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Aim: This post-marketing surveillance study evaluated the safety and effectiveness of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma in Korea. Materials & methods: Adverse drug reactions (ADRs) and other safety and effectiveness end points were assessed in patients who initiated lenvatinib according to the approved label in republic of Korea. Results: Among 658 lenvatinib-treated patients, ADRs were reported in 57.8%; ADRs grade ≥3 in 13.5%. The most common grade ≥3 ADRs were asthenia (1.2%) and hepatic encephalopathy (1.2%). Physician-reported tumor responses (n = 511) were complete (1.0%) or partial (12.9%) response and stable (45.2%) or progressive disease (40.9%); objective response rates were higher with longer lenvatinib treatment duration (p < 0.001). Conclusion: Lenvatinib was generally well tolerated and effective in real-world clinical practice in Korea. Clinical trial registration:ClinicalTrials.govNCT05225207 Article highlights Since 2018, lenvatinib has been available in several countries as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). This was a prospective, multicenter, observational, post-marketing surveillance of the safety and effectiveness of lenvatinib as first-line treatment for uHCC in routine clinical practice in republic of Korea. Among 700 case report forms of patients who initiated lenvatinib according to the approved label in republic of Korea at 29 institutions, 658 were included in the safety analysis and 511 in the effectiveness analysis. None of the safety population (median age 64 years, 85% male) had received prior chemotherapy, 64.1% had received non-chemotherapy treatment, and 42.1% had a history of hypertension treatment. Among 658 lenvatinib-treated patients, the incidence of adverse drug reactions (ADRs) was 57.8% and the incidence of ADRs grade ≥3 was 13.5%. The most common ADRs were hypertension (14.4%) diarrhea (10.5%), palmar-plantar erythrodysesthesia syndrome (10.0%) and decreased appetite (7.6%); the most common grade ≥3 ADRs were asthenia (1.2%) and hepatic encephalopathy (1.2%). Factors significantly associated with adverse events were history of non-chemotherapy treatment, hypertension treatment; and the average daily dose of lenvatinib (12 mg/day compared with <8 mg/day and 8 – <10 mg/day). Physician-reported tumor responses evaluated by RECIST v1.1 or mRECIST criteria were: complete response (1.0%); partial response (12.9%); stable disease (45.2%); and progressive disease (40.9%). Objective response rates were significantly higher with longer (≥3 months to >9 months) lenvatinib treatment duration compared with <3 months. This PMS study shows that lenvatinib has a manageable tolerability profile and provides clinically meaningful effectiveness as first-line treatment for patients with uHCC in the real-world clinical setting in Korea. [ABSTRACT FROM AUTHOR]

The treatment decisions for patients with hepatocellular carcinoma are determined by a wide range of factors, and there is a significant difference between the recommendations of widely used staging systems and the actual initial treatment choices. Herein, we propose a machine learning-based clinical decision support system suitable for use in multi-center settings. We collected data from nine institutions in South Korea for training and validation datasets. The internal and external datasets included 935 and 1750 patients, respectively. We developed a model with 20 clinical variables consisting of two stages: the first stage which recommends initial treatment using an ensemble voting machine, and the second stage, which predicts post-treatment survival using a random survival forest algorithm. We derived the first and second treatment options from the results with the highest and the second-highest probabilities given by the ensemble model and predicted their post-treatment survival. When only the first treatment option was accepted, the mean accuracy of treatment recommendation in the internal and external datasets was 67.27% and 55.34%, respectively. The accuracy increased to 87.27% and 86.06%, respectively, when the second option was included as the correct answer. Harrell's C index, integrated time-dependent AUC curve, and integrated Brier score of survival prediction in the internal and external datasets were 0.8381 and 0.7767, 91.89 and 86.48, 0.12, and 0.14, respectively. The proposed system can assist physicians by providing data-driven predictions for reference from other larger institutions or other physicians within the same institution when making treatment decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: We aimed to compare the prognosis of patients with advanced hepatocellular carcinoma treated with the first-line atezolizumab plus bevacizumab (AB) combination chemotherapy and the less popular locoregional treatment mainly used in East Asia, hepatic artery infusion chemotherapy (HAIC). We conducted a retrospective study with 114 patients treated with AB and 193 patients treated with HAIC and compared the overall survival (OS) and progression-free survival (PFS). Our results showed comparable OS between the two therapy groups; however, PFS was superior in patients treated with AB combination therapy. After compensating for confounding variables via propensity score matching, there was no significant difference in PFS and OS between the two groups. This study aimed to compare the prognosis and characteristics of patients with advanced hepatocellular carcinoma treated with first-line atezolizumab plus bevacizumab (AB) combination therapy and hepatic artery infusion chemotherapy (HAIC). We retrospectively assessed 193 and 114 patients treated with HAIC and AB combination therapy, respectively, between January 2018 and May 2023. The progression-free survival (PFS) of patients treated with AB combination therapy was significantly superior to that of patients treated with HAIC (p < 0.05), but there was no significant difference in overall survival (OS). After propensity score matching, our data revealed no significant differences in OS and PFS between patients who received AB combination therapy and those who received HAIC therapy (p = 0.5617 and 0.3522, respectively). In conclusion, our propensity score study reveals no significant differences in OS and PFS between patients treated with AB combination therapy and those treated with HAIC. [ABSTRACT FROM AUTHOR]

Simple Summary: This multicenter cohort study is the first to compare the clinical outcomes between the Atezolizumab-plus-bevacizumab (Ate/Bev) and transarterial-chemoembolization-plus-radiotherapy (TACE + RT) therapies in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) who had no metastasis. Through detailed analyses, our study revealed that the Ate/Bev treatment provided superior one-year survival compared to the TACE + RT treatment. The superior outcome of the Ate/Bev therapy was constantly observed in patients with an extensive HCC burden. Meanwhile, patients with unilobar disease demonstrated comparable outcomes between the two treatment groups. Finally, in the propensity score-matching analysis, both one-year survival and progression-free survival rates were higher in the Ate/Bev treatment group. These results suggest that Ate/Bev treatment should be considered as the primary treatment option for HCC patients with PVTT. With respect to TACE + RT, this could also be considered as an alternative treatment option alongside Ate/Bev therapy in patients with unilobar intrahepatic HCC. This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy. [ABSTRACT FROM AUTHOR]

Background and Aim: Antiviral therapy (AVT) is the mainstay of hepatitis B virus (HBV) management. We investigated whether AVT improves the outcomes of HBV‐related decompensated cirrhosis and undetectable HBV‐DNA. Methods: Between 2000 and 2017, treatment‐naïve patients with HBV‐related decompensated cirrhosis and undetectable HBV‐DNA were recruited from two tertiary hospitals. The endpoints included death and hepatocellular carcinoma (HCC). Results: A total of 429 patients were analyzed (50 and 379 patients in the AVT and non‐AVT groups, respectively). Patients in the AVT group were significantly younger and had higher alanine aminotransferase and alpha‐fetoprotein levels than those in the non‐AVT group (all P < 0.05). During follow‐up (median 49.6 months), 98 patients died and 105 developed HCC. The cumulative incidence rates of death (2.0%, 4.1%, and 6.4%, and 4.9%, 7.2%, and 10.2% at 6 months, 1 year, and 2 years, respectively) and HCC (8.6%, 15.8%, and 26.4% vs 1.6%, 7.7%, and 24.4% at 1, 2, and 5 years, respectively) were statistically comparable between the AVT and non‐AVT groups (all P > 0.05). Using Cox regression analysis, AVT was not significantly associated with death nor HCC (all P > 0.05). Similar results were observed after balancing baseline characteristics with inverse probability of treatment weighting. In the non‐AVT group, the cumulative incidence rates of HBV‐DNA detection at 6 months, 1 year, and 2 years were 2.0%, 3.1%, and 6.4%, respectively. Conclusions: Antiviral therapy did not attenuate the risk of death nor HCC in patients with HBV‐related decompensated cirrhosis and undetectable HBV‐DNA. [ABSTRACT FROM AUTHOR]

Multikinase inhibitors (MKIs) such as sorafenib and lenvatinib are first-line treatments for unresectable hepatocellular carcinoma (HCC) and are known to have immunomodulatory effects. However, predictive biomarkers of MKI treatment in HCC patients need to be elucidated. In the present study, thirty consecutive HCC patients receiving lenvatinib (n = 22) and sorafenib (n = 8) who underwent core-needle biopsy before treatment were enrolled. The associations of CD3, CD68, and programmed cell death-ligand-1 (PD-L1) immunohistochemistry with patient outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), were evaluated. High and low subgroups were determined according to median CD3, CD68, and PD-L1 values. Median CD3 and CD68 counts were 51.0 and 46.0 per 20,000 µm2, respectively. The median combined positivity score (CPS) of PD-L1 was 2.0. Median OS and PFS were 17.6 and 4.4 months, respectively. ORRs of the total, lenvatinib, and sorafenib groups were 33.3% (10/30), 12.5% (1/8), and 40.9% (9/22), respectively. The high CD68+ group had significantly better PFS than the low CD68+ group. The high PD-L1 group had better PFS than the low subgroup. When we analyzed the lenvatinib subgroup, PFS was also significantly better in the high CD68+ and PD-L1 groups. These findings suggest that high numbers of PD-L1-expressing cells within tumor tissue prior to MKI treatment can serve as a biomarker to predict favorable PFS in HCC patients. [ABSTRACT FROM AUTHOR]

Predicting the development of hepatocellular carcinoma (HCC) is a key clinical issue in patients with chronic hepatitis B (CHB). The aim of this study was to develop a precise and simple HCC risk score for up to 10 years. A total of 1895 CHB patients treated with entecavir or tenofovir disoproxil fumarate were retrospectively recruited and randomized into derivation (n = 1239) and validation cohorts (n = 656). Variables proven to be independent risk factors for HCC in the derivation cohort were used to develop the prediction model. The ACCESS-HCC model included five variables (age, cirrhosis, consumption of ethanol, liver stiffness, and serum alanine aminotransferase). Areas under curves were 0.798, 0.762, and 0.883 for HCC risk at 3, 5, and 10 years, respectively, which were higher than those of other prediction models. The scores were categorized according to significantly different HCC incidences: 0–4, low; 5–8, intermediate; and 9–14, high-risk. The annual incidence rates were 0.5%, 3.2%, and 11.3%, respectively. The performance of this model was validated in an independent cohort. The ACCESS-HCC model shows improved long-term prediction and provides three distinct risk categories for HCC in CHB patients receiving antiviral therapy. Further research is needed for external validation using larger cohorts. [ABSTRACT FROM AUTHOR]

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti-VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) is administered when the above-described combination fails to confer sufficient clinical benefit. The present study aimed to explore the association between tumor programmed cell death-ligand 1 (PD-L1) positivity and HAIC response. A total of 40 patients with HCC who had undergone HAIC with available biopsy samples obtained between January 2020 and May 2023 were retrospectively enrolled. Tumor response, progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) were evaluated. PD-L1 expression in tumor samples was assessed using a combined positivity score. The response rates of HAIC-treated patients with advanced HCC after failure of atezolizumab/bevacizumab combination therapy were recorded. OS (P=0.9717) and PFS (P=0.4194) did not differ between patients with and without PD-L1 positivity. The objective response rate (P=0.7830) and DCR (P=0.7020) also did not differ based on PD-L1 status. In conclusion, the current findings highlight the consistent efficacy of HAIC, regardless of PD-L1 positivity. [ABSTRACT FROM AUTHOR]

Background/Aim: Uniform treatment of hepatocellular carcinoma (HCC) with molecular targeted drugs (e.g., sorafenib) results in a poor overall tumor response when tumor subtyping is absent. Patient stratification based on actionable gene expression is a method that can potentially improve the effectiveness of these drugs. Here we aimed to identify the clinical application of actionable genes in predicting response to sorafenib. Methods: Through quantitative real-time reverse transcription PCR, we analyzed the expression levels of seven actionable genes (VEGFR2, PDGFRB, c-KIT, c-RAF, EGFR, mTOR, and FGFR1) in tumors versus noncancerous tissues from 220 HCC patients treated with sorafenib. Our analysis found that 9 responders did not have unique clinical features compared to nonresponders. A receiver operating characteristic curve evaluated the predictive performance of the treatment benefit score (TBS) calculated from the actionable genes. Results: The responders had significantly higher TBS values than the nonresponders. With an area under the curve of 0.779, a TBS combining mTOR with VEGFR2, c-KIT, and c-RAF was the most significant predictor of response to sorafenib. When used alone, sorafenib had a 0.7–3% response rate among HCC patients, but when stratifying the patients with actionable genes, the tumor response rate rose to 15.6%. Furthermore, actionable gene expression is significantly correlated with tumor response. Conclusions: Our findings on patient stratification based on actionable molecular subtyping potentially provide a therapeutic strategy for improving sorafenib's effectiveness in treating HCC. [ABSTRACT FROM AUTHOR]

We assessed the incidence of hepatocellular carcinoma (HCC) in those outside of current treatment recommendations and risk factors associated with HCC development. A multi‐centre, retrospective cohort of 3624 patients who were monitored without antiviral treatment was analysed. Incident HCC risk according to the Asian Pacific Association for the study of the Liver (APASL), the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) treatment recommendations was assessed. A risk score was developed using independent factors associated with HCC development among patients who were outside current treatment criteria. During a median follow‐up of 4.6 years, incident HCC was diagnosed in 161 (4.4%) patients. The proportions of patients who developed HCC outside treatment recommendation according to APASL, AASLD and EASL criteria were 64.0%, 46.0% and 33.5%, respectively. The 5‐year cumulative HCC incidence rate was 13.9% for cirrhotic patients with low‐level viremia and 6.1 ~ 7.3% for chronic hepatitis patients with elevated HBV DNA levels plus mildly elevated alanine aminotransferase levels. Among patients who were outside treatment recommendation, age, sex, hepatitis B e antigen, cirrhosis, alanine aminotransferase and platelet levels were independent factors associated with HCC development. When these factors were used to calculate the risk score for each patient, those with a score ≥8 had a higher HCC incidence rate (14.3% at 5‐year), although they were currently outside treatment recommendations. Thus, HCC was observed among patients who were outside current treatment criteria indicating that careful monitoring for HCC and efforts to identify patients at risk are required. [ABSTRACT FROM AUTHOR]

Aim & Background: Advanced hepatocellular carcinoma (HCC) (Barcelona clinic liver cancer [BCLC] stage C) needs subclassification to more accurately predict survival. This study aims to establish a substaging system of BCLC stage C HCC patients for accurate prognosis. Methods: Data from 564 patients with newly diagnosed BCLC stage C HCC from three tertiary‐care hospitals affiliated with the Korea University (training set) were assessed retrospectively. Variables affecting overall survival (OS) were analysed, and patients were substaged according to the number of prognostic factors they fulfilled. The substaging system was validated using a nationwide database from the Korean Liver Cancer Association (validation set; n = 742). Results: In the training set, tumour factors such as tumour burden ≥10 cm, major portal vein invasion and distant metastasis, as well as underlying liver function, were independently associated with OS. BCLC stage C was classified into four substages (C1‐4) according to the number of prognostic factors. Substages C1, C2, C3 and C4 showed a median OS of 17.50 months (95% confidence interval [CI], 8.57‐26.43), 10.13 months (95% CI, 8.17‐12.09), 4.20 months (95% CI, 3.42‐4.98), and 2.90 months (95% CI, 2.34‐3.46) respectively (P < 0.05). This substaging system also had good discriminative ability in predicting survival in the validation set. In addition, it was considered that the BCLC substaging is better than Hong Kong liver cancer substaging in predicting the OS for patients with advanced HCC. Conclusion: Our substaging for BCLC stage C might help predict patients' prognosis better. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma ( HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 ( PD-1) and programmed cell death ligand-1 ( PD-L1), and cytotoxic T lymphocyte-associated molecule-4 ( CTLA-4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD-1, PD-L1, and CTLA-4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD-1 and PD-L1 expressions were significant related to high CD8+ tumor-infiltrating lymphocytes ( TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson-Steiner grade was statistically related to high PD-1 expression. High PD-L1 expression was demonstrated as an independent poor prognostic factor for disease-free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/ dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD-L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD-1/ PD-L1 blocking agent for HCC patients. [ABSTRACT FROM AUTHOR]

Background & Aims: Single large (>5 cm) hepatocellular carcinoma (HCC) is classified as Barcelona Liver Clinic (BCLC) stage early stage (A). Yet, controversies exist whether single large HCC can be considered as early stage. We have analyzed long-term outcome to see which stage is appropriate for these patients. Methods: From 2005 to 2006, 1,546 consecutive patients who were newly diagnosed as HCC (BCLC A or B) at four tertiary hospitals in Korea were analyzed. BCLC A was sub-classified into A1 (single 2–5 cm), A2 (2–3 nodules ≤3 cm), and A3 (single >5 cm). BCLC B1 included patients beyond-Milan criteria, and within up-to-7 criterion. Survival prediction between subgroupings (1: A1 + A2 + A3 vs. B1 and 2: A1 + A2 vs. A3 + B1) was compared based on c-index and Akaike information criterion (AIC). Results: The 5-year overall survival (OS) rate was 62.3, 58.6, 36.8, and 42.0% for A1, A2, A3 and B1, respectively. In multivariate Cox-regression analysis, OS was significantly different between A3 + B1 vs. A1 + A2 (hazard ratio [HR] 1.85; P<0.001), but not between A1 + A2 + A3 vs. B1 (HR 1.19; P = 0.258). For A3, surgical resection showed superior OS over transarterial chemoembolization. Survival prediction was superior in subgrouping 2 (AIC 5727.2; c-index 0.652) than subgrouping 1 (AIC 5766.3; c-index 0.619) even after inverse probability weighting. Conclusions: This large scale long-term follow-up data shows that single large tumor should be considered as intermediate stage in terms of prognosis. However, in terms of treatment, resection might be the first line treatment option. [ABSTRACT FROM AUTHOR]

Background & aims There has been remarkable progress in the management of hepatocellular carcinoma ( HCC) during the last several decades, but its effect on the prognosis of HCC patient needs clarification. We analysed the changes that affected prognosis of HCC patients diagnosed over two different eras. Methods A retrospective study of 1318 patients diagnosed with HCC from 1986 to 2012 was conducted. Analysis was done according to two cohorts, cohort 1 (patients diagnosed with HCC from 1986 to 1992) and cohort 2 (patients diagnosed from 2006 to 2012). Results Hepatitis B virus was the most common cause of liver disease for both cohorts (66.2% and 66.0%). The proportion of patients with Barcelona Clinic Liver Cancer stage 0/A was significantly lower in cohort 1 than in cohort 2 (14.4% vs. 39.5%, P < 0.001). The proportions of patients diagnosed during surveillance and general health check-up were significantly higher in cohort 2 than in cohort 1 (28.6% vs. 10.6% and 26.3% vs. 7.9%, respectively) while those diagnosed during symptomatic evaluation was significantly higher in cohort 1 than in cohort 2 (45.1 vs. 81.4%, P < 0.001). Surgical resection rate was similar between the two cohorts (26.1% vs 26%) while the transcatheter arterial chemoembolization rate which was the highest in cohort 1 (40.6%) was overtaken by radiofrequency ablation in cohort 2 (55%) at BCLC stage 0/A. Median survival duration in cohort 2 was significantly longer than cohort 1 (65.0 vs. 7.9 months, P < 0.001). Conclusions Implementation of national cancer surveillance and the advancement of treatment modalities have likely led to early detection of HCC and improvements in prognosis over the last 20 years. [ABSTRACT FROM AUTHOR]

Objectives: Interferon (IFN)-based therapy for chronic hepatitis C (CHC) is cost-effective and is associated with reduced risk of disease progression. We aimed to assess the incidence of cirrhosis and hepatocellular carcinoma (HCC) and to identify risk factors associated with disease progression. Methods: We retrospectively reviewed 280 CHC patients who were registered at our hospital between 2001 and 2010. Results: About 80% of patients received antiviral treatment. The 10-year cumulative incidence of cirrhosis was significantly lower among patients who received antiviral therapy than among those who did not (8.3 vs. 44.0%; p = 0.001). Among them, patients with sustained virological response (SVR) had a significantly lower incidence of cirrhosis than those without SVR (0.6 vs. 33.9%; p < 0.001). Cox proportional hazards regression showed that SVR was the significant independent factor for reducing the risk of cirrhosis (hazard ratio, HR = 0.03; p = 0.034). The 10-year cumulative incidence of HCC was higher among patients who did not receive antiviral therapy than among those who did (43.9 vs. 6.1%; p < 0.001). Multivariate analysis showed that underlying cirrhosis was the only independent risk factor associated with HCC development (HR = 7.70; p = 0.010). Conclusions: SVR secondary to IFN-based therapy could reduce cirrhosis development in CHC patients. Underlying cirrhosis was the strongest predictor of HCC development. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification. [ABSTRACT FROM AUTHOR]

Background and Aims NS398, a selective cyclooxygenase-2 inhibitor, and simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, both exert an anticancer effect on hepatocellular carcinoma cells, but the effect of co-administration of the two drugs remains unknown. We aimed to investigate the synergistic in vitro anticancer effect of co-administration of NS398 and simvastatin and its mechanism. Methods The Hep3 B and Huh-7 cell lines were cultured. Cells were treated with simvastatin, NS398, or a combination. 5-bromo-2′-deoxyuridine ELISA assay, flow cytometry, Western blot analyses, and immunofluorescence assay were performed. Results In both cell lines, co-administration of simvastatin and NS398 resulted in a greater effect on proliferation and apoptosis. In Hep3 B cells, co-administration of the two drugs resulted in a greater decrease in procaspase 3 and Bcl-2 and an increase in cleaved caspase 9 than that noted with monotherapy. In Huh-7 cells, co-administration of the two drugs resulted in a greater decrease in procaspase 3 and cyclin D1 and an increase in cleaved caspase 9. Expression of NF- κB and Akt were also decreased to a greater extent when the two drugs were co-administered in both cell lines. Immunofluorescence assay showed suppression of the nuclear localization of NF- κB by simvastatin or NS398. The effect was greater by co-administration. Conclusions The co-administration of NS398 and simvastatin produced greater antiproliferative and proapoptotic effects against Hep3 B cells and Huh-7 cells. Inhibition of the NF- κB and Akt pathway and activation of caspase cascade, which are considered as the major mechanism of synergistic anticancer properties, were observed in both cell lines. [ABSTRACT FROM AUTHOR]

Background & Aims: Recently, new methods, including the concept of viable enhancing tumor such as EASL and mRECIST, have been proposed for substitution of the conventional WHO and RECIST criteria in hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Herein, we evaluated the differences of four methods and compared the association of these methods with the prognosis of HCC patients undergoing TACE. Methods: We retrospectively reviewed 114 consecutive newly diagnosed HCC patients who underwent TACE as initial treatment. We evaluated the intermethod agreement (κ values) between the methods and compared their association with the prognosis of HCC patients. Results: The κ values for EASL vs. WHO, EASL vs. RECIST, mRECIST vs. WHO, and mRECIST vs. RECIST were low, of 0.102, 0.088, 0.112, and 0.122, respectively. However, good correlations were observed for WHO vs. RECIST and EASL vs. mRECIST (κ =0.883, κ =0.759, respectively p <0.001). The median OS was 32.3months. Hazard ratios (HR) for survival in responders compared with non-responders were 0.21 (95% CI; 0.12–0.37, p <0.001) for EASL and 0.27 (95% CI; 0.15–0.48, p <0.001) for mRECIST. The mean survival of responders was significantly longer than that of non-responders in both EASL (40.8 vs. 16.9months, p <0.001) and mRECIST (41.1 vs. 20.7months, p <0.001). In multivariate analysis, EASL response (HR 0.21, 95% CI 0.11–0.40, p <0.001) and mRECIST response (HR; 0.31, 95% CI, 0.17–0.59, p <0.001) were independently associated with survival. Conclusions: The response assessment by EASL and mRECIST could reliably predict the survival of HCC patients undergoing TACE and could be applicable in practice in preference to the conventional WHO and RECIST criteria. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether three-dimensional conformal radiotherapy (3D-CRT) influences hepatitis B virus (HBV) reactivation and chronic hepatitis B (CHB) exacerbation in patients with HBV-related hepatocellular carcinoma (HCC). Methods and Materials: Of the 48 HCC patients with HBV who underwent 3D-CRT to the liver, 16 underwent lamivudine therapy before and during 3D-CRT (Group 1) and 32 did not receive antiviral therapy before 3D-CRT (Group 2). To analyze spontaneous HBV reactivation, we included a control group of 43 HCC patients who did not receive any specific treatment for HCC or CHB. Results: The cumulative rate of radiation-induced liver disease for Groups 1 and 2 was 12.5% (2 of 16) and 21.8% (7 of 32), respectively (p > 0.05). The cumulative rate of HBV reactivation was significantly greater in Group 2 (21.8%, 7 of 32) than in Group 1 (0%, 0/16) or the control group (2.3%, 1 of 43; p < 0.05 each). The cumulative rate of CHB exacerbation, however, did not differ significantly between Groups 2 (12.5%, 4 of 32) and 1 (0%, 0 of 16) or the control group (2.3%, 1 of 43; p > 0.05 each). The CHB exacerbations in the 4 Group 2 patients had radiation-induced liver disease features but were differentiated by serum HBV DNA changes. Two of these patients required antiviral therapy and effectively recovered with lamivudine therapy. Conclusions: In patients with HBV-related HCC undergoing 3D-CRT, HBV reactivation and consequent CHB exacerbation should be considered in the differential diagnosis of radiation-induced liver disease, and antiviral therapy might be considered for the prevention of liver function deterioration after RT. [Copyright &y& Elsevier]

Background: Anatomical segmentectomy is a technically challenging procedure because tertiary portal pedicles are multiple, variable, and deep inside the liver.1 Anatomical segmentectomy can be performed using the transfissural Glissonean approach through the opening main portal fissure or umbilical fissure.1–3 We present laparoscopic anatomical resection of segment 4b using the transfissural Glissonean approach. Methods: A 67-year-old man was referred for treatment of single nodular mass in segment 4b. The surgical procedure involved the following steps: (1) Opening of the umbilical fissure along the umbilical fissure vein (2) Dissection of Glissonean pedicle 4b (3) Identification of ischemic territory of segment 4b (4) Right-side parenchymal transection along the ischemic line. Results: The operative time was 230 min, and the estimated blood loss was 100 mL. The final histopathological diagnosis was hepatocellular carcinoma. The tumor size was 30 mm and the resection margin was 25 mm. The patient had an uneventful postoperative recovery, and he was discharged on postoperative day 6. Conclusion: The transfissural Glissonean approach for laparoscopic anatomic resection of segment 4 b is a feasible and effective technique. The opening of the umbilical fissure allows the surgeon to dissect the target portal pedicles of segment 4b directly. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic right posterior sectionectomy is technically challenging secondary to poor exposure of the surgical field and difficulty with controlling hemorrhage during deeper parenchymal transection Cho et al., Surgery 158:135-141, 2015; Lee et al., Surgery 160:1219-1226, 2016. We present laparoscopic right posterior sectionectomy using the Glissonean approach and a modified liver hanging maneuver.Methods: A 57-year-old man presented with a single mass in segment 7 of the liver. He was placed in the lithotomy position, and five trocars were used in the upper abdomen. The hepatoduodenal ligament was encircled using an umbilical tape to perform the intermittent Pringle maneuver. After detachment of the hilar plate, the right posterior Glissonean pedicle was dissected and clamped to confirm ischemic delineation Takasaki, J Hepato-Biliary-Pancreat Surg 5:286-291, 1998. After complete mobilization of the right liver, the hanging tape was placed along the inferior vena cava between the caval ligament and the right hepatic vein. The hanging tape elevates the liver and guides the surgeon to achieve an accurate transection plane Belghiti et al., J Am Coll Surg 193:109-111, 2001; Kim et al., Surg Endosc 30:3611-3617, 2016; Kim, Choi, J Gastrointest Surg 21:1181-1185, 2017; Kim et al., Langenbecks Arch Surg 403:131-135, 2018 . The transection plane used during a right posterior sectionectomy is horizontal and follows the inferior vena cava. However, with the liver hanging maneuver, the horizontal transection plane becomes vertical.Result: The operation time was 290 min, the estimated blood loss was 120 mL, and the total Pringle maneuver time was 60 min. Final histopathological diagnosis showed a 1.7-cm-sized hepatocellular carcinoma with the resection margin measuring 1.5 cm. The patient was discharged on postoperative day 7 without any complications.Conclusion: A Glissonean approach with a modified liver hanging maneuver is feasible and useful for laparoscopic right posterior sectionectomy. [ABSTRACT FROM AUTHOR]

Potent antiviral agents effectively reduce liver-related events in patients with chronic hepatitis B. This study aimed to determine whether alanine aminotransferase normalization using potent antiviral agents was related to hepatocellular carcinoma development. From 2007 to 2017, we included 610 patients with chronic hepatitis B who received entecavir or tenofovir disoproxil fumarate. The patients were divided into the alanine aminotransferase normalization group (Gr.1) and non-normalization group (Gr.2) within a year of potent antiviral treatment. Liver-related events included hepatic encephalopathy, variceal bleeding, and ascites. The mortality rate and hepatocellular carcinoma incidence were investigated for each group. The patients who showed ALT normalization at 1 year of treatment were 397 (65.1%) of 610. During a median follow-up period of 86 months, 65 (10.7%) patients developed hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly lower in Gr.1 than in Gr.2 (p < 0.001). Risk factors for alanine aminotransferase non-normalization were body mass index, cholesterol, and liver cirrhosis at baseline. Male sex, age, platelet level, alcohol use, presence of cirrhosis at baseline, and non-normalization after 1 year of treatment were independent risk factors for hepatocellular carcinoma. Alanine aminotransferase normalization within 1 year of initiating antiviral agents reduces the risk of hepatocellular carcinoma development. [ABSTRACT FROM AUTHOR]

Simple Summary: The outcome of hepatocellular carcinoma (HCC) patient varies depending on tumor burden and liver function. The BCLC staging system is based on these two factors while AJCC staging system is based on tumor burden only. However, the outcome of HCC does not solely depend on these two factors, but also the aggressiveness of tumor behavior represented by tumor morphology. The morphology of HCC can be divided into three types; nodular, multinodular confluent and infiltrative type. The infiltrative type is known to be associated with poor prognosis and should be staged differently from other tumors. This study revealed that large infiltrative type HCC (≥4 cm) was associated with worse survival especially in early AJCC T-stages (T1b/2) and BCLC stages (A/B). In addition, reassignment of large infiltrative tumor to T3 and T4 and to BCLC B and C increased the discriminatory ability of each staging system. Infiltrative gross morphology of hepatocellular carcinoma (HCC) is known to be associated with poor prognosis, but this is not considered for staging. A total of 774 HCC patients who underwent curative liver resection were retrospectively reviewed and the prognostic significance of infiltrative type HCC was assessed using the American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) staging systems. Seventy-four patients (9.6%) had infiltrative HCCs with a higher proportion of multifocal tumors, larger tumors, vessel invasion, increased tumor marker levels, and advanced T-stages than those with nodular HCC (all, p < 0.01). Infiltrative morphology was independently associated with lower overall survival (OS), but its impact was significant when the tumor size was ≥ 4 cm (p < 0.001). Under current AJCC and BCLC staging criteria, these large infiltrative HCCs were associated with significantly worse OS in early AJCC T-stages (T1b/T2, p < 0.001) and BCLC stage A/B (both, p < 0.01) but not in late AJCC (T3/T4) and BCLC C. The reassignment of this subtype to T3 and T4 increased the discriminatory ability of AJCC T-staging with lower AIC values (3090 and 3088 vs. 3109) and higher c-index (0.69 and 0.69 vs. 0.67), respectively (both, p < 0.001). Similarly, the reassignment of large infiltrative HCC to BCLC stages B and C also improved the prognostic performance. Large infiltrative HCCs should be assigned to more advanced stages in current staging systems for their prognostic impact. [ABSTRACT FROM AUTHOR]

Alpha fetoprotein (AFP) has been used as a serologic indicator of hepatocellular carcinoma (HCC). We aimed to identify an HCC-specific serum biomarker for diagnosis using a multiplexed proteomic technique in HCC patients with normal AFP levels. A total of 152 patients were included from Guro Hospital, Korea University. Among 267 identified proteins, 28 and 86 proteins showed at least a two-fold elevation or reduction in expression, respectively. Multiple reaction monitoring (MRM) analysis of 41 proteins revealed 10 proteins were differentially expressed in patients with liver cirrhosis and HCC patients with normal AFP. A combination of tripartite motif22 (Trim22), seprase, and bone morphogenetic protein1 had an area under receiver operating characteristic of 0.957 for HCC diagnosis. Real-time PCR and western blot analysis of the paired tumor/non-tumor liver tissue in HCC revealed a reduced expression of Trim22 in the tumor tissue. Also, serum levels of Trim22 were significantly reduced in HCC patients with normal AFP compared to those with liver cirrhosis (p = 0.032). Inhibition of Trim22 increased cellular proliferation in human hepatoma cell lines, whereas overexpression of Trim22 decreased cellular proliferation in hepatoma cell lines. In conclusion, the combination of three serum markers improved the chance of diagnosing HCC. MRM-based quantification of the serum protein in patients with normal AFP provides the potential for early diagnosis of HCC. [ABSTRACT FROM AUTHOR]

The article presents a research apoptotic effects of diol-type Ginseng Sapogenins on human hepatoma cell lines when caspase mediated. It states that novel types of ginseng-derived metabolites such as 20(S)-dihydroprotopanaxadiol (2H-PPD) and 20(S) -dihydroprotopanaxatriol (2H-PPT) and 20 (S) -dihydroprotopanaxatriol (2H-PPT)3. It reports that ginseng sapogenins are aglycone parts of ginsenosides that have anticancer effects on several types of human cancers including hepatocarcinoma.

Purpose: To assess the usefulness of intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) for predicting lipiodol uptake in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). Materials and methods: The institutional review board approved this study. 44 HCC patients underwent IVIM-DWI and Gd-EOB-DTPA-enhanced MRI prior to TACE. Using post-TACE CT as a reference standard, each HCC was classified into either lipiodol good uptake (LGU) or poor uptake (LPU) group. Apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion coefficient (D*), and perfusion fraction (f) in HCC were calculated. Arterial enhancement ratio (AER) and IVIM parameters were compared between those two groups using the Mann-Whitney U test. Results: Of the 51 HCCs, 37 (72.5%) were LGU group and 14 (27.5%) were LPU group. AER of HCC was significantly higher in LGU than LPU (0.99±0.54 and 0.67±0.45; P =.034). ADC, D, and f values were not significantly different (P =.073, .059, and .196, respectively) between these two groups. D* was significantly elevated in LGU than LPU (48.10±15.33 and 26.75±9.55; P =.001). Conclusion: Both AER derived from contrast enhanced MRI and D* values derived from IVIM-DWI for HCC were significantly higher in LGU than in LPU. These parameters would be helpful for predicting the lipiodol uptake. [ABSTRACT FROM AUTHOR]

Purpose: To compare the response to transcatheter arterial chemoembolization (TACE) between hepatocellular carcinoma (HCC) with paradoxical uptake on the hepatobiliary phase (HBP) (HCCpara) and HCC with defect on the HBP (HCCdef), and to identify some imaging features that can differentiate between two groups.Materials and Methods: Ninety-three HCCs from 54 patients who underwent gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) prior to TACE were included. HCCs were classified into two groups according to the signal intensity (SI) on the HBP: HCCpara and HCCdef. Using post-TACE computed tomography (CT) as a reference standard, initial compact lipiodol uptake was assessed and compared between groups. The arterial enhancement ratio (AER), SI ratios of the arterial phase and HBP, and presence of the capsule appearance were compared between groups. After initial response, local tumor recurrence within 6 and 18 months was evaluated based on follow-up CT or MRI.Results: Fifteen HCCpara and 78 HCCdef were included. Compared to HCCdef, HCCpara showed more frequent initial compact lipiodol uptake (p=0.009), larger mean size (p=0.019), lower AER (p=0.005), higher SI ratio of the HBP (p<0.0001), and more frequent capsule appearance (p<0.0001). Local tumor recurrence rate within 6 months was also significantly lower in HCCpara than in HCCdef (p=0.008).Conclusion: Despite larger size and lower AER, HCCpara showed more frequent initial compact lipiodol uptake and lower early local recurrence rate after TACE than did HCCdef. [ABSTRACT FROM AUTHOR]