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Abstract Background/Aims Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) have been used as diagnostic tools for hepatocellular carcinoma (HCC). However, prediction of outcome using AFP and DCP has not been elucidated. We investigated the clinical role of AFP and DCP as predictors of treatment outcome in patients with HCC undergoing trans-arterial chemoembolization (TACE). Methods Between January 2003 and December 2005, we enrolled 115 treatment-naïve patients who received TACE as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 50% from the baseline level 1 month after TACE. Patients with AFP Results The median age was 59 years and the male gender predominated (n = 81, 70.4%). AFP and DCP response was identified in 91 (79.1%) and 77 (66.9%) patients after TACE. Although progression-free survival (PFS) did not differ according to AFP response (P = 0.150), AFP responders showed significantly better overall survival (OS) than non-responders (34.9 vs. 13.2 months; P = 0.002). In contrast, DCP response did not influence either PFS or OS (all P > 0.05). Multivariate analyses showed that gamma-glutamyltranspeptidase and baseline AFP were predictors of PFS (all P P Conclusions AFP response and higher baseline DCP level are significant predictors of OS in treatment-naïve patients with HCC receiving TACE who showed pretreatment elevation of both AFP and DCP.

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]

Introduction: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with treatment outcomes closely tied to liver function. This study evaluates the prognostic utility of the albumin-bilirubin (ALBI) score compared to the traditional Child-Pugh (CP) grading, leveraging real-world evidence from a large-scale, multi-center database. Methods: The Liver Cancer IN Korea (LINK) research network, a multi-center initiative, retrospectively collected electronic health records from three academic hospitals in South Korea, encompassing HCC patients diagnosed between 2015 and 2020. Inclusion criteria mandated at least one HCC treatment and excluded patients with other primary cancer diagnoses. The study followed patients until death, the last visit, or June 2021, employing standardized data processing and rule-based algorithms for data consistency. The prognostic efficacy of ALBI scores and CP scores was compared through time-dependent receiver operating characteristic (ROC) curves and the inverse probability censoring weighting method. Results: From 25,248 newly diagnosed patients, 10,297 were included, with 65.82% having hepatitis B etiology and a mean follow-up of 27.49 months. Patients' classification by modified ALBI (mALBI) grade at diagnosis revealed: grade 1 (48.87%), 2a (20.50%), 2b (24.54%), and 3 (5.17%), with a minimal percentage missing (0.92%). Transarterial therapy (54.07%) and tyrosine kinase inhibitors (84.14% as the first-line systemic therapy) were predominant treatments. The ALBI score demonstrated greater prognostic efficacy than the CP score in long-term outcomes, with time-dependent area under the ROC curve analysis showing a score of 0.71 for ALBI versus 0.67 for CP at 60 months. Furthermore, higher mALBI grades were significantly associated with poorer survival outcomes, as indicated by both univariate and multivariate Cox proportional regression model analyses (p < 0.001). Conclusions: The study confirmed the ALBI score's superior prognostic ability over the CP score, especially evident in long-term outcomes, suggesting a shift toward more nuanced liver function assessment tools in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Atezolizumab and bevacizumab show promise for treating hepatocellular carcinoma (HCC), but identifying responsive patients remains challenging, due to tumor heterogeneity. This study explores immune dynamics following this combination therapy. Between 2020 and 2023, 29 patients with advanced HCC who received atezolizumab plus bevacizumab at Severance Hospital, Seoul, were enrolled in this study. Peripheral blood mononuclear cells were analyzed using flow cytometry and statistical methods to assess immune alterations and identify biomarkers. Baseline characteristics showed a diverse HCC cohort with a mean age of 64 years and 82.8% male predominance. Absence of extrahepatic metastasis was associated with better overall survival. Immune responses revealed distinct CD4+ T-cell phenotypes between the 'partial response (PR) + stable disease (SD)' and 'progressive disease (PD)' groups, with an overall increase in CD8+ T-cell phenotypes. Patients with higher frequencies of CD8+PD-1+Ki-67+ T cells experienced significantly improved overall survival, while those with lower frequencies of CD4+Foxp3+PD-1+LAG3+ T cells also had notable survival benefits. These findings enhance the overall understanding of immune responses to this combination therapy, facilitating improved patient stratification and personalized therapeutic approaches for HCC. [ABSTRACT FROM AUTHOR]

Background & Aims: Accumulating evidence suggests that certain imaging features of hepatocellular carcinoma (HCC) may have prognostic implications. This study aimed to intraindividually compare MRIs with extracellular contrast agent (ECA‐MRI) and hepatobiliary agent (HBA‐MRI) for prognostic imaging features of HCC and to compare the prediction of microvascular invasion (MVI) and early recurrence between the two MRIs. Methods: The present study included 102 prospectively enrolled at‐risk patients (median age, 61.0 years; 83 men) with surgically resected single HCC with both preoperative ECA‐MRI and HBA‐MRI between July 2019 and June 2023. The McNemar test was used to compare each prognostic imaging feature between the two MRIs. Significant imaging features associated with MVI were identified by multivariable logistic regression analysis, and early recurrence rates (<2 years) were compared between the two MRIs. Results: The frequencies of prognostic imaging features were not significantly different between the two MRIs (p =.07 to >.99). Non‐smooth tumour margin (ECA‐MRI, odds ratio [OR] = 5.30; HBA‐MRI, OR = 7.07) and peritumoral arterial phase hyperenhancement (ECA‐MRI, OR = 4.26; HBA‐MRI, OR = 4.43) were independent factors significantly associated with MVI on both MRIs. Two‐trait predictor of venous invasion (presence of internal arteries and absence of hypoattenuating halo) on ECA‐MRI (OR = 11.24) and peritumoral HBP hypointensity on HBA‐MRI (OR = 20.42) were other predictors of MVI. Early recurrence rates of any two or more significant imaging features (49.8% on ECA‐MRI vs 51.3% on HBA‐MRI, p =.75) were not significantly different between the two MRIs. Conclusion: Prognostic imaging features of HCC may be comparable between ECA‐MRI and HBA‐MRI. [ABSTRACT FROM AUTHOR]

Simple Summary: The YAP/TAZ signaling pathways, which is involved in tumor development and proliferation in a variety of solid tumors, inhibits hypoxia-induced cell death, increases and stabilizes angiogenesis, and activates tumor proliferation, both independently and in conjunction with HIF in hypoxic tumors. It also promotes tumor metastasis by regulating different TME environments. Therefore, understanding the activity of YAP/TAZ as a mechanism of tumor development may lead to the development of novel therapeutic strategies. In solid tumors such as hepatocellular carcinoma (HCC), hypoxia is one of the important mechanisms of cancer development that closely influences cancer development, survival, and metastasis. The development of treatments for cancer was temporarily revolutionized by immunotherapy but continues to be constrained by limited response rates and the resistance and high costs required for the development of new and innovative strategies. In particular, solid tumors, including HCC, a multi-vascular tumor type, are sensitive to hypoxia and generate many blood vessels for metastasis and development, making it difficult to treat HCC, not only with immunotherapy but also with drugs targeting blood vessels. Therefore, in order to develop a treatment strategy for hypoxic tumors, various mechanisms must be explored and analyzed to treat these impregnable solid tumors. To date, tumor growth mechanisms linked to hypoxia are known to be complex and coexist with various signal pathways, but recently, mechanisms related to the Hippo signal pathway are emerging. Interestingly, Hippo YAP/TAZ, which appear during early tumor and normal tumor growth, and YAP/TAZ, which appear during hypoxia, help tumor growth and proliferation in different directions. Peculiarly, YAP/TAZ, which have different phosphorylation directions in the hypoxic environment of tumors, are involved in cancer proliferation and metastasis in various carcinomas, including HCC. Analyzing the mechanisms that regulate the function and expression of YAP in addition to HIF in the complex hypoxic environment of tumors may lead to a variety of anti-cancer strategies and combining HIF and YAP/TAZ may develop the potential to change the landscape of cancer treatment. [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: Trans-arterial radioembolization (TARE) can effectively treat patients with locally advanced hepatocellular carcinoma (HCC). However, TARE is not widely used in clinical practice due to the lack of consensus on how to select the best candidates for this therapy. Therefore, it is crucial to find predictive biomarkers or clinical parameters that can differentiate the patients who will respond well to TARE and improve their outcomes. Low skeletal muscle mass (LSMM) is one of the factors that affects the prognosis of HCC patients and has been extensively studied in relation to different treatments. We used a semi-automated program that has been validated and proven to be reliable for assessing LSMM. In this study, we aimed to identify prognostic factors, including pre-treatment LSMM, for survival outcomes in patients with HCC undergoing TARE. Trans-arterial radioembolization (TARE) is a form of radiation therapy performed for hepatocellular carcinoma (HCC) via selective intra-arterial injection of Yttrium-90-loaded microspheres. This was a multi-center retrospective study of consecutive patients with HCC who underwent TARE between July 2009 and May 2019. Using pre-treatment computed tomography imaging, the total cross-sectional area (cm2) of the abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI) was calculated by normalizing the muscle area to patient height. In total, 347 patients (median age, 65 years; 284 male) were included in the study. A total of 108 (31.1%) patients had portal vein tumor thrombus (PVTT), and 126 (36.3%) were classified as LSMM. The median overall survival (OS) was 28.1 months (95% CI, 24.8–35.7), and median progression-free survival was 8.0 months (95% CI, 6.4–9.4). Multivariate Cox regression analysis revealed that LSMM (hazard ratio [HR], 1.36; 95% CI, 1.00–1.85, p = 0.05), PVTT (HR, 1.82; 95% CI, 1.33–2.49, p < 0.01), alpha-fetoprotein (AFP) (≥200 ng/mL) (HR 1.41; 95% CI, 1.04–1.92, p = 0.03), and albumin–bilirubin grade (2–3) (HR 1.74; 95% CI, 1.24–2.43, p < 0.01) were independently associated with poor OS. TARE provided favorable long-term outcomes for patients with advanced HCC. Pre-treatment LSMM independently associated with survival, suggesting its utility as a surrogate biomarker for identifying TARE candidates. [ABSTRACT FROM AUTHOR]

Background: Machine learning (ML) algorithms can be used to overcome the prognostic performance limitations of conventional hepatocellular carcinoma (HCC) risk models. We established and validated an ML‐based HCC predictive model optimized for patients with chronic hepatitis B (CHB) infections receiving antiviral therapy (AVT). Methods: Treatment‐naïve CHB patients who were started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were enrolled. We used a training cohort (n = 960) to develop a novel ML model that predicted HCC development within 5 years and validated the model using an independent external cohort (n = 1937). ML algorithms consider all potential interactions and do not use predefined hypotheses. Results: The mean age of the patients in the training cohort was 48 years, and most patients (68.9%) were men. During the median 59.3 (interquartile range 45.8–72.3) months of follow‐up, 69 (7.2%) patients developed HCC. Our ML‐based HCC risk prediction model had an area under the receiver‐operating characteristic curve (AUC) of 0.900, which was better than the AUCs of CAMD (0.778) and REAL B (0.772) (both p <.05). The better performance of our model was maintained (AUC = 0.872 vs. 0.788 for CAMD and 0.801 for REAL B) in the validation cohort. Using cut‐off probabilities of 0.3 and 0.5, the cumulative incidence of HCC development differed significantly among the three risk groups (p <.001). Conclusions: Our new ML model performed better than models in terms of predicting the risk of HCC development in CHB patients receiving AVT. [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]

Liver resection can induce complete remission after tumor downstaging in patients with locally advanced hepatocellular carcinoma. However, additional benefits of liver resection have not been investigated in patients expected to have complete pathological necrosis (CPN) following HCC downstaging. Between 2002 and 2019, 999 patients with locally advanced HCC underwent concurrent chemoradiotherapy (CCRT) (n = 800) or transarterial radioembolization (TARE) (n = 199). Among these patients, excluding those who underwent liver transplantation, 94 who underwent liver resection (OP group) and 867 who did not undergo surgical treatment (non-OP group) were included in this study. CPN predictive factors in the OP group were analyzed using logistic regression analysis. Long-term outcomes were compared between patients with CPN (op-CPN) and those with CPN predictive factors in the non-OP group (nop-CPNPF). Of the 94 patients in the OP group, 38 (40.4 %) had CPN (CCRT, n = 72; TARE, n = 22). In the multivariate analysis, CPN predictive factors were complete radiologic response and tumor marker responders (odds ratio [OR] 18.468, p = 0.006; OR 3.698, p = 0.045). Among the non-OP group, 21 patients were in the nop-CPNPF group. There was no difference in DFS between the nop-CPNPF and op-CPN groups (40.0 ± 18.3 vs. 60.0 ± 14.0 months, p = 0.838). The OS of the op-CPN group was not higher than that of the nop-CPNPF group (5-year OS: 39.4 % vs. 33.3 %, p = 0.328). The nop-CPNPF group showed long-term outcomes similar to those of the op-CPN group, suggesting that liver resection may not provide additional benefits for long-term outcomes in patients with CPN-PF after HCC downstaging. [ABSTRACT FROM AUTHOR]

Background: Since atezolizumab plus bevacizumab (ATE+BEV) regimen for patients with unresectable hepatocellular carcinoma (HCC) was released quite recently, real‐world data are lacking. We evaluated efficacy, safety, and predictive biomarkers for survival in patients receiving ATE+BEV. Methods: Between 2020 and 2021, HCC patients receiving ATE+BEV at academic teaching hospitals were recruited. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). Results: Among 121 patients enrolled, the median age was 63 years, with male predominance (82.6%). Complete response, partial response, stable disease, and progressive disease were identified in 2.5%, 26.4%, 54.5%, and 16.6%, respectively. Patients with alpha‐fetoprotein and des‐gamma‐carboxy prothrombin (DCP) response, defined as ≥30% and ≥50% decreases, respectively, at the first response evaluation relative to baseline, and those with neutrophil‐to‐lymphocyte ratio (NLR) <2.5, had significantly higher objective response rates (42.6% vs. 21.5%, 50.0% vs. 26.2%, and 39.0% vs. 19.4%, respectively; all p < 0.05). During follow‐up, the median overall survival (OS) was not reached, and the median progression‐free survival (PFS) was 5.7 months. Multivariable analyses showed that macrovascular invasion (adjusted hazard ratio [aHR] 2.541; p = 0.017), DCP ≥186 mAU/ml (aHR 5.102; p < 0.001), NLR ≥2.5 (aHR 3.584; p = 0.001), and an NLR decrease ≥10% at the first response (aHR 0.305; p = 0.002) were independent predictors of OS, and DCP ≥186 mAU (aHR 2.311; p = 0.002) and NLR ≥2.5 (aHR 1.938; p = 0.012) were independent predictors of PFS. Grade ≥3 treatment‐related adverse events (AEs) occurred in 33 (27.3%) patients. Conclusion: ATE+BEV showed favorable efficacy and safety. Baseline high DCP and NLR may be useful prognostic predictors for OS and PFS. [ABSTRACT FROM AUTHOR]

Background: Current major guidelines for diagnosis of hepatocellular carcinoma (HCC) based on imaging findings are different from each other and do not include clinical risk factors as a diagnostic criteria. Purpose: To developed and validated a new diagnostic score system using MRI and clinical features as applied in chronic hepatitis B patients. Study Type: Retrospective observational study. Subject: A total of 418 treatment‐naïve patients (out of 902 patients) with chronic hepatitis B having 556 lesions suspected for HCC which were eligible for curative treatment. Field Strength/sequence: T1W GRE in‐ and opposed‐phase, T2W FSE, DWI, and T1W 3D‐GRE dynamic contrast‐enhanced sequences at 1.5 T and 3 T. Assessment: Six radiologists with 7–22 years of experience independently evaluated MR images based on Liver Imaging Reporting and Data System (LI‐RADS) version 2018. Statistical Tests: Based on logistic regression analysis of MRI features and clinical factors, a risk score system was devised in derivation cohorts (268 patients, 352 lesions) and externally validated (150 patients, 204 lesions). The performance of the new score system was assessed by Harell's c‐index. Using cutoff value of 12, maintaining positive predictive value ≥95%, the diagnostic performances of the score system were compared with those of LR‐5. Results: The 15‐point diagnostic scoring system used MRI features (lesion size, nonrim arterial phase hyperenhancement, portal venous phase hypointensity, hepatobiliary phase hypointensity, and diffusion restriction) and clinical factors (alpha‐fetoprotein and platelet). It showed good discrimination in the derivation (c‐index, 0.946) and validation cohorts (c‐index, 0.907). Using a risk score of 12 as a cut‐off, this system yielded higher sensitivity than LR‐5 (derivation cohort, 76.8% vs. 52.1%; validation cohort, 73.4% vs. 49.5%) without significant decrease in specificity (derivation cohort, 93.1% vs. 97.2%, P = 0.074; validation cohort, 91.7% vs. 96.1%, P = 0.299). Data Conclusion: A new score system showed improved sensitivity in chronic hepatitis B patients compared to LI‐RADS without significant compromise in specificity. Evidence Level: 3 Technical Efficacy: Stage 2. [ABSTRACT FROM AUTHOR]

Simple Summary: Activation of YAP/TAZ (mediators of Hippo signaling) is associated with the development of liver cancer. The expression level of YAP is known to relate to chemoresistance. However, the therapeutic effect of YAP/TAZ inhibition when combined with sorafenib and conventional chemotherapy in HCC is not known. Recent studies have highlighted the importance of the tumor microenvironment (TME) in chemoresistance. The multicellular tumor spheroid (MCTS) model has emerged as a promising tool for studying cancer drugs as it mimics actual TME. Here, we aimed at assessing the YAP/TAZ expression level of HCCs and identifying the therapeutic effects of CA3 (novel YAP inhibitor) when combined with sorafenib using a patient-derived MCTS model. We established patient-derived MCTS and confirmed that patient-derived MCTS with high YAP/TAZ expression responded more sensitively to the combination therapy (sorafenib with CA3) than MCTS with low or medium YAP/TAZ expression. These findings suggest that the YAP/TAZ inhibitor may serve as a potential therapeutic strategy to enhance sensitivity to sorafenib in HCCs with high YAP/TAZ expression. Purpose: To assess the expression levels of YAP and TAZ in patient-derived HCC tissue and identify the effects of YAP/TAZ inhibition depending on the baseline YAP/TAZ expression when combined with sorafenib using a patient-derived multicellular tumor spheroid (MCTS) model. Methods: Primary HCC cell lines were established from patient-derived tissue. Six patient-derived HCC cell lines were selected according to YAP/TAZ expression on Western blot: high, medium, low. Then, MCTS was generated by mixing patient-derived HCC cells and stroma cells (LX2, WI38, and HUVECs) and YAP/TAZ expression was assessed using Western blot. Cell viability of MCTS upon 48 h of drug treatment (sorafenib, sorafenib with CA3 0.1 µM, and CA3 (novel YAP1 inhibitor)) was analyzed. Results: Out of six patient-derived HCC cell lines, cell lines with high YAP/TAZ expression at the MCTS level responded more sensitively to the combination therapy (Sorafenib + CA3 0.1 μM) despite the potent cytotoxic effect of CA3 exhibited in all of the patient-derived HCCs. Conclusion: Targeting YAP/TAZ inhibition using the novel YAP1 inhibitor CA3 could be a promising therapeutic strategy to enhance sensitivity to sorafenib especially in HCCs with high YAP/TAZ expression in MCTS. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that aberrant activation of NRF2 accelerates the proliferation and progression of cancer cells. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. This prompted us to assess the effects of sulforaphane (SFN), a prototypic NRF2 activating chemopreventive phytochemical, on experimentally induced carcinogenesis. In the present study, SFN was daily injected intraperitoneally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The liver to body weight ratio, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than those in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1, and the cell proliferation marker, proliferating cell nuclear antigen was further elevated in DEN plus SFN-treated mice. These results suggest that once hepatocarcinogenesis is initiated, SFN may stimulate tumor progression. [ABSTRACT FROM AUTHOR]

Simple Summary: We investigated the efficacy of liver-directed concurrent chemoradiotherapy compared with sorafenib in hepatocellular carcinoma patients with portal vein tumor thrombosis. Patients in the sorafenib group presented higher incidences of unfavorable clinical features, and propensity score matching was performed to compensate for the differences between the two groups. We found that liver-directed concurrent chemoradiotherapy resulted in significantly improved survival compared to the sorafenib group. 3.6% and 13.8% of patients in the sorafenib and liver-directed concurrent chemoradiotherapy groups underwent surgical treatment after initial treatment, and those who received surgical treatment had significantly longer overall survival. This study aimed to investigate the efficacy of liver-directed concurrent chemoradiotherapy (LD-CCRT) compared with sorafenib in patients with liver-confined locally advanced hepatocellular carcinoma (HCC) presenting portal vein tumor thrombosis (PVTT). This single institute retrospective cohort study included patients treated with sorafenib or LD-CCRT between 2005 and 2016. Patients with extrahepatic disease and those without PVTT were excluded, leaving 28 and 448 patients in the sorafenib and LD-CCRT groups, respectively. Propensity score matching was performed to balance the differences in clinical features between the two groups. At baseline, the sorafenib group presented higher incidences of unfavorable clinical features, including type III-IV PVTT (53.6% vs. 30.6%, p = 0.048) and bilateral disease extent (64.3% vs. 31.5%, p = 0.001), than the LD-CCRT group. A total of 27 patients from the sorafenib group and 52 patients from the LD-CCRT group were matched. At a median follow-up of 73 months, the median overall survival (OS) was 4.3 and 9.8 months in the sorafenib and LD-CCRT groups, respectively (p = 0.002). Patients with PVTT type II and higher benefited more from LD-CCRT in terms of OS. The Cox proportional hazard model showed that LD-CCRT was a significant prognostic factor for OS. One patient from the sorafenib group and seven patients from the LD-CCRT group underwent curative surgical treatment. Patients who underwent surgical treatment had significantly longer OS. In conclusion, LD-CCRT showed superior survival outcomes to sorafenib in HCC patients with PVTT. LD-CCRT needs further consideration for its substantial local tumor control that can enable curative surgical treatment in selected patients. [ABSTRACT FROM AUTHOR]

Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB. We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs). Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P <.05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ2) (76.2 vs 71.4) and linear trend (χ2) (74.1 vs 58.6) than the CAGE-B model, whereas the CAGE-B model showed higher Akaike information criteria (64.3 vs 50.3). Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB. [ABSTRACT FROM AUTHOR]

Simple Summary: This study compared the therapeutic efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). A total of 232 patients from three academic hospitals in Korea were included. No significant differences in objective response rate, overall survival, progression-free survival, or the incidence of adverse events were noted. Similar results were obtained after propensity score matching and inverse probability of treatment weighting analyses. This study makes a significant contribution to the literature because it provides the first comparison of lenvatinib and atezolizumab/bevacizumab for the treatment of unresectable HCC in the real-world setting. Lenvatinib (LENV) and atezolizumab/bevacizumab (ATE/BEV) have been approved as first-line regimens for the treatment of unresectable hepatocellular carcinoma (HCC). We aimed to compare their clinical efficacy and safety. Patients receiving ATE/BEV (n = 86) or LENV (n = 146) as first-line treatment were recruited from three academic hospitals in Korea. Overall survival (OS), progression-free survival (PFS), and radiological response were assessed according to the Response Evaluation Criteria in Solid Tumors. Clinical features of the two groups were balanced through propensity score (PS) matching with a 1:1 ratio and inverse probability of treatment weighting (IPTW) analyses. The median age was 62 years, with male predominance (83.6%). There was no significant difference in the objective response rate between the ATE/BEV and LENV groups (32.6% vs. 31.5%; p = 0.868). Neither median OS (not reached vs. 12.8 months; p = 0.357) nor PFS (5.7 vs. 6.0 months; p = 0.738) was different between ATE/BEV and LENV groups. PS-matched and IPTW analyses yielded comparable results in terms of OS and PFS (all p > 0.05). Grade ≥ 3 adverse events occurred in 42.8% and 21.9% of patients in the ATE/BEV and LENV groups, respectively (p = 0.141). The two first-line therapy regimens for unresectable HCC had comparable clinical efficacy and safety in real-world practice settings. Further studies with a larger sample size and longer follow-up are needed to validate these results. [ABSTRACT FROM AUTHOR]

Lenvatinib is an oral multikinase inhibitor approved for use as first‐line treatment for patients with advanced hepatocellular carcinoma (HCC). However, like other agents in this drug class, lenvatinib is associated with clinically important adverse events (AEs) that could adversely affect patient outcomes. Hypertension, diarrhea, decreased appetite/weight, hand–foot skin reaction, and proteinuria are among the most common AEs associated with lenvatinib therapy. This article provides strategies for the effective management of lenvatinib‐associated AEs based on the expert opinion of authors and currently available literature. Due to the high risk of AEs in patients receiving lenvatinib, prophylactic measures and regular monitoring for AEs are recommended. Lenvatinib dose interruption, adjustment, or discontinuation of treatment may be required for patients who develop AEs. For grade 1 or 2 AEs, dose interruption is generally not required. For persistent or intolerable grade 2 or 3 AEs, lenvatinib treatment should be interrupted until symptoms improve/resolve to grade 0–1 or baseline levels. Thereafter, treatment should be resumed at the same or a lower dose. Disease progression may occur in patients who do not initially respond to treatment or receive a suboptimal lenvatinib dose following dose reduction, resulting in lack of efficacy. Therefore, to derive maximum treatment benefit and ensure long‐term disease control, lenvatinib should be maintained at the highest possible dose when managing AEs. To conclude, lenvatinib‐associated AEs can be managed with prophylactic measures, regular monitoring and symptomatic management, which can ensure continued treatment and maximum survival benefit in patients with advanced HCC receiving first‐line lenvatinib therapy. [ABSTRACT FROM AUTHOR]

Background & Aims: Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ‐specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs. Methods: We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast‐associated protein (FAP), CAIX, VEGF, PD‐L1, CD3, CD8, Foxp3, CD163 and epithelial–mesenchymal transition (EMT)‐related markers were performed. Results: Independent factors for extrahepatic metastasis included BCLC stage B–C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)‐HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P <.05 for all). Lung metastases (n = 63) had the highest proportion of VETC‐HCC and macrotrabecular‐massive (MTM)‐HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT‐high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD‐L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P <.05 for all). In both cohorts, EMT‐high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD‐L1 expression and CD3+ T cell infiltration, whereas EMT‐low HCCs were more frequent among VETC‐HCCs (P <.05 for all). Overall phenotypic features were not significantly different between paired primary‐metastatic HCCs (n = 32). Conclusions: Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT‐high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis. [ABSTRACT FROM AUTHOR]

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment‐naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF‐based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first‐line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan‐Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person‐years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p =.438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis‐4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score‐matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p =.708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p =.446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow‐up are required to validate our results. [ABSTRACT FROM AUTHOR]