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Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

Introduction: It is unclear whether the relationships between changes in fibrosis and circulating microRNA-122 (miR-122) dynamics might influence the prognosis of nonalcoholic fatty liver disease (NAFLD). Methods: This study investigates the impact of serum miR-122 dynamics and histological changes on the incidence of liver cancer and mortality in 81 Japanese NAFLD patients who underwent serial liver biopsies. The median interval between the first and second liver biopsies was 2.9 years. Results: The fibrosis stage scores indicated progression, no change, and improvement (a decrease of one point or more) in 21.0%, 56.8%, and 22.2% of the patients, respectively. There were 64 patients in the high-risk group who had no improvement in stage scores. Among these, the miR-122 levels were significantly lower in 7 patients with liver cancer than those of the 54 patients who had no liver cancer at the second liver biopsy. The cumulative rates of liver cancer were significantly higher in cases with miR-122 ratios <0.5 (serum miR-122 level at second biopsy to that at first biopsy) than those with ratios ≥0.5. The cumulative survival rates in cases with miR-122 ratios <0.5 tended to be lower than those with ratios ≥0.5. Of the 64 high-risk patients, 39 indicated stage 2 or greater (severe fibrosis stage) at the first liver biopsy and also showed similar results of cumulative liver cancer and survival rates. Conclusions: Longitudinal examination of serial liver biopsies indicated that the circulating miR-122 dynamics might be useful in predicting the prognosis for NAFLD patients with severe fibrosis stage and no improvement of the stage scores. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection is an aetiologic factor for hepatocellular carcinoma (HCC). Baseline HBV DNA is a known independent predictor of HCC, and the serum hepatitis B core‐related antigen (HBcrAg) level corresponds to intrahepatic covalently closed circular DNA. Aim: To investigate whether the baseline and on‐treatment serum HBcrAg levels can predict HCC incidence in patients with chronic hepatitis B following nucleos(t)ide analogue (NA) therapy. Methods: This retrospective cohort study included 1268 patients treated with NAs for >1 year. In all patients, serum HBcrAg and hepatitis B surface antigen levels were measured at baseline and 1 year. Results: During a median follow‐up of 8.9 years, 113 patients (8.9%) developed HCC (10.3/1000 person‐years). These patients were stratified by baseline hepatitis B e‐antigen (HBeAg) status into HBeAg+ and HBeAg‐ cohorts. High on‐treatment HBcrAg levels at 1 year were found to associate significantly with HCC (HBeAg+ cohort: P = 0.017; HBeAg‐ cohort: P = 4.30 × 10−5; cut‐off values: 4.9 log U/mL and 4.4 log U/mL, respectively). In a multivariate Cox regression analysis, patients with persistently high on‐treatment HBcrAg levels had a higher risk of HCC than those with low HBcrAg levels (HBeAg+: hazard ratio [HR], 6.15, 95% confidence interval [CI]: 1.89‐20.0, P = 0.003; HBeAg‐ cohort: HR, 2.54, 95% CI: 1.40‐4.60; P = 0.002). A sub‐analysis of patients without alcoholism yielded similar findings. Conclusions: Patients with persistently high on‐treatment HBcrAg levels were more likely to develop HCC despite sustained viral suppression via long‐term NA 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]

Abstract: Background & Aims: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long‐term efficacy and safety of daclatasvir‐based regimens administered during clinical studies. Methods: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow‐up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non‐responders or responders who relapsed, and characterization of liver disease progression. Results: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir‐based regimens (follow‐up cut‐off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype‐1a (42%) or ‐1b (45%) infection, and 18% had cirrhosis. Median follow‐up from parent study follow‐up Week 12 was 111 (range, 11‐246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow‐up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon‐free or interferon‐containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non‐responders, emergent non‐structural protein‐5A (NS5A) and ‐3 (NS3) substitutions were replaced by wild‐type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. Conclusions: SVR12 was durable in 99% of recipients of daclatasvir‐based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non‐responders. [ABSTRACT FROM AUTHOR]

Background: This prospective study investigated the superiority of transarterial chemoembolization (TACE) with miriplatin over TACE with epirubicin regarding overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC).Methods: Patients with unresectable HCC were randomized 1:1 to receive TACE with miriplatin or epirubicin in lipiodol. The primary endpoint was OS; secondary endpoints were percentages of patients who achieved treatment effect (TE) 4 (100% necrotizing effect or tumor reduction), duration of time to TACE failure, and adverse events (AEs). OS was compared using a stratified log-rank test adjusted for clinical stage, Child–Pugh class, and institution.Results: Of 257 patients enrolled from August 2008 to August 2010, 247 were analyzed for efficacy and toxicity (miriplatin, n = 124; epirubicin, n = 123). Baseline characteristics were well balanced between the two groups. Median OS times were 1111 days for miriplatin and 1127 days for epirubicin (adjusted hazard ratio 1.01, 95% confidence interval 0.73–1.40, P = 0.946). TE4 rates were 44.4% for miriplatin and 37.4% for epirubicin. Median times to TACE failure were 365.5 days for miriplatin and 414.0 days for epirubicin. AEs of grade 3 or higher, including elevated aspartate aminotransferase (miriplatin, 39.5%; epirubicin, 57.7%) and elevated alanine aminotransferase (miriplatin, 31.5%; epirubicin, 53.7%), were less frequent in the miriplatin than the epirubicin group.Conclusions: OS after TACE with miriplatin was not superior to that after TACE with epirubicin; however, hepatic AEs were less frequent with miriplatin.Clinical Trial Registration: JapicCTI-080632. [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]

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]

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]

Background: Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC).Methods: Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS).Results: Between July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5-9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7-25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without.Conclusions: Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight. TRIAL REGISTRATION ID: www.ClinicalTrials.gov NCT00946153. [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]

Background & Aims The effect of ethanol consumption on hepatocarcinogenesis in patients with fatty liver disease (FLD) is not clear. We aimed to investigate the influence of alcohol consumption on hepatocarcinogenesis and determine the risk factors for hepatocellular carcinoma (HCC) in a large number of Japanese patients with FLD without viral hepatitis. Methods This multicenter, retrospective cohort study was conducted at a specialized center for hepatology in Japan and included 9959 patients with FLD without viral hepatitis, diagnosed by ultrasonography from January 1997 through December 2011. The patients’ level of ethanol consumption was divided into 4 categories: <20 g/day (n = 6671), 20–39 g/day (n = 753), 40–69 g/day (n = 1589), and ≥70 g/day (n = 946). The primary endpoint was the onset of HCC. Statistical analyses performed included the Kaplan-Meier method and Cox proportional hazard analysis. The median follow-up period was 5.4 years. Results Of the study cohort, 49 cases (0.49%) developed HCC during the follow-up period. The annual incidence rate of HCC was 0.05% in patients with FLD and a daily ethanol consumption <20 g/day. Increasing levels of ethanol consumption were associated with increased annual incidence rates of HCC: 0.06% for patients with 20–39 g/day ethanol consumption (hazard ratio [HR], 1.54; 95% confidence interval [CI], 0.34–7.04), 0.16% for patients with 40–69 g/day ethanol consumption (HR, 3.49; 95% CI, 1.50–8.12), and 0.22% for patients with ≥70 g/day ethanol consumption (HR, 10.58; 95% CI, 5.06–22.13), compared with patients with ethanol consumption <20 g/day. Multivariate analysis showed that ethanol consumption ≥40 g/day was an independent risk factor for HCC: for 40–69 g/day the HR was 2.48 (95% CI, 1.01–6.05; P < .047) and for ≥70 g/day the HR was 12.61 (95% CI, 5.68–28.00; P < .001). Conclusions Based on a multicenter, retrospective analysis of almost 10,000 patients with FLD, ethanol consumption ≥40 g/day is an independent risk factor for HCC. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is the second most lethal cancer caused by lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. Methods: Hepatocellular carcinoma classification defined in our previous transcriptome meta-analysis (S1, S2 and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumours (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumours (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. Results: Hepatocellular carcinoma subclass-predictive indices were steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-foetoprotein (>400 ng/ml) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with the activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184 and 53 to 30, 43 and 22 for S1, S2 and S3 subclass-targeting therapies respectively. Conclusions: Hepatocellular carcinoma molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways. [ABSTRACT FROM AUTHOR]

Background: Small hepatocellular carcinomas (HCC) with poorly differentiated components (PDC) are reportedly at risk of dissemination and needle tract seeding after percutaneous radiofrequency ablation, although it is the preferred treatment for HCC ≤ 2 cm because of the low rate of vascular invasion. On the other hand, the clinical outcomes after hepatectomy for these tumors are still unclear because of their rarity. Methods: A total of 233 cases of solitary HCC ≤ 2 cm were retrospectively reviewed and divided into two groups according to the presence of PDC: 199 without PDC (NP-HCCs) and 34 with PDC (P-HCCs). The clinicopathological characteristics and prognosis were compared. Results: A comparison of clinicopathological characteristics showed that the elevation of the tumor markers alpha-fetoprotein (AFP) (>20 ng/mL) and des-gamma-carboxyprothrombin (DCP) (>40 AU/L) was significantly frequent in P-HCCs. The 3- and 5-year recurrence-free survival rates for P-HCCS were 39 and 29 %, respectively, which were significantly worse than those for NP-HCCs (64 and 50 %, respectively) ( p < 0.01). Initial recurrence of P-HCCs was significantly more frequent, as well as extrahepatic recurrence and advanced recurrence in the early period after the operation. Recurrences with tumor dissemination were observed in 15 % of P-HCCs and 4 % of NP-HCCs ( p = 0.03). Conclusion: PDC is present in 15 % of HCC < 2 cm and should be suspected when the both tumor markers are elevated. Moreover, significantly worse post-hepatectomy outcomes such as early advanced recurrence or recurrence with dissemination should be taken into account if PDC is present even in HCCs ≤ 2 cm. [ABSTRACT FROM AUTHOR]

Background: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients. Methods: After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan-Meier method and Cox proportional hazard regression. Results: The proportion of patients with non-viral etiologies increased from 10.0 % in 1991 to 24.1 % in 2010. Of the patients, 92 % were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m in 39 %. Diabetes was most prevalent in NAFLD (63 %), followed by unclassified etiology (46 %) and ALD (45 %). Approximately 80 % of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2 %, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score. Conclusions: Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis. [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: Hepatocellular carcinoma (HCC) often consists of various differentiation components in a single tumor. However, the categorization of histologic grade in hepatectomy for those tumors has not been standardized. Some studies have determined the differentiation grade of the tumor according to its worst component, whereas others have determined it according to its predominant component. The present study aimed to resolve the controversy about whether the worst component or the dominant component determines the nature of the tumor, especially focusing on the presence of a poorly differentiated component (PDC). Methods: In total, 427 hepatectomized patients with solitary HCC were divided into three groups, tumors without a PDC (NP), tumors with a PDC but dominantly consisting of non-PDC as poorly contained (PC), and tumors predominantly consisted of a PDC as poorly dominant (PD). PC was compared with PD and NP. Results: Statistical analysis revealed that large tumors and high alpha-fetoprotein level were significantly more frequent in PC than in NP ( P < 0.01 and P = 0.04, respectively), although no remarkable difference was observed between PC and PD. Both recurrence-free and overall survival rates were significantly worse in the PC and PD groups than in the NP group (PC vs. NP: P = 0.01 and P < 0.01, PD vs. NP: P < 0.01 and P < 0.01, respectively), but there was no significant difference in these parameters between PC and PD. Conclusions: All HCC, including PDC, should be categorized as poorly differentiated HCC regardless of the predominant differentiation component. [ABSTRACT FROM AUTHOR]

Aim Hepatectomy for hepatocellular carcinoma ( HCC) in patients with primary biliary cirrhosis ( PBC) has seldom been reported, and the clinical significance of this procedure remains unclear, although HCC has often been observed in end-stage PBC patients. Methods To understand the characteristics of hepatectomy on HCC in PBC patients, we examined seven cases at our institute, as well as 22 reported hepatectomy cases in the English-language and Japanese published work. Furthermore, to assess the treatment efficacy of hepatectomy for HCC in PBC patients, we compared these patients with viral hepatitis patients who underwent hepatectomies at our institute during the same period. Results In the review of 29 cases, more than 70% of the patients were aged over 65 years, and the mean Mayo risk score was low at 5.17. The resected tumors were mainly solitary (79%), and the median maximum tumor size was 37 mm. Approximately two-thirds of the patients met the Milan criteria. In the comparison between the PBC and viral hepatitis cases, there were no differences in the postoperative prognoses, although the tumor size was greater in the PBC cases. Conclusion Hepatectomy for HCC in selected PBC cases is a feasible and potentially curative treatment option, similar to hepatectomy for HCC in viral hepatitis patients. This procedure is particularly useful for patients with preserved liver function who are not ideal candidates for liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Archived tissues from previously completed prospective trials represent invaluable resource for biomarker development. However, such specimens are often stored as sections on glass slides, in which RNA is severely degraded due to prolonged air exposure. We evaluated whether a proportion of archived sectioned formalin-fixed paraffin-embedded (AS-FFPE) tissues yield transcriptome profiles comparable to freshly cut (FC) FFPE tissues, which can be used for retrospective class prediction analysis. Methods: Genome-wide transcriptome profiles of 6 to 7-year-old AS-FFPE tissue sections (generated from 5 to 16-year-old blocks) of 83 hepatocellular carcinoma (HCC) and 47 liver cirrhosis samples were generated by using whole-genome DASL assay (Illumina) and digital transcript counting (nCounter) assay (NanoString), and gene signature-based prediction of HCC subclasses and prognosis was compared with previously generated FC-FFPE profiles from the same tissue blocks. Results: RNA quality and assay reproducibility of AS-FFPE RNA were comparable to intermediate to poor quality FC-FFPE samples (RNA Integrity Number: up to 2.50, R-square for technical replicates: up to 0.93). Analyzable transcriptome profiles were obtained in 64 (77%) HCC and 36 (77%) cirrhosis samples. Statistically more confident predictions based on random resampling-based method (nearest template prediction) were obtained in 37 (58%) HCC and 13 (36%) cirrhosis samples. Predictions made in FC-FFPE profiles were reproduced in 36 (97%) HCC and 11 (85%) cirrhosis AS-FFPE profiles. nCounter assay was tested in 24 cirrhosis samples, which yielded confident prediction in 15 samples (63%), of which 10 samples (67%) showed concordant predictions with FC-FFPE profiles. Conclusions: AS-FFPE tissues yielded poorer quality RNA and transcriptome profiles compared to FC-FFPE tissues. Statistically more confident class prediction was feasible in 37 of 83 HCC samples and 13 of 47 cirrhosis samples. These results suggest that AS-FFPE tissues can be regarded as a resource for retrospective transcriptome-based class prediction analysis when they are the only available materials. [ABSTRACT FROM AUTHOR]

Aim In patients with hepatoviral infection, although a wide resection margin can eradicate the microsatellite lesions around hepatocellular carcinoma ( HCC), a large-volume hepatectomy may diminish remaining liver function and become an obstacle for treating recurrent HCC. The optimal width of the resection margin for these patients is still controversial. This study was conducted to investigate the optimal resection margin in hepatectomy for hepatoviral infection patients. Methods We retrospectively investigated the influences of the resection margin status on recurrence patterns and long-term prognosis in a group of 311 HCC patients with hepatoviral infection who had a solitary HCC without perioperative anti- HCC treatment. Results The resection margin status did not statistically influence the postoperative recurrence-free and overall survival rates (3-year recurrence-free survival of 61.0% vs 55.1%, P = 0.33; 5-year overall survival of 74.9% vs 81.5%, P = 0.77 in without a margin vs with a margin, respectively), although resection without a margin increased the local recurrence with marginal significance ( P = 0.055). Regarding the width of the resection margin, in 30-mm or smaller HCC, resection margin did not significantly improve the prognosis among hepatoviral infection patients. However, for tumors larger than 30 mm, a resection margin wider than 3 mm showed significant impacts on the prevention of recurrence in spite of the influence of multicentric carcinogenesis. Conclusion The resection margin used for eradication of microsatellite lesions showed differences that were dependent on tumor size in hepatoviral infection patients. Resection margin should be based on not only background liver function but also tumor characteristics. [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]

Background: Radiofrequency ablation (RFA) is minimally invasive and can achieve a high rate of cure of liver cancer. This study was conducted to evaluate the efficacy and safety of a bipolar RFA device (CelonPOWER System) in the treatment of Japanese liver cancer patients. Methods: The study was a multicenter, single-group, open-label trial. The indications for RFA were based on the Japanese guidelines for the management of liver cancer. The subjects had a Child-Pugh classification of A or B, and the target tumors were defined as nodular, numbering up to 3 lesions, each of which was 3 cm or less in diameter, or solitary lesions up to 4 cm in diameter. To test for the non-inferiority of the CelonPOWER System, this system was compared with the Cool-tip RF System, which has already been approved in Japan, in terms of the complete necrosis rate (CNR). Results: The CNR obtained with the CelonPOWER System was 97.8 % (88/90 patients). The CNR obtained with the Cool-tip RF System was 86.2 % (50/58 patients), confirming the non-inferiority of the CelonPOWER System ( p < 0.001, Fisher's exact test based on binomial distribution). Throughout the treatment and follow-up periods, there were no adverse events regarding safety that were uniquely related to the CelonPOWER System and there were no cases of device failure. Conclusions: The CelonPOWER System was confirmed to be an effective and safe RFA device. It could become extensively used as a safe next-generation RFA device, reducing the physical burden on patients. [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]

Aim: Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non-alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). Methods: A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow-up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan-Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. Results: The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P < 0.001). The incident rates of hepatocellular carcinoma in all the malignancies were 6.0% (10/167) in the NAFLD group and 67.6% (267/395) in the HCV group ( P < 0.001). The malignancies in the NAFLD group were observed in the following order: gastric cancer 34 cases (20.4%) > colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). Conclusions: The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two-thirds in the HCV group. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD).METHODS:This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis.RESULTS:In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P<0.001), platelet count <150 × 103/μl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780).CONCLUSIONS:This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC. [ABSTRACT FROM AUTHOR]

Aim: The micro-total analysis system (µTAS), a fully automated immunoassay system using microchip capillary electrophoresis, is highly sensitive and able to quickly assay the AFP-L3%. The clinical usefulness of this system was studied. Methods: We retrospectively enrolled 250 patients who underwent curative treatment for primary hepatocellular carcinoma (HCC) (93 patients underwent hepatic resection and 157, radiofrequency ablation [RFA]). Results: The sensitivity for µTAS AFP-L3% was 40.3% at the cutoff value of 5% in a range of AFP less than 20 ng/mL where the conventional method was unable to determine AFP-L3%. The sensitivity for AFP-L3% remained high even at stage I and at tumor size less than 2 cm (42.5% and 46.0%, respectively). Recurrence rate of patients with AFP-L3% greater than 5% was significantly higher than that of patients with less than 5% ( P = 0.001). Furthermore, in resected patients, the postoperative AFP-L3% remained elevated with value greater than 5% was related to HCC recurrence ( P = 0.001). Multivariate analysis revealed that multiple tumors ( P = 0.004), preoperative AFP-L3% greater than 5% ( P = 0.003), albumin less than 3.5 g/dL ( P = 0.008), and RFA ( P = 0.003) were significant prognostic factors of recurrence. Conclusions: The µTAS was found to be a highly sensitive assay for AFP-L3% in patients with curative treatment of HCC. A cutoff value of 5% was useful for predicting recurrence after the curative treatment and detecting small tumors and early stage HCC. Additionally, postoperative AFP-L3% was found to be a prognostic factor of HCC recurrence. [ABSTRACT FROM AUTHOR]

Aim: This study was conducted to clarify the incidence of hepatocellular carcinoma (HCC) and the factors contributing to its occurrence by following chronic hepatitis C patients who received pegylated interferon (PEG-IFN) α-2b plus ribavirin (RBV) combination therapy. Methods: Patients who received PEG-IFN α-2b and RBV combination therapy with no history of HCC or HCC within 3 months after the start of treatment were observed for the onset of HCC at 67 centers. Results: Sustained virological response (SVR) was observed in 999 (53.5%) of 1865 patients eligible for analysis. During the observation period (median duration: 4 years and 3 months), HCC developed in 59 patients (3.1%). A significant difference was observed in the 5-year cumulative incidence of HCC between SVR and non-SVR patients (1.1% vs. 7.1%). Factors contributing to HCC selected in multivariate analysis were therapeutic efficacy, sex, age, alanine aminotransferase (ALT) level at 24 weeks after the end of treatment, and platelet count. Non-SVR patients with ALT improvement after the end of treatment had a significantly lower 5-year cumulative incidence of HCC than those without (3.4% vs. 11.0%). HCC developed in 10 patients who achieved SVR, and multivariate analysis indicated that ALT level at 24 weeks after the end of treatment was the only significant factor contributing to HCC. Conclusion: Several known risk factors for HCC contributed to HCC in patients who received PEG-IFN α-2b and RBV combination therapy, and ALT abnormality after the end of treatment contributes to the onset of HCC in both non-SVR and SVR patients. [ABSTRACT FROM AUTHOR]

Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, Pcombined = 1.27 × 10?13, odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 × 10?14, odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection. [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]

Recently, much progress has been made in the field of hepatitis B, such as natural history of the disease in relation to the amount of hepatitis B virus (HBV) DNA, genotypes of HBV influencing the natural course and treatment effects, mutations of HBV influencing the severity of the disease and development of hepatocellular carcinoma, and antiviral treatment such as nucleos(t)ide analogues and pegylated interferon. To make the consensus for the diagnosis, management and treatment of hepatitis B, a meeting was held during 45th annual meeting of Japan Society of Hepatology (JSH) in June 2009. In the meeting, recommendations and informative statements were discussed on the following subjects: (i) natural history of HBV infection; (ii) clinical implication of HBV genotypes; (iii) HBV mutations and their potential impact on pathogenesis of HBV infection; (iv) indications for antiviral treatment of chronic hepatitis B; (v) nucleos(t)ide analogues for chronic hepatitis B; and (vi) interferon therapy for chronic hepatitis B. The presenters reviewed the data on these subjects and proposed the consensus statements and recommendations. These statements were discussed among the organizers and presenters, and were approved by the participants of the meeting. In the current report, the relevant data were reviewed and the 12 consensus statements and nine recommendations on chronic hepatitis B were described. [ABSTRACT FROM AUTHOR]

Since hepatocellular carcinoma often recurs after surgical resection or radiofrequency ablation, we analyzed a retrospective large cohort of patients with small hepatocellular carcinoma caused by hepatitis C virus (HCV). Among 379 patients with HCV RNA-positive small hepatocellular carcinoma (multiple up to three nodules, 3 cm or less each), 77 received interferon-alpha injection and 302 received no anti-viral therapy. Four patients (5.2%) attained sustained virological response (SVR). Cumulative recurrence rates in the treated and untreated groups were 41.1% and 57.5% at the end of the third year, and 63.0% and 74.5% at the fifth year, respectively ( P = 0.013). Fifth year-recurrence rates in treated group were 25.0% in SVR, 85.7% in biochemical response, 71.1% in no response, and 46.7% in patients with continuous administration. When four patients with SVR were excluded, recurrence rates in short-term interferon therapy (<2 years) and long-term therapy (≥2 years) were 46.2% and 39.3% at the third year, and 66.2% and 57.4% at the fifth year, respectively ( P = 0.012). Multivariate analysis showed that long-term interferon therapy significantly decreased recurrence rate (hazard ratio for interferon <2 years 0.80, interferon ≥2 years 0.60, P = 0.044), after adjustment with background covariates including indocyanine green retention rate ( P = 0.018), alpha-fetoprotein ( P = 0.051), and tumor treatment ( P = 0.066). A long-term administration of low-dose interferon significantly decreased recurrence of hepatocellular carcinoma after surgical resection or radiofrequency ablation. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to elucidate whether the histopathological characteristics of hepatocellular carcinoma (HCC) can be predicted from baseline dynamic computed tomography (CT) images. Methods: This retrospective study included 86 consecutive patients with HCC who underwent surgical resection between January 2000 and September 2008. The arterial- and portal-phase dynamic CT images obtained preoperatively 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, heterogeneous enhancement pattern with septum-like structure; and Type-4, heterogeneous enhancement pattern with irregular ring-like structures. We also evaluated the predictive factors for poorly-differentiated HCC, specific macroscopic type of HCC (simple nodular type with extranodular growth [SNEG] and confluent multinodular [CMN]) by univariate and multivariate analyses. Results: The percentages of poorly-differentiated HCC according to the enhancement pattern were three of 51 nodules (6%) of Type-1 and -2, three of 24 (13%) of Type-3, and eight of 11 (73%) of Type-4. The percentages of SNEG/CMN according to the enhancement pattern were 12 of 51 nodules (24%) of Type-1 and -2, 13 of 24 (54%) of Type-3, and five of 11 (45%) of Type-4. Multivariate analysis identified Type-4 pattern as a significant and independent predictor of poorly-differentiated HCC ( P < 0.001) while Type-3 pattern was a significant predictor of SNEG/CMN ( P = 0.017). Conclusion: Heterogeneity of dynamic CT images correlates with malignant characteristics of HCC and can be potentially used to predict the malignant potential of HCC before treatment. [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 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]

Background: The tumour recurrence rate after resection is still high even in patients with small hepatocellular carcinoma (HCC). The advanced patterns of recurrence occasionally occur after resection. In this study, we analysed the clinical and histological characteristics of small HCC and evaluated the predictive factors of advanced tumour recurrence. Methods: One hundred and sixty-five patients underwent resection of small HCC measuring 3 cm or less in greatest dimension. Patterns of tumour recurrences were classified into advanced recurrence and minor recurrence based on size, number, vascular invasion and extrahepatic metastasis of recurrent tumour. We created a simple index to closely evaluate the malignant potential of small HCC, named α-foetoprotein–size ratio index (ASRI). Results: Overall tumour recurrence was significantly associated with tumour multiplicity ( P<0.001) and ASRI ( P=0.001). Tumour multiplicity, ASRI and tumour differentiation were independent and significant predictive factors of advanced recurrences. The overall survival rates were lower in the advanced recurrence group than the minor recurrence or the no recurrence group. Conclusions: Patients with advanced recurrences have a poor prognosis, although they have undergone curative resection of small HCC. On the other hand, patients with minor recurrences have a relatively good prognosis. ASRI was a useful index to predict advanced recurrence after curative resection of small HCC. The therapeutic management to prevent advanced recurrences is needed. [ABSTRACT FROM AUTHOR]

Aim: Hepatocellular carcinoma (HCC) often shows resistance to transcatheter arterial chemoembolization (TACE). Such patients often have a poor prognosis and are unresponsive to other forms of therapy. The aim of this retrospective study was to determine the response to TACE using platinum analogues in patients deemed resistant to TACE using epirubicin. Methods: We studied 152 consecutive patients with advanced HCC resistant to TACE using epirubicin. All cases were treated with platinum analogue using transcatheter arterial chemotherapy with or without embolization. Results: Computed tomography at 3 months after therapy showed complete response (CR) in 6 patients (4.0%), partial response (PR) in 28 (18%), stable disease (SD) in 35 (23%), and progressive disease (PD) in 83 (55%). The cumulative survival rates for PR/CR patients who received platinum analogue-transcatheter arterial chemotherapy with or without embolization (81.8% at first year, 53.9% at second year, and 33.1% at third year) were significantly higher than those of SD/PD patients (36.6%, 17.5% and 7.4%, respectively) ( P < 0.001). The 50% survival period was extended almost 1.4 year in PR/CR patients who received platinum analogue-transcatheter arterial chemotherapy with or without embolization. Conclusion: Our retrospective study is the first to report the efficacy of platinum analogues for advanced HCC unresponsive to TACE using epirubicin. [ABSTRACT FROM AUTHOR]

The article reports on a study analyzing treatment strategies for small hepatocellular carcinoma (HCC) measuring less than or equal to 13 cm by comparing the long-term outcome of patients treated with either hepatectomy or radiofrequency ablation (RFA) as the first-line treatment for HCC. In the study, 199 patients who underwent surgery and 209 patients who underwent RFA for HCC were analysed. It was found that high DCP levels reflect the biologic aggressiveness and progression of HCC tumors.

The aim of this retrospective study was to determine the incidence and characteristics of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) antibody-positive elderly patients with chronic hepatitis without cirrhosis. The study included 65 patients who developed HCC at ≥75 years of age and who received their first HCC therapy at Toranomon Hospital between 1985 and 2005. Their clinicopathological and laboratory data were analyzed and compared with those of 33 patients who developed HCC at ≤50 years of age during the same period. The ratio of women patients in the elderly group (M: F = 1.1: 1) was higher than in the younger group (M: F = 5.6: 1). Also, patients in the elderly group had better liver function and prothrombin activity ( P = 0.001), and lower total bilirubin ( P = 0.002) than the young group. Only 11 of 65 elderly patients were diagnosed with liver cirrhosis by biopsy or peritoneoscopy before or at the time of development of HCC. Based on a discriminate score using γ-globulin, hyaluronate level, platelet count, and sex, 27 (41.5%) elderly patients were considered to have chronic hepatitis, compared with six of 33 (18.1%) patients in the young group ( P = 0.025). There were no differences in tumor number or size or tumor markers between the two groups. Survival rate was higher in the younger patients ( P = 0.002), who were more likely to receive radical treatment. Our results showed distinct differences in HCV-related HCC between elderly and young patients and suggested that elderly patients (especially women) could develop HCC even when liver histology shows chronic hepatitis and lack of cirrhosis. [ABSTRACT FROM AUTHOR]

Aims: The long-term efficacy of adefovir dipivoxil in combination with lamivudine to chronic hepatitis B virus (HBV) infection is still unclear. Methods: Virological response and hepatocarcinogenesis during lamivudine + adefovir were investigated in 183 lamivudine-resistant Japanese patients with chronic genotype C-dominant HBV infection. As the predictors of virological response, an assessment of clinical parameters and a nucleotide (nt) sequence analysis of the negative regulatory element to core gene (nt 1611–2450) were performed at the start of adefovir. Results: The cumulative HBV-DNA non-detectable and ALT normalization rates were 93.6 and 97.6% at the end of 3 years, respectively. Multivariate analysis identified total bilirubin, AST, and nt substitutions (nt 1762, 1768, 1846, 1896, 2134, 2288, 2441) as determinants of early non-detectable HBV-DNA. The yearly incidence of hepatocellular carcinoma (HCC) during the first 3 years was 2.7%. At the diagnosis of HCC, ALT normalization, HBV-DNA non-detectable, and HBeAg-seronegative conversion rates were 75.0, 83.3, and 57.1%, respectively. Furthermore, the cumulative HBV-DNA non-detectable and ALT normalization rates were not significantly different according to the development of HCC or not. Conclusions: Lamivudine-resistant patients treated with lamivudine + adefovir could achieve the excellent virological response and biochemical response, but the low hepatitis activity was not enough to suppress hepatocarcinogenesis. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of this retrospective study was to examine the relationship between diabetes mellitus and recurrence of hepatocellular carcinoma after potentially curative therapy for hepatocellular carcinoma with nonviral hepatitis. Methods: We studied 40 consecutive hepatocellular carcinoma patients who were diagnosed between 1980 and 2006 with hepatocellular carcinoma associated with non-B, non-C hepatitis, and later underwent surgical resection or radiofrequency ablation. Results: Twenty-two out of the 40 patients developed hepatocellular carcinoma recurrence within a median of 3.7 years. In the 18 patients with diabetes mellitus, the cumulative rates of hepatocellular carcinoma recurrence were 22.2% at the first year, 55.6% at the second year, 61.1% at the third year, 61.1% at the fourth year, and 80.6% at the fifth year. The cumulative rates of hepatocellular carcinoma recurrence in 22 nondiabetic patients were 24.6% at the first year, 24.6% at the second year, 31.5% at the third year, 31.5% at the fourth year, and 31.5% at the fifth year. The hepatocellular carcinoma recurrence rate was significantly higher in diabetic patients than in nondiabetics ( P = 0.026). The multivariate Cox proportional model identified old age and diabetes as the only significant predictors for recurrence. The hazard ratio of hepatocellular carcinoma recurrence in diabetic patients was 4.61 ( P = 0.007). There was no significant difference in overall survival rate between diabetic and nondiabetic patients ( P = 0.392). Conclusion: Diabetes is a significant predictor of tumor recurrence after potentially curative therapy for hepatocellular carcinoma in patients with nonviral hepatitis. [ABSTRACT FROM AUTHOR]

Objectives: Intrahepatic metastasis is one of the serious complications of radiofrequency ablation (RFA) therapy for hepatocellular carcinoma. The aim of this study was to investigate how liver tissue could be disseminated during the RFA procedure with different devices and protocols in an in vivo porcine model. Methods: Three pigs underwent RFA procedures using 2 different devices: needles that could be expanded (LeVeen needle) and those that could not (cool-tip needle). A LeVeen needle was used with a single-step full extension method or a stepwise extension method. Before RFA, a mixture of lipiodol and blue dye was injected intrahepatically into a precoagulated area. After the ablation procedure, the specimen was cut to evaluate the amount of dye remaining in the ablated region and the distribution of the dye outside the ablated area. Results: The stepwise extension method resulted in the disappearance of the smallest amount of the dye and lipiodol at the ablation site, compared with the full extension method and cool-tip needle. Dye was found at sites distant from the ablated area in all cases using the cool-tip needle, but in none with the stepwise extension method. Conclusions: The stepwise procedure using the expandable needle can reduce tumor cell scattering, which can cause intrahepatic metastasis, compared with other methods. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The stepwise hook extension technique for an expandable needle, which we reported previously, allowed roll-off in short time with low power. The aim of this study was to investigate experimentally the efficacy of a modified extension procedure. Methods: Three pigs underwent 10 radiofrequency ablation (RFA) procedures using the 10-hook electrode of LeVeen needle. The conventional technique was used in five RFA (group 1; the electrode was deployed in four steps to full extension), while the new technique was used in the other five RFA (group 2; the electrode was closed after the same three steps as group 1 and then fully extended). Results: The shape of the RFA-induced zone was cone-like or irregular in group 1 and oval-like in group 2. The diameter vertical to the shaft was larger in group 2 (37, range 33–42 mm) than in group 1 (23, range 20–29 mm). The median ablation time was longer in group 2 (10 min 13 s) than in group 1 (3 min 56 s). Although the required energy was higher in group 2 than in group 1, that per volume was comparable between the groups (median 0.9 vs. 1.4 kJ/mm3). Conclusions: Our new procedure requires a longer session but produces larger necrosis of a uniform ellipsoid volume, making it potentially suitable for tumours more than 3 cm in diameter. [ABSTRACT FROM AUTHOR]

Background: We assessed the efficacy and anticarcinogenic effects of interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related cirrhosis. Methods: The study subjects were 123 Japanese patients with HCV-related cirrhosis with genotype 1b low viral load or genotype 2 who received IFN from 1989 to 2005 (18 patients continue to receive IFN therapy). They included 81 men and 42 women aged 29–74 years (median, 56 years). Results: Univariate analysis identified four parameters that significantly influenced SVR; viral load (low HCV concentration, P < 0.001), duration of IFN therapy (≥ 52 weeks, P = 0.029), daily dose of IFN (≥ 6 million units, P = 0.018), induction therapy (presence, P = 0.010) and choline esterase (> 1.0 ΔpH, P = 0.037). Multivariate analysis identified viral load (risk ratio = 6.329, P < 0.001) and daily dose of IFN (risk ratio = 2.62, P = 0.042) as two independent parameters thatinfluenced SVR. During the observation period, newly developed hepatocellular carcinoma (HCC) was detected in 22 patients. The rates of development of HCC in patients with SVR were 5.8% at the fifth year and 10.3% at the 10th year, compared with 25.8% at the fifth year and 42.5% at the 10th year in non-SVR patients. Multivariate analysis showed that IFN efficacy (SVR) was the only independent factor of hepatocarcinogenesis (hazard ratio: 0.185, 95% confidence interval: 0.042–0.810, P = 0.025) Conclusion: Among patients with HCV-related cirrhosis, the rate of development of HCC is significantly less in patients with SVR. [ABSTRACT FROM AUTHOR]