUTHOR]

Background and Aims: A sustained virological response (SVR) decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We investigated the longterm outcomes of patients who developed HCC after achieving SVR with interferon therapy. Patients: Of 75 patients who developed HCC after SVR, 40 patients underwent radical therapies (SVR group). From 436 patients undergoing surgical resection for hepatitis C virus-positive HCC, 80 patients were randomly chosen as a control cohort, after adjusting for age, gender, and extent of hepatic fibrosis (non- SVR group). Patients were observed for a median of 5.08 years. Results: HCC recurrence was found in 16 SVR patients and in 66 non-SVR patients. The respective HCC recurrence rates of SVR and non-SVR patients were 23 and 56% at 3 years, 42 and 77% at 5 years, and 53 and 90% at 10 years (p = 0.001). The respective overall survival rates in the SVR and non-SVR groups were 93 and 68% at 5 years, 88 and 34% at 10 years, and 53 and 21% at 15 years (p = 0.001). Conclusion: Although SVR patients had a significantly lower HCC recurrence rate than the non-SVR patients, the cumulative recurrence rate of SVR patients increased to 86% at 15 years. [ABSTRACT FROM AUTHOR]

Objectives: A randomized controlled trial was conducted to evaluate the efficacy of impedance control of a radiofrequency interstitial thermal ablation system (RITA) used to treat hepatocellular carcinoma (HCC). Methods: Fifteen patients with hypervascular HCCs <20 mm in diameter were randomly treated with radiofrequency ablation (RFA) using conventional temperature control (group A) or impedance control methods (group B). RITA needle electrodes were used in all cases. We compared ablation time, extent of lesion ablation, and energy use between the two groups. Results: The median long and short diameters of the axial cross sections of radiofrequency-induced necrotic areas visualized by CT were 32 mm (range, 26-36) and 25 mm (20-31) in group A and 32 mm (28-40) and 31 mm (24-37) in group B, respectively. The short diameter of group B patients was significantly greater than that of group A patients (p = 0.029). The median ablation time was 18.8 min in group A and 13.4 min in group B, thus significantly shorter in group B (p = 0.001). The energy requirement did not differ significantly between the groups. Conclusions: Impedance control of the RITA system resulted in an increased size of the ablation zone and a decreased ablation time. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim Treatment of hepatocellular carcinoma located on the liver surface is frequently difficult because direct puncture of the tumor must be avoided during needle insertion. The aim of this study was to investigate the utility of a no-touch pincer ablation procedure that uses a multipolar radiofrequency ablation ( RFA) system for a tumor located on the liver surface. Methods The experimental animals were three pigs, and RFA was performed with two internally cooled bipolar electrodes. Three ablative procedures were compared: linear insertion at regular 13-mm intervals (pattern 1; virtual target tumor size, <10 mm); fan-shape insertion, maximum interval 20 mm (pattern 2; virtual target tumor size, <15 mm); and 25 mm (pattern 3; virtual target tumor size, <20 mm). All electrodes were inserted at a 30-mm depth. For patterns 1 and 2, ablation was performed on three other parts of the liver, and for pattern 3, ablation was performed on two other parts. Results For the median transverse and longitudinal diameter to the shaft, with the pattern 1 procedure, the ablative areas were 32 mm × 30 mm, and with the pattern 2 procedure, the ablative areas were 27 mm × 30 mm with carbonization of the liver surface. In contrast, with the pattern 3 procedure, the ablative areas were 45 mm × 26 mm; however, the ablative margin did not reach the surface, and carbonization was not apparent. Conclusion The no-touch pincer ablation procedure (with an electrode interval of ≤20 mm) may be useful when performed with two internally cooled bipolar electrodes for small nodules that protrude from the liver surface. [ABSTRACT FROM AUTHOR]

Background: The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. Patients and Methods: We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. Results: In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). Conclusion: Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Alfa-fetoprotein (AFP) is used as a marker of early hepatocarcinogenesis. However, the impact of hepatitis B virus surface antigen (HBsAg) on this relationship in patients with HBV infection is not clear. The present study evaluated the relation between HBsAg and AFP levels at the initial visit in 1,610 untreated HBV patients, free of hepatocellular carcinoma (HCC) or severe hepatitis. The cumulative rate of HCC was significantly lower in patients with a low AFP level (≤10 µg/L; below the upper limit of normal) than in those with a high AFP level (≥11 µg/L) at the initial visit. In patients with HBsAg levels more than 500 IU/ml, HBsAg levels correlated significantly and negatively with AFP levels, and significantly with platelet count. Multivariate analysis of data of patients with HBsAg more than 500 IU/ml identified HBsAg (<7,000 IU/ml), albumin (<3.9 g/dl), platelet count (<20.0 × 104/mm3), gamma-glutamyl transpeptidase (≥50 IU/L), aspartate aminotransferase (≥34 IU/L), HBeAg (positive), and HBV core-related antigen (≥3.0 log U/ml) as determinants of a high AFP. Especially, in patients with HBsAg more than 500 IU/ml and low transaminase levels (below the upper limit of normal), HBsAg was identified as significant determinant of a high AFP. On the other hand, in patients with HBsAg less than 500 IU/ml, multivariate analysis identified albumin, gamma-glutamyl transpeptidase, and HBV core-related antigen as determinants of a high AFP. The results indicated that HBsAg level seems to affect, at least in part, the AFP levels, and that it can be used as a surrogate marker of early hepatocarcinogenesis. J. Med. Virol. 86:131-138, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim Patients with unresectable hepatocellular carcinoma ( HCC) often undergo transcatheter arterial chemoembolization ( TACE). Miriplatin is a lipophilic cisplatin derivative used in TACE that is effective in HCC. However, the difference in antitumor efficacy between warmed versus room temperature miriplatin is unclear. Methods Chemotherapy efficacy was evaluated by dynamic computed tomography 1-3 months after TACE, according to the Modified Response Evaluation Criteria in Solid Tumors. A total of 203 patients with HCC who received TACE with miriplatin for the first time were included in a follow-up study to retrospectively investigate its efficacy and safety. Overall, 45 patients underwent TACE with warmed (40° C) miriplatin and 158 patients received TACE with room temperature miriplatin. Results Seventy patients (44.3%) treated with room temperature miriplatin and 32 patients (71.1%) who received warmed miriplatin experienced complete or partial responses. Multivariate analysis identified miriplatin temperature (warmed miriplatin, risk ratio ( RR) = 2.26, P = 0.047), tumor number (solitary, RR = 3.48, P = 0.007), α-fetoprotein ( AFP) level (<50 ng/ mL, RR = 2.35, P = 0.012) and history of TACE (no history, RR = 2.22, P = 0.041) as predictors of objective response following TACE with miriplatin, and no serious complications were observed. Conclusion Warm temperature, solitary tumors, low AFP level and first TACE are significant and independent predictors of objective response after TACE using miriplatin. These results suggest that warmed miriplatin can be considered as one of the standard treatments for unresectable HCC. [ABSTRACT FROM AUTHOR]

Aim To evaluate the efficacy of a new ablation procedure for the stepwise hook extension technique using a SuperSlim needle for radiofrequency ablation ( RFA) treatment of hepatocellular carcinoma ( HCC), a randomized controlled trial was performed. Methods Thirty patients with HCC measuring 20 mm or less were randomly treated with a conventional four stepwise expansion technique (group 1) and the new stepwise expansion technique (group 2; the electrode was closed in the shaft after the same three steps of the conventional procedure and then fully extended). All patients underwent the RFA procedure using a 10-hook expandable electrode of 17-G diameter ( Le Veen SuperSlim 30 mm). We compared the ablation time, required energy and ablated lesions in the two groups. Results The long and short diameters of RFA-induced necrosis were significantly larger in group 2 (37 and 28 mm) than group 1 (30 and 26 mm, P = 0.001 and =0.045, respectively). Irregular and small needle expansion resulting in the parachute-like or irregularly shaped ablated zone was observed in more cases in group 1 than in group 2. The new technique made all tines expand uniformly and largely, which produced a near-oval ablated zone of which the long axis is perpendicular to the needle shaft. Conclusion The two kinds of stepwise procedures allow the selection of a more suitable procedure according to the tumor size and shape in each RFA. [ABSTRACT FROM AUTHOR]

Miriplatin is a novel lipophilic platinum complex that was developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, little prospective data are available regarding the clinical toxicity of chemotherapeutic agents used to treat HCC patients with chronic renal failure. In a phase II study, the plasma concentration of total platinum in patients who received miriplatin was very low, and no severe renal toxicity caused by miriplatin injection was reported. Here, we present three cases of HCC with stage 4 chronic renal failure who received transcatheter arterial chemotherapy with miriplatin. All cases were male, ages 72, 84, and 83 years, and had serum creatinine levels of 2.3, 1.6, and 1.9 mg/dL, respectively. Their estimated glomerular filtration rates were 21.9, 20.3, and 22.2 mL/min, respectively. All cases were treated for unresectable HCC with transcatheter arterial chemotherapy with miriplatin. No serious adverse events were observed, and serum creatinine levels did not elevate, even in the patient who experienced renal failure caused by cisplatin administration. These results might suggest that transcatheter arterial chemotherapy with miriplatin can be safely used in HCC patients with chronic renal failure. [ABSTRACT FROM AUTHOR]

Objective: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear. Methods: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy. Results: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively. Conclusion: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Substitution of amino acid 70 and/or 91 in the core region of hepatitis C virus (HCV) genotype 1b (HCV-1b) is an important predictor of hepatocellular carcinoma (HCC), but its impact on HCC in nonresponders to interferon (IFN) and ribavirin (RIB) combination therapy is not clear. Methods: A total of 292 patients with HCV-1b-related chronic liver disease who did not achieve a sustained virological response to 24-48 weeks of IFN+RIB combination therapy were included in a follow-up study to investigate the risk factors for HCC. Results: Sixteen patients developed HCC during the follow-up. The cumulative HCC rates were 5.0, 13.1 and 16.9% at the end of 3, 5 and 7 years, respectively. Multivariate analysis identified substitution of core amino acid 70 (Gln70/His70; hazard ratio 4.64, p = 0.018) and low serum levels of high-density lipoprotein cholesterol (<50 mg/dl; hazard ratio 9.35, p = 0.041) as determinants of HCC. Gender, stage of fibrosis and interleukin-28B showed no such relationship. Conclusions: Amino acid substitution in the core region of HCV-1b and low serum levels of high-density lipoprotein cholesterol are significant and independent predictors of HCC in nonresponders to IFN+RIB combination therapy. These results emphasize the importance of viral and lipid metabolic factors in the development of HCC after combination therapy. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: The purpose of this retrospective study was to evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) with miriplatin in patients with unresectable hepatocellular carcinoma (HCC). Methods: From 2007 to 2010, 122 consecutive patients with unresectable HCC were treated by TACE with miriplatin-lipiodol suspension in our institute. Twenty-two patients (18%) had a solitary nodule and 100 patients (82%) had multiple nodules. Ninety-eight patients (80%) had a history of TACE. Results: Thirty-five of the 122 treated patients (29%) showed complete response (CR). And no serious complications were observed. Patients who had shown CR after previous TACE (pre-CR) were significantly more likely to show CR in the current study compared with patients who had shown less successful responses after previous TACE (56 vs. 20%, p = 0.003). Multivariate analysis revealed that response after previous TACE (pre-CR, risk ratio: 4.76; p = 0.035), tumor multiplicity (solitary, risk ratio: 9.69; p = 0.003), and injection artery (peripheral to segmental hepatic artery, risk ratio: 5.28;p = 0.040) were significant independent predictors associated with CR after TACE using miriplatin. Conclusion: In repetition of TACE treatment, switching the TACE agent from epirubicin or cisplatin to miriplatin offered a favorable treatment effect, especially in patients who had shown a CR after previous TACE. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Stage progression of 374 small hepatocellular carcinomas (HCC) was retrospectively analysed. During 8 years, 236 patients with the early stage of HCC received radiofrequency ablation (RFA), and 138 underwent surgery as an initial therapy. More patients of young age and with better liver function tended to undergo surgical treatment. Based on 1892 patient-year data, the Markov model analysed the stepwise progression of early stage (multiple up to three nodules, 3 cm or less each) to intermediate stage (four nodules or more, or larger than 3 cm), to advanced stage (portal invasion, extrahepatic metastasis or Child-Pugh C) and to death. The recurrence rates after RFA and surgery were 53.3 and 40.6% in the third year. The annual progression rates from the early stage to the intermediate stage, advanced stage and death were 5.40, 1.63 and 1.73% in the RFA group and 3.90, 1.87 and 0.62% in the surgery group respectively. The progression rate from the early to the intermediate stage was significantly lower (2.34% annually) in the younger patient group (<60 years) than that in the older group (≥60 years, 5.70%, P=0.0053). In contrast, the progression rate from the intermediate to the advanced stage was significantly higher in the younger patient group (<60 years, 37.50% annually) than that in the older groups (60-69 years, 30.30%, 70 years or older 22.09%, P=0.0011). Multivariate hazard analysis showed that initial treatment did not significantly affect the stage progression rate (hazard ratio of RFA 1.09, P=0.70) and the survival rate (hazard ratio of RFA 1.09, P=0.73). Although the recurrence rate was slightly higher in the RFA group, additional ablation procedures could control the progression of HCC, with a rate comparable to the surgical group. [ABSTRACT FROM AUTHOR]

The consensus meeting for the diagnosis, management and treatment for hepatitis C was held in 45th annual meeting for the Japan Society of Hepatology (JSH) in June 2009 where the recommendations and informative statements were discussed including organizers and presenters. The Several important informative statements and recommendations have been shown. This was the fourth JSH consensus meeting of hepatitis C, however, the recommendations have not been published in English previously. Thus, this is the first report of JSH consensus of hepatitis C. The rate of development of hepatocellular carcinoma (HCC) in HCV-infected patients in Japan is higher than in the USA, because the average age of the HCV-infected patients is greater and there are more patients with severe fibrosis of the liver than in the USA. In Japan, more than 60% of HCV-infected patients are genotype 1b infection, and they show lower response to perinterferon and ribavirin combination treatment. To improve the response rate is also an important issue in our country. To establish the original recommendations and informative statements to prevent the development of HCC is a very important issue in Japan. [ABSTRACT FROM AUTHOR]

Aim: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add-on lamivudine for treatment of lamivudine-resistant hepatitis B virus (HBV) mutants. Methods: A total of 247 patients who developed lamivudine-resistant HBV mutants, with an increase of HBV DNA ≥ 1 log copies/mL, received adefovir dipivoxil 10 mg add-on lamivudine 100 mg daily during a median of 115 weeks (range: 25–282 weeks). They were followed for the development of HCC by imaging modalities every 3−6 months. Results: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and α-fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan-Meier analysis, AST levels ≥ 70 IU/L, YIDD mutants, cirrhosis and age ≥ 50 years increased the risk of HCC ( P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). Conclusion: HCC can develop in cirrhotic patients receiving adefovir add-on lamivudine. Hence, the patients with baseline AST ≥ 70 IU/L and YIDD mutants would need to be monitored closely for HCC. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with cirrhosis, who are infected with hepatitis B virus (HBV), the main goal is to normalize levels of alanine and aspartate aminotransferases by eliminating HBV or reducing viral loads. In patients with compensated cirrhosis, the clearance of HBV from serum is aimed for by entecavir, as the main resort, for histological improvement toward the prevention of hepatocellular carcinoma (HCC). In patients with decompensated cirrhosis, by contrast, meticulous therapeutic strategies are adopted for the reversal to compensation, toward the eventual goal of decreasing the risk of HCC. For maintaining liver function and preventing HCC, branched chain amino acids and nutrient supplements are applied, in addition to conventional liver supportive therapies. For patients with chronic hepatitis B, separate guidelines are applied to those younger than 35 years and those aged 35 years or older. Even for patients with chronic hepatitis who are negative for hepatitis e antigen (HBeAg), but who harbor HBV DNA in titers of 7 log copies/mL or more, a “drug-free state” is aimed for by sequential treatment with interferon (IFN) plus entecavir as the first line. For patients with chronic hepatitis B aged 35 years or older, who are HBeAg-negative and carry HBV DNA in titers of less than 7 log copies/mL, long-term IFN for 24–48 weeks is adopted anew. To HBeAg-negative patients who have either or both platelet counts of less than 150 × 103/mm3 and less than 7 log copies of HBV DNA, also, long-term IFN for 24–48 weeks is indicated. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13–36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2–8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm3 prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted. [ABSTRACT FROM AUTHOR]

Objective. Hepatocellular carcinoma (HCC) in the elderly infected with hepatitis C virus (HCV) is expected to increase globally within the next two decades. The purpose of the study was to define the natural history of elderly patients with chronic hepatitis C needs in order to prevent HCC from arising in these patients. Material and methods. Treatment-naive patients aged ≥65 years with platelet counts >120×103/mm3 were classified as 120 with aspartate and alanine aminotransferase (ASAT and ALAT) levels ≦40 IU/l (group A) and 212 with either or both levels ≥41 (group B) and followed-up for 3 years or longer without antiviral treatment. Results. Cirrhosis and HCC developed more frequently in group B than in group A (p<0.001 for both). In particular, of the patients aged 65-69 years at entry, cirrhosis and HCC developed more frequently in group B than in group A (p<0.001 and p=0.001, respectively). Liver-related causes of death were more common in group B than in group A (20/34 (59%) versus 1/9 (11%), p=0.021). HCC developed more frequently in men than in women (p=0.033). Conclusions . In elderly patients with chronic hepatitis C, cirrhosis and HCC develop more frequently in those with elevated transaminase levels than in those without elevated transaminase levels. Therefore, transaminase levels need to be suppressed below ≦40 IU/l, using antiviral treatments or other agents, in order to prevent cirrhosis and HCC arising in these patients. In view of rare liver-related deaths, aggressive antiviral treatment would not be necessary in the elderly with chronic hepatitis C who have normal transaminase levels. [ABSTRACT FROM AUTHOR]

Aims: We showed previously that amino acid (aa) substitutions in HCV genotype 1b (HCV-1b) core region are negative predictors of virological response to peginterferon + ribavirin therapy, and also risk factors of hepatocarcinogenesis. The aim of this study was to evaluate the impact of core aa substitutions on mortality in elderly patients. Methods: We compared the characteristics and survival of 92 elderly (≥75 years) patients with HCV-related hepatocellular carcinoma (HCC) (including 62 patients with HCV-1b) with those of 44 younger patients (<50 years, 34 patients with HCV-1b). Results: For all patients, univariate analysis identified female sex, history of blood transfusion, preserved liver function and glucose metabolism as significant variables in the elderly patients. In patients with HCV-1b-related HCC, univariate analysis identified preserved lipid metabolism as significant variable in addition to significant variables in overall patients. In elderly patients with HCV-1b-related HCC, multivariate analysis identified male sex, methionine of core aa91, and non-radical therapy as factors that influenced mortality after first treatment for HCC. Conclusions: Our results characterized elderly patients who develop HCC after HCV-1b infection, and suggested that aa substitutions of HCV-1b core region correlate with mortality of patients after first treatment for HCC. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]