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Background: Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC., Methods: Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks., Results: A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%)., Conclusions: In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Although hepatocellular carcinoma (HCC) is frequently associated with thrombosis, it is also associated with liver cirrhosis (LC) which causes hemostatic abnormalities. Therefore, hemostatic abnormalities in patients with HCC were examined using a clot waveform analysis (CWA). Methods: Hemostatic abnormalities in 88 samples from HCC patients, 48 samples from LC patients and 153 samples from patients with chronic liver diseases (CH) were examined using a CWA-activated partial thromboplastin time (APTT) and small amount of tissue factor induced FIX activation (sTF/FIXa) assay. Results: There were no significant differences in the peak time on CWA-APTT among HCC, LC, and CH, and the peak heights of CWA-APTT were significantly higher in HCC and CH than in HVs and LC. The peak heights of the CWA-sTF/FIXa were significantly higher in HCC than in LC. The peak times of the CWA-APTT were significantly longer in stages B, C, and D than in stage A or cases of response. In the receiver operating characteristic (ROC) curve, the fibrin formation height (FFH) of the CWA-APTT and CWA-sTF/FIXa showed the highest diagnostic ability for HCC and LC, respectively. Thrombosis was observed in 13 HCC patients, and arterial thrombosis and portal vein thrombosis were frequently associated with HCC without LC and HCC with LC, respectively. In ROC, the peak time×peak height of the first derivative on the CWA-sTF/FIXa showed the highest diagnostic ability for thrombosis. Conclusion: The CWA-APTT and CWA-sTF/FIXa can increase the evaluability of HCC including the association with LC and thrombotic complications.

In cirrhosis, several molecular alterations such as resistance to apoptosis could accelerate carcinogenesis. Recently, mechanotransduction has been attracting attention as one of the causes of these disturbances. In patients with cirrhosis, the serum sodium levels progressively decrease in the later stage of cirrhosis, and hyponatremia leads to serum hypo-osmolality. Since serum sodium levels in patients with cirrhosis with liver cancer are inversely related to cancer's number, size, stage, and cumulative survival, we hypothesized that hypo-osmolality-induced mechanotransduction under cirrhotic conditions might contribute to oncogenesis and/or progression of hepatocellular carcinoma (HCC). In this study, we adjusted osmosis of culture medium by changing the sodium chloride concentration and investigated the influence of hypotonic conditions on the apoptosis resistance of an HCC cell line, HepG2, using a serum-deprivation-induced apoptosis model. By culturing the cells in a serum-free medium, the levels of an antiapoptotic protein Bcl-2 were downregulated. In contrast, the hypotonic conditions caused apoptosis resistance by upregulation of Bcl-2. Next, we examined which pathway was involved in the apoptosis resistance. Hypotonic conditions enhanced AKT signaling, and constitutive activation of AKT in HepG2 cells led to upregulation of Bcl-2. Moreover, we revealed that the enhancement of AKT signaling was caused by intracellular calcium influx via a mechanosensor, TRPV2. Our findings suggested that hyponatremia-induced serum hypotonic in patients with cirrhosis promoted the progression of hepatocellular carcinoma. NEW & NOTEWORTHY Our study first revealed that hypo-osmolarity-induced mechanotransduction enhanced calcium-mediated AKT signaling via TRPV2 activation, resulting in contributing to apoptosis resistance. The finding indicates a possible view that liver cirrhosis-induced hyponatremia promotes hepatocellular carcinogenesis.

Background: The aims of this study were to evaluate the clinical impact of curative-intent subsequent treatment on overall prognosis in lenvatinib-treated hepatocellular carcinoma (HCC) patients., Methods: Eighty-three consecutive patients with intrahepatic target nodules who received lenvatinib were reviewed. The clinical impact of curative-intent subsequent treatments was investigated through analysis of overall survival (OS) according to pathological deterioration stratified by mALBI grade., Results: In patients with mALBI grade 1 and 2a liver function, R0 resection and lenvatinib-transarterial chemoembolization (lenvatinib-TACE) sequential therapy resulted in significantly better OS compared with other, non-curative-intent subsequent therapy and lack of additional treatment (median OS, 37.6 vs 29.0 months and 17.1 vs 8.9 months, respectively; P < 0.001). Multivariate analysis confirmed that use of R0 resection and lenvatinib-TACE sequential therapy were associated with better OS (hazard ratio [HR], 0.021; P < 0.001 and 0.108; P < 0.001) compared with other, non-curative-intent subsequent treatment (HR 0.256; P = 0.010). In contrast, in patients with mALBI grade 2b liver function, multivariate analysis confirmed higher treatment efficacy for non-curative-intent subsequent treatment with respect to OS (HR 0.041; P < 0.001) compared with R0 resection and lenvatinib-TACE sequential therapy (HR 0.057; P = 0.027 and 0.063; P = 0.001)., Conclusion: Curative-intent subsequent treatment is more useful for HCC patients with better liver function (mALBI grade 1 and 2a) and intrahepatic target nodules who have received lenvatini b-based treatment., (© 2022. Japanese Society of Gastroenterology.)

Introduction: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear., Methods: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs., Results: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC., Conclusions: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background & Aims: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy., Methods: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization., Results: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC., Conclusions: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease., Gov Number: NCT01761266., Impact and Implications: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To compare the clinicopathological features of typical steatohepatitic HCC (SH-HCC) with other HCCs., Methods: Subjects were 486 patients with untreated HCC who underwent hepatectomy at our hospital from January 2015 to December 2020. We compared patient backgrounds, preoperative laboratory data, imaging findings (ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI]), and postoperative pathological findings (tumor and background of liver). The Liver Imaging Reporting And Data System (LI-RADS) was used to examine CT and MRI findings., Results: Typical SH-HCCs were significantly different from other HCCs with respect to age, hepatitis B virus (HBV) infection, and nonalcoholic steatohepatitis (NASH). Diabetes and hyperlipidemia were also significantly more common. Regarding histopathology, tumor size and background steatosis were significantly different between groups. Although ultrasonography, CT, and MRI could each alone diagnose SH-HCCs with a diameter < 20 mm in ≥ 50% of patients, the combined use of these tests improved diagnostic accuracy. By LI-RADS, 87% of SH-HCC cases were classified as LR-5, which are considered to be malignant tumors., Conclusions: It seems possible to diagnose SH-HCC by combining ultrasonography, CT, and MRI., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that might influence the research reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective The relationship between the prognosis and magnitude of a decrease in tumor blood flow according to estimated tumor differentiation remains unclear. This study investigated the relationship between reductions in the rate of mean computed tomography (CT) attenuation values and the clinical prognosis. Methods We evaluated 63 consecutive patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). The oncological aggressiveness of the tumors was estimated using classification by dynamic CT enhancement patterns. The utility of changes in mean CT attenuation values of intra-hepatic targets during treatment to estimate the prognosis was investigated by calculating the progression-free survival (PFS) and post-progression survival (PPS). A multivariate analysis was used to identify potential confounders for the survival after progression during lenvatinib therapy. Results The rate of decrease in the mean CT attenuation value gradually increased according to the degree of deterioration in estimated tumor differentiation, and the rate of a decrease in attenuation ≥40% showed a tendency to increase (p=0.064). This trend was reflected by a better objective response in oncological aggressiveness heterogeneous enhancement patterns (Type-3 and Type-4) than a homogeneous enhancement pattern (Type-2) (83% vs. 56% of modified Response Evaluation Criteria in Solid Tumors). This resulted in a similar PFS between the groups (p=0.773), whereas the PPS was significantly worse when the rate of decrease in the attenuation value was ≥40% (p=0.012). A multivariate analysis confirmed that a rate of decease in attenuation value ≥40% was a poor prognostic factor for the PPS (hazard ratio, 2.993; 95% confidence interval, 1.196-7.490; p=0.019). Conclusion A rate of decrease in attenuation ≥40% may reflect a good response of a highly malignant tumor to lenvatinib. Therefore, this value may have utility as a surrogate marker for estimating the oncological aggressiveness of tumors and their associated prognosis.

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., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser 897 , whereas the EpCAM+ cells exhibited higher abundance of ERK, RSK and its phosphorylated form. This demonstrates that pro-oncogenic, ligand-independent EphA2 signaling plays a dominant role in CD90+ cells with higher motility and metastatic activity than EpCAM+ cells. We also showed that an AKT inhibitor reduced the proliferation and survival of CD90+ cells but did not affect those of EpCAM+ cells. Taken together, our results suggest that AKT activation may be a key pro-oncogenic regulator in HCC.

Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group., Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed., Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5-15.7] compared to 13.7 months (95% CI 12.0-15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4-9.2; ≥ 60 kg group: 95% CI 6.9-9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group., Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups., Clinincal Trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.

Background: Hepatitis C virus is the leading cause of liver cirrhosis and hepatocellular carcinoma in Japan. We aimed to examine the long-term (> 20 years) mortality and hepatocellular carcinoma rates and associated risk factors in 1412 Japanese patients with decompensated hepatitis C virus-related cirrhosis (Child-Pugh B or C)., Methods: Cumulative survival and hepatocellular carcinoma rates were determined using Kaplan-Meier analysis. Independent risk factors were identified by multivariate analysis. A two-tailed P-value of < 0.05 was considered significant., Results: The patients were followed up for a median of 2 years (range 0.5-24.2 years). In total, 62.3%, 41.7%, 4.7%, and 68.3% of the patients had a history of hepatocellular carcinoma, ascites, hepatic encephalopathy, and esophageal varices, respectively. The 1-, 5-, 10-, and 20-year cumulative overall survival rates in the total cohort was 74.9%, 29.0%, 9.1%, and 1.4%, respectively. The 1-, 3-, 5-, and 10-year cumulative survival rates for patients without hepatocellular carcinoma were 93.1%, 54.4%, 18.2%, and 4.0%, respectively, and the corresponding cumulative post-decompensation hepatocellular carcinoma rates were 14.0%, 31.6%, 46.1%, and 66.2%, respectively. The independent risk factors for mortality were older age, Child-Pugh C cirrhosis, the presence of hepatocellular carcinoma, low estimated glomerular filtration rate, low serum sodium level, low platelet count, and high γ-glutamyl transferase and α-fetoprotein levels for all patients and older age, Child-Pugh C cirrhosis, and low estimated glomerular filtration rate for patients without hepatocellular carcinoma. Overall, 1035 patients (73.3%) died; the causes of death were liver failure with/without hepatocellular carcinoma, pneumonia, sepsis, cardiovascular disease, and non-hepatocellular carcinoma malignancies. The corresponding morality rates per person-year were 133.4, 59.9, 10.9, 10.6, 9.0, and 5.2, respectively., Conclusions: Among Japanese patients with decompensated hepatitis C virus-related cirrhosis, hepatocellular carcinoma is associated with poor prognosis. Our results highlight the importance of managing liver-related events, including hepatocellular carcinoma, in these patients.

Objective A survival benefit was demonstrated for ramucirumab (RAM) in patients with unresectable hepatocellular carcinoma (uHCC) and α-fetoprotein (AFP) concentrations ≥400 ng/mL who had previously received sorafenib (SOR). However, it is unclear whether RAM has a similar efficacy in patients with uHCC that progresses after lenvatinib (LEN) treatment. This study aimed to evaluate the early anti-tumor response to RAM as a second-line treatment for advanced uHCC after LEN treatment. Methods We retrospectively assessed the efficacy and safety of RAM at 6 weeks after initiation. The therapeutic effects were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients We evaluated 7 patients with uHCC who received RAM as a second- or third-line treatment after LEN failure. Results The disease control rate (DCR) was 28.6% (2 of 7 patients). After the initiation of RAM, a rapid disease progression resulted in 1 patient death after 19 days. The median progression-free survival (PFS) was 41 days. There were no grade 3 or 4 treatment-related adverse events. At 6 weeks, there was no deterioration in the modified albumin-bilirubin (mALBI) grade. In patients with an imaging response of stable disease (SD), the rate of AFP production decreased from the baseline. Conclusion RAM may have a therapeutic potential for the suppression of uHCC progression in patients previously treated with LEN, as well as for maintaining the liver function during treatment. Evaluating the AFP trends may therefore be useful for predicting RAM effectiveness.

A male patient in his 70s underwent a right lobectomy because of a hepatocellular carcinoma(HCC)located in the right lobe(S6)of his liver. Eleven months after surgery, contrast-enhanced CT showed multiple masses in the residual liver, which were diagnosed as HCC recurrence. He was then treated with hepatic arterial infusion chemotherapy(HAIC). Ten months after the recurrence, the liver tumors progressed. Therefore, treatment was switched to sorafenib(400 mg/day orally)and HAIC(low-dose FP: 5-FU 250 mg plus CDDP 5 mg 5 days/week 4 weeks)sequential therapy. The patient received 2 cycles of sorafenib-HAIC sequential therapy for 11 months, and his liver tumors shrunk considerably. Unfortunately, 24 months after the recurrence of HCC, he died of respiratory failure. The cause of his death was officially determined to be primary lung cancer. An autopsy revealed that most tissues were necrotic, and only a small number of viable tumor cells were present in the liver tumors. This suggests that sorafenib-HAIC sequential therapy was significantly effective in targeting the multiple HCCs in this case.

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., (© 2020 S. Karger AG, Basel.)

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., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

We report a case of recurrent hepatocellular carcinoma(HCC)successfully treated by radiation therapy. A 79-year-old woman was diagnosed with HCC and underwent liver resection. Seven months after resection, CT and MRI detected a new HCC, and she had a surgery again. One year after the surgery, CT and MRI detected local recurrence, and she underwent the third operation. Three months after the operation, the third liver recurrence was treated by transcatheter arterial chemoembolization( TACE). Four months later, a new lesion was detected and treated by stereotactic body radiation therapy(SBRT) twice. She remains alive without recurrence 27 months after the last radiation therapy. Very few evidence is reported of radiation therapy for HCC, but this case suggests that radiation therapy provides a benefit for patients with HCC after other treatments.

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., (© 2020 Wiley Periodicals, Inc.)

We report a 71-year-old man with non-B non-C chronic liver damage who had been regularly visiting our hospital since he was 38 years of age. He underwent three partial hepatectomies for hepatocellular carcinoma (HCC) diagnosed at 65, 67, and 71 years of age, respectively. A histopathological examination showed moderately-differentiated HCC, and chronic hepatitis with mild fibrosis stage in non-tumor areas. alpha-fetoprotein (AFP) and PIVKAII were not useful for the early prediction of HCC, but TERT promotor mutation (C228T) in serum cell-free DNA was useful. This is the first report on the importance of long-term follow-up in non-B non-C chronic liver damage, regardless of the fibrosis stage.

We herein report a 48-year-old healthy woman who visited our hospital to investigate a 25-mm space-occupying lesion in the liver. The tumor was irregularly shaped and exhibited heterogeneous enhancement on dynamic computed tomography (CT). Whole-body positron emission tomography-CT showed an abnormal fluorodeoxyglucose uptake in the liver tumor, with a maximum standardized uptake value of 12.82. During the ensuing three months, the tumor grew rapidly and the serum alpha-fetoprotein levels also rose; partial hepatectomy was therefore performed. Microscopic findings revealed a moderately-to-poorly differentiated hepatocellular carcinoma in the normal liver.

Background: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported., Methods: The intent-to-treat population enrolled in Japan was analyzed., Results: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm., Conclusions: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC., Trial Registration Id: ClinicalTrials.gov. No. NCT01761266.

Purpose: This study sought to investigate the clinical impact of repeated interventions for recurrent hepatocellular carcinoma (HCC) and to establish a new surrogate measure for survival: the time-to-interventional failure (TIF)., Methods: Based on a retrospective review of 1158 patients who underwent curative resection for HCC, the abilities of recurrence-free survival (RFS) and TIF, which was defined as the elapsed time from resection to unresectable/unablatable recurrence, to predict overall survival (OS) were compared., Results: Within a median follow-up period of 84.9 months, 676 (59.0%) recurrence events occurred, 78.1% of which were resectable/ablatable recurrences. Of these, 99.1% of the patients underwent repeated treatments. TIF had a stronger correlation than RFS (r = 0.921 vs. r = 0.631) in prediction of OS. Patients who underwent curative-intent treatment (i.e., resection or ablation) for recurrence showed significantly better survival outcomes compared with those who underwent non-curative treatment (e.g., TACE, chemotherapy) (median OS, 89.1 months vs. 55.0 months; P < 0.0001). This tendency was constant across the AJCC stages and multivariate analysis confirmed that curative-intent treatment is associated with improved survival after initial recurrence (hazard ratio, 0.55; 95% CI, 0.37-0.81; P = 0.003)., Conclusions: OS after HCC resection is more strongly dependent on TIF than on RFS. Aggressive curative-intent interventions for recurrent HCC may prolong survival regardless of the cancer stage.

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.

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., (© 2019 John Wiley & Sons Ltd.)

Little is known about the effects of virus- and host-related factors on hepatocarcinogenesis in patients who show viral clearance after HCV RNA eradication by direct-acting antivirals (DAAs). The subjects of this retrospective study were 1,922 patients with HCV genotype 1 (HCV-1)- or HCV-2-related chronic liver disease who showed a sustained virological response (SVR; defined as negative results for HCV RNA at 12 weeks after the cessation of all-oral DAAs). All patients were confirmed to be hepatocellular carcinoma (HCC) free before and during DAAs. HCC was diagnosed in 43 patients during the follow-up, with an incidence rate per 1,000 person years of 9.44. The cumulative HCC rates were 1.2, 2.0, and 3.1% at the end of 1, 2, and 3 years, respectively. The annual rate of HCC during the first 3 years was 1.0%. The incidence rate was significantly higher in patients infected with the HCV-1b core amino acid (aa) 70 mutant than in those infected with HCV-2a/2b, and the rate in patients infected with the HCV-1b core aa 70 wild type tended to be higher than that in patients infected with HCV-2a/2b. The rate in patients infected with the HCV-1b NS5A aa 93 mutant was significantly higher than that in patients infected with HCV-2a/2b. However, the rate was not different between patients infected with the IL28B rs8099917 TT genotype and patients infected with the non-TT genotype. Multivariate analysis identified a Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA + M2BP) cutoff index (COI) of ≥2.5 and infection with the HCV-1b core aa 70 mutant subgroup to be pretreatment predictors of posttreatment HCC. The same analysis identified an alpha-fetoprotein concentration of ≥5 μg/liter and an WFA + M2BP COI of ≥1.0 to be predictors of HCC at 24 weeks after the end of antiviral therapy. We conclude that both virus- and host-related factors seem to influence the development of HCC after HCV RNA eradication., (Copyright © 2019 American Society for Microbiology.)

Background: Given that patients with hepatocellular carcinoma (HCC) usually suffer from dual diseases (i.e., HCC and underlying liver disease), a complete survival estimation model is difficult to establish because both the oncological stage and the underlying liver function affect the survival outcome., Methods: A new surgical risk model for estimating the survival of patients undergoing resection for HCC was created using a cohort treated between 1995 and 2013 (training set, n = 889), and its efficacy was then validated using a cohort treated between 2014 and 2017 (validation set, n = 310)., Results: The following statistical model was developed based on the results of multivariate analysis: albumin-platelet (PAL) score = - 0.777 × albumin (g/dL) - 0.575 × log 10 (platelet count [10 4 /μL]) (cut-off value, - 3.77 and - 3.04 for grading). A time-dependent receiver-operating curve analysis revealed that the area under the curve for 3-year survival was 0.644 in the training set and 0.666 in the validation set. The incidences of postoperative morbidity were 14.0% for PAL grade 1, 18.7% for PAL grade 2, and 26.1% for PAL grade 3 (P = 0.039), while the incidences of refractory ascites were 2.2, 7.1, and 12.5% (P = 0.005), respectively, in the training set. The reproducibility of these results was confirmed in the validation set with morbidity rates of 13.5, 23.3, and 40.7% (P = 0.003), respectively, and the incidences of refractory ascites were 0.7, 10.7, and 22.2% (P < 0.0001), respectively., Conclusions: The PAL score can be used as a grading system for the stratification of survival outcomes and surgical risks of patients undergoing HCC resection.

Background: The incidence of liver-related events, cardiovascular events and type 2 diabetes mellitus in patients with histopathologically confirmed NAFLD remains unclear., Methods: We retrospectively investigated the incidence of liver events, cardiovascular events, malignancy, and type 2 diabetes mellitus in 402 Japanese patients with histopathologically confirmed NAFLD for a median follow-up of 4.2 years. We also investigated predictors of the development of hepatocellular carcinoma and type 2 diabetes mellitus in these patients., Results: The rate of liver-related events per 1000 person years was 4.17 (hepatocellular carcinoma, 3.67; hepatic encephalopathy, 1.60; esophago-gastric varices, 2.43; ascites, 0.80; and jaundice, 0.40). The rate of cardiovascular events and type 2 diabetes mellitus was 5.73 and 9.95, respectively. Overall mortality was 3.33 (liver-related events, 1.25; cardiovascular events, 0.42; and malignancies other than hepatocellular carcinoma, 0.83), in patients free of previous or current malignancies. Multivariate analyses identified old age (≥70 years) and advanced fibrosis stage 4 as significant determinants of hepatocellular carcinoma development, and hepatocyte steatosis (> 33%), female sex, and serum ferritin (≤80 μg/l) as significant determinants of type 2 diabetes mellitus development in these patients., Conclusions: Our results highlighted the importance of cardiovascular and liver-related events in Japanese patients with histopathologically-confirmed NAFLD. Hepatocellular carcinoma was the most common liver-related event, and the incidence of hepatocellular carcinoma was more than half of that of cardiovascular events.

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., (© 2018 Wiley Periodicals, Inc.)

Background: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma., Methods: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266., Findings: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib., Interpretation: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed., Funding: Eisai Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

A 35-year-old male patient who showed sustained virological response (SVR) following treatment for hepatitis C virus infection developed liver cancer. The lesion was identified by imaging studies, with atypical findings suggestive of hepatocellular carcinoma. Partial hepatectomy was performed and the histopathological diagnosis was cholangiolocellular carcinoma (CLC). Only a few cases of CLC have been described in young patients who achieved SVR. Hepatologists should recognize the potential development of CLC even in young patients who achieve SVR, and the need for a close follow-up by imaging studies. In addition, true characteristics and cell origin of CLC were discussed in this report.

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.

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.

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., (© 2016 Wiley Periodicals, Inc.)

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., (© 2017 S. Karger AG, Basel.)

Background: Sorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population., Methods: Patients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected., Results: This interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299-389 days], and the median duration of treatment was 87 days (95 % CI 78-98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection., Conclusions: In general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients., Clinical Trial Registration Number: NCT01411436., Competing Interests: Compliance with ethical standard Conflict of interest Shuichi Kaneko has received research grants from Bayer Yakuhin and Nippon Shinyaku, and grants from Chugai Pharmaceutical, MSD, Kowa, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, Eli Lilly, Boehringer Ingelheim Japan, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Eisai, Daiichi Sankyo, AstraZeneca, Novartis Pharma, Astellas Pharma, Teijin Pharma, Zeria Pharmaceutical, Sanofi, Toray Industries, Shionogi, Novo Nordisk Pharma, and Pfizer Japan. Kenji Ikeda has received lecture fees from Sumitomo Dainippon Pharma and Eisai. Yasushi Matsuzaki has received research grants from Mitsubishi Tanabe Pharma, MSD, Ajinomoto Pharmaceuticals, Eisai, Sumitomo Dainippon Pharma, AbbVie, Daiichi Sankyo, Toray Industries, Minophagen Pharmaceutical, Otsuka Pharmaceutical and Kyowa Hakko Kirin, and lecture fees from Mitsubishi Tanabe Pharma, MSD, Ajinomoto Pharmaceuticals, Bristol-Myers Squibb and Janssen Pharmaceutical. Junji Furuse has received research grants from Taiho Pharma, Ono Pharmaceutical, OncoTherapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, GlaxoSmithKline and Yakult, and lecture fees from Taiho Pharma, Chugai Pharmaceutical, Yakult and Kyowa Hakko Kirin. Hironobu Minami has received research grants from Kyowa Hakko Kirin, Chugai Pharmaceutical, Taiho Pharma and Bristol-Myers Squibb. Yutaka Okayama, Toshiyuki Sunaya, Yuichiro Ito and Lyo Inuyama are employees of Bayer Yakuhin, Ltd. The other authors declare that they have no conflicts of interest.

Background and Aim: Relationships between circulating microRNA-122 (miR-122) and histological features of nonalcoholic fatty liver disease (NAFLD) are unclear., Methods: The impact of serum miR-122 levels for histological features and hepatocellular carcinoma (HCC) was investigated in 305 Japanese patients with histological proven NAFLD. Twenty-three patients were with HCC at the time of diagnosis of NAFLD, and four patients developed HCC during the follow-up. The cross-sectional or longitudinal evaluations were performed to investigate the impact for HCC., Results: Serum miR-122 levels (calibrated relative to the median levels of patients) partly affected severity of steatosis, ballooning, lobular inflammation, and stage. Multivariate analysis identified HCC and/or histological components of NASH as morphological factors that independently influenced serum miR-122 levels at the diagnosis of NAFLD. There was a strong correlation between serum miR-122 levels and AST, ALT levels. In cross-sectional evaluation, serum miR-122 levels of patients without HCC were significantly higher than those with HCC in patients of stage 3 but not stage 4. In longitudinal evaluation of one patient with follow-up time of 25 years, from the diagnosis of NAFLD until HCC, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage., Conclusions: HCC and/or histological components of NASH affected serum miR-122 levels, independently. In longitudinal evaluation of HCC patients, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage. Further prospective studies are needed to investigate the impact of serum miR-122 for histological features and hepatocarcinogenesis of NAFLD.

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., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: A sustained virological response (SVR) decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We investigated the long-term 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., (© 2016 S. Karger AG, Basel.)

Objectives: The aim of this study was to generate three-dimensional (3D) images of the ablative zone in patients with hepatocellular carcinoma (HCC) treated with multipolar radiofrequency ablation (RFA) using contrast-enhanced ultrasound (CEUS) and 3DUS and to investigate the shape of the ablative zone among several patterns after insertion of two or three electrodes., Methods: This study included 16 patients and 20 HCCs treated with a multipolar RFA system. All patients underwent CEUS within 14 days after multipolar RFA therapy. The 3D scanning functionality of the LOGIQ E9 US imaging system (GE Healthcare, Milwaukee, Wis., USA), which acquires volume data using a manually controlled sweep on perfusion defects of CEUS, was used in this study to acquire CEUS/3DUS data. The ablative-area shapes resulting from three insertion patterns were investigated, using two electrodes (T20-T20 and T30-T30) or three electrodes (T30-T30-T30)., Results: The resulting shapes using two electrodes were globule-like (T20-T20) or elliptical (T30-T30). The shape using three electrodes (T30-T30-T30) was almost ellipse-like but slightly irregular., Conclusions: Generating 3D images using CEUS/3DUS techniques is simple and useful for evaluating the shape of the ablative area, and these images provide informational or educational tools for patients and medical staff associated with multipolar RFA procedures., (© 2016 S. Karger AG, Basel.)

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., (© 2016 S. Karger AG, Basel.)

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC&#95;NT and HCC&#95;NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC&#95;NT, HCC, and HCC&#95;NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.

The impact of the HCV genotype 1b core amino acid (aa) 70 mutant on the cumulative rate of hepatocellular carcinoma following eradication of HCV RNA by antiviral therapy was investigated with the Q-Invader assay. Multivariate analysis based on 649 patients indicated that a core aa70 Q-Invader mutant level ≥20% is a predictor of hepatocellular carcinoma., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Dexmedetomidine (Precedex®)is an agonist of a2-adrenergic receptors in certain parts of the brain. It was approved for "procedural sedation in the non-intubation in under local anesthesia" in June 2013 in Japan. However, because of metabolism delay, dexmedetomidine has to be administered carefully to patients with liver dysfunction., Purpose: To evaluate the feasibility and safety of sedation using dexmedetomidine in percutaneous arterial chemoembolization for hepatocellular carcinoma with liver dysfunction., Methods: Thirty consecutive cases of percutaneous arterial chemoembolization for hepatocellular carcinoma with hepatitis C-related cirrhosis(male, 23; female, 7; age, 74±5.9; weight, 62.7±12.3 kg; Child-Pugh A, 23; Child-Pugh B, 7)were analyzed retrospectively. Dexmedetomidine was administered at 3 mg/kg/h for 15 minutes as the initial loading dose and at 0.4 mg/kg/h as the maintenance dose. The sedation level was evaluated using the Ramsay sedation scale., Results: In 30 of 30 cases, percutaneous arterial chemoembolization therapy could be performed with dexme- detomidine sedation. In 27 of 30 cases, the procedure was completed with the maintenance dose of 0.4 mg/kg/h. In 3 of 30 cases, the maintenance dose was increased to 0.6 mg/kg/h because of patient body motion. The mean administration time of dexmedetomidine was 82±30 minutes. The level of sedation measured with the Ramsay sedation scale at the end of the procedure was 3 points in 29 cases and 5 points in one case. Adverse events occurred in 3 of 30 cases. Intravenous drip leakage occurred in one case, vertigo occurred in one case, and vomiting occurred in one case. There were no adverse events requiring treatment., Conclusion: Sedation with dexmedetomidine in percutaneous arterial chemoembolization for hepatocellular carcinoma with liver dysfunction was feasible and safe.

Background: This study examined the effects of peretinoin, an acyclic retinoid, on the survival of patients with hepatitis C virus-related hepatocellular carcinoma (HCC) who had completed curative therapy and participated in a randomized, placebo-controlled trial., Methods: This study was an investigator-initiated retrospective cohort study. Subjects were all patients who were administered the investigational drug (peretinoin 600 mg/day, peretinoin 300 mg/day, or placebo) in the randomized trial. Survivals between the groups were compared using the log-rank test, and hazard ratios were estimated by Cox regression., Results: Survey data were collected from all patients (n = 392) who participated in the randomized trial, all of whom were then divided into the peretinoin 600 mg/day (n = 132), peretinoin 300 mg/day (n = 131), and placebo (n = 129) groups. At the median follow-up of 4.9 years, 5-year cumulative survival rates for patients in the 600 mg/day, 300 mg/day, and placebo groups were 73.9, 56.8, and 64.3 %, respectively. Comparison of overall survival among patients classified as Child-Pugh A revealed that survival of the 600 mg/day group (n = 105) was significantly longer than that of the placebo group (n = 108) (hazard ratio 0.575, 95 % CI 0.341-0.967; P = 0.0347)., Conclusions: Administration of 600 mg/day peretinoin to patients with hepatitis C virus-related HCC who have completed curative therapy may improve survival for those classified as Child-Pugh A, for whom liver function is relatively stable.

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.

Background: The implication of extremely high preoperative alpha-fetoprotein (AFP) values for the long-term outcomes of hepatectomy for resectable hepatocellular carcinoma (HCC) remains uncertain., Methods: A total of 762 hepatectomized HCC patients were divided into 3 groups according to preoperative AFP serum concentrations: 578 patients with AFP <100 ng/mL (low [LAP]), 147 patients with AFP 100-4,000 ng/mL (high [HAP]), and 37 patients with AFP ≥4,000 ng/mL (extremely high [EAP]). The clinicopathologic features and prognosis of the EAP group were compared with those of the other 2 groups to investigate their characteristics and whether the choice of hepatectomy was valid., Results: The EAP group had a greater proportion of younger patients and those with hepatitis B compared with the other 2 groups. Large tumor size, poor histologic differentiation, and microscopic vascular invasion were also more common in the EAP group. The recurrence-free and overall survival rates of the EAP group were worse than those of the LAP group (both P < .01) but were not greatly different from those of the HAP group (P = .65 and P = .80, respectively). When the analysis was limited to solitary HCC cases, both recurrence-free and overall survival rates of EAP were not significantly different from those of LAP (P = .79 and P = .99, respectively)., Conclusion: An extremely high AFP level does not provide additional postoperative prognostic implications beyond those provided by a high AFP level. Hepatectomy should be performed without reservation for cases of HCC associated with an extremely high AFP value., (Copyright © 2015 Elsevier Inc. All rights reserved.)