Efficacy and features of balloon-occluded transarterial chemoembolization for hepatocellular carcinoma: a narrative review.

Background and Objective: Systemic therapy for hepatocellular carcinoma (HCC) is recommended in transarterial chemoembolization (TACE)-refractory and unsuitable cases. In Japan, TACE is broadly classified into conventional TACE (C-TACE), balloon occluded TACE (B-TACE), and drug-eluting beads TACE. However, the type of TACE recommended for TACE-refractory or unsuitable cases has not been elucidated, and a targeted approach for individual cases and appropriate TACE selection is important. B-TACE is considered a valuable therapeutic option in the management of HCC. The technique involves the precise placement of a microcatheter with a balloon into the target hepatic artery, followed by selective occlusion of the hepatic artery, including tumor-feeding vessels, using the balloon. By leveraging the hemodynamic changes resulting from arterial occlusion, B-TACE enables effective accumulation of chemotherapeutic agents within the tumor. Incorporating B-TACE into the treatment strategy for HCC is of utmost importance. Therefore, this article provides an overview of the technique. Methods: A comprehensive review of all available literature in the English language through December 1, 2023 utilizing PubMed was conducted. Key Content and Findings: In the intermediate stage, TACE and systemic therapy play complementary roles, and it is important to select a treatment strategy that considers tumor status and hepatic reserve. However, no study has investigated the various types of TACE in the treatment of such patients. Currently, TACE in Japan is broadly classified into C-TACE, B-TACE, and drug-eluting beads TACE (DEB-TACE). This article outlines the evolution of B-TACE for HCC. We identified retrospective and prospective studies evaluating B-TACE. In this review, we evaluate data on B-TACE for HCC. Conclusions: In the era of systemic therapy, B-TACE may play a complementary and synergy effect role.

Factors affecting an increase in spleen volume and association of spleen volume variation with the clinical outcomes of atezolizumab and bevacizumab treatment for hepatocellular carcinoma: A retrospective analysis.

INTRODUCTION: Gastrointestinal varices rupture is considered to be prone to occur during atezolizumab and bevacizumab (Atez/Bev) treatment. This study aimed to investigate predictive factors affecting the increase in spleen volume (SpV) and the association of SpV variation with the clinical outcomes of Atez/Bev. METHODS: A total of 164 HCC patients were included in this retrospective multicenter study. We measured SpV based on CT scans obtained before treatment and at evaluations. We used the inverse probability of treatment weight to address the imbalance between patient characteristics. RESULTS: The median pretreatment SpV was 184 (130-257) cm3 and the median SpV variation was 27 (9-60) cm3. An increase in the SpV was observed in 140 patients (85.4%). Age <74 years (p = 0.03), mALBI grade 2b or 3 (p = 0.03), and pretreatment SpV ≥184 cm3 (p < 0.001) were significantly associated with increased SpV. There were no significant differences in progression-free survival (PFS) or overall survival (OS) between patients with SpV variation <25 cm3 and those with SpV variation ≥25 cm3 in the crude (p=0.3 and 0.7) and IPTW-weighted cohorts (p = 0.08 and 0.8, respectively). Regarding pretreatment SpV, there were no significant differences in PFS or OS between patients with and without pretreatment spleen enlargement in the crude (both p = 0.3) and IPTW-weighted cohort (p = 0.6 and 0.3, respectively). CONCLUSION: Caution is warranted to detect the aggravation of portal hypertension when administering Atez/Bev to young patients or patients with an impaired liver function or pretreatment spleen enlargement. The impact of spleen modulation by Atez/Bev appears to be limited on clinical efficacy.

Relationship Between Sleep Quality and Quality of Life: Analysis of Hepatocellular Carcinoma Survivors.

BACKGROUND:  We analyzed the correlation between the Pittsburgh Sleep Quality Index (PSQI) subcategories (sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, sleep medications, and daytime dysfunction) and a comprehensive measure of quality of life (QOL), the 36-Item Short Form Survey (SF-36) items, in patients with hepatocellular carcinoma (HCC) to determine the components that require intervention to improve QOL. METHODS: A total of 75 patients with recurrent HCC admitted to our hospital between May 2021 and May 2023 were included in this study. The QOL score was used for the SF-36 items, and the sleep disorder score was used for PSQI questionnaires. RESULTS: Correlations were found between sleep quality, sleep disturbance, and SF-36 for all QOL items and between sleep onset time and SF-36 for six QOL items: bodily pain, mental health, physical functioning, role-emotional, role-physical, and vitality. Correlations between daytime dysfunction and SF-36 were found for all QOL items, except for physical functioning. No correlation was found between sleep duration, sleep efficiency, sleep medications, and SF-36 for any QOL item. CONCLUSION: Sleep duration, sleep efficiency, and sleep medications may not contribute to QOL improvement in patients with HCC and sleep disturbances. Factors that improve sleep quality and sleep difficulty may contribute to QOL improvement. Therapeutic interventions aimed at improving general health and social functioning for sleep latency and physical functioning for daytime arousal difficulty are required.

Linear ether-based highly concentrated electrolytes for Li-sulfur batteries.

Li-S batteries have attracted attention as next-generation rechargeable batteries owing to their high theoretical capacity and cost-effectiveness. Sparingly solvating electrolytes hold promise because they suppress the dissolution and shuttling of polysulfide intermediates to increase the coulombic efficiency and extend the cycle life. This study investigated the solubility of polysulfide (Li2S8) in a range of liquid electrolytes, including organic electrolytes, highly concentrated electrolytes, and ionic liquids. The Li2S8 solubility was well correlated with the donor number (DNNMR), estimated via23Na-NMR, and was lower than 100 mM_(elemental sulfur) in electrolytes with DNNMR < 14, regardless of the type of electrolyte. Highly concentrated electrolytes comprising lithium bis(trifluoromethanesulfonyl)amide (LiTFSA) and linear chain dialkyl ethers such as methyl propyl ether (MPE), n-butyl methyl ether (BME), and ethyl propyl ether (EPE) were studied as sparingly solvating electrolytes for Li-S batteries. Monomethyl ethers, such as BME, showed more pronounced Li-ion coordination and higher ionic conductivity, whereas the steric hindrance of the longer alkyl chains in EPE lowered the solvation number, enhanced ion association, and lowered the ionic conductivity despite the solvents having similar dielectric constants. The charge-discharge rate capabilities of Li-S cells with dialkyl ether-based electrolytes were more impressive than those of cells with a localized high-concentration electrolyte using sulfolane (SL) and hydrofluoroether (HFE), [Li(SL)2][TFSA]-2HFE. The higher rate performance was attributed to the superior Li-ion transport properties of the dialkyl ether-based electrolytes. A pouch-type cell using lightweight [Li(BME)3][TFSA] demonstrated an energy density exceeding 300 W h kg-1 under lean electrolyte conditions.

Serum zinc concentration as a potential predictor of presarcopenia in patients with chronic liver disease: a preliminary study.

Background: Presarcopenia is a common complication of chronic liver disease. However, the relationship between serum zinc concentration and presarcopenia in patients with chronic liver disease remains unclear. Herein, we examined whether serum zinc concentration could predict presarcopenia in patients with chronic liver disease. Methods: Between October 2015 and December 2019, 278 patients with chronic liver disease (median age, 68 years; women/men, 133/145; hepatitis B virus/hepatitis C virus/negative hepatitis B surface antigen and negative anti-hepatitis C virus antibody, 55/124/99) who underwent abdominal computed tomography (CT) and simultaneous measurement of serum zinc concentration were included. Zinc deficiency and subclinical zinc deficiency were classified using serum zinc concentration cutoff values of <60 and <80 µg/dL [based on the Japanese Society of Clinical Nutrition (JSCN) guidelines], respectively. Additionally, presarcopenia was evaluated based on the skeletal muscle mass as per the Japan Society of Hepatology (JSH)'s sarcopenia criteria. Results: Univariate analysis revealed that the following factors were significantly associated with the presence of presarcopenia in patients with chronic liver disease: age (P<0.001), male sex (P<0.001), body mass index (BMI) (P<0.001), serum zinc concentration (P=0.005), fibrosis-4 index (P<0.001), and serum albumin concentration (P=0.03). Additionally, the median L3 skeletal muscle indices were as follows: men, non-presarcopenia group/presarcopenia group, 47.56/37.91 cm2/m2 (P<0.001); women, non-presarcopenia group/presarcopenia group, 41.64/32.88 cm2/m2 (P<0.001). Multivariate analysis using logistic regression analysis revealed that male sex [odds ratio (OR), 0.194; 95% confidence interval (CI): 0.089-0.419; P<0.001], BMI (OR, 0.666; 95% CI: 0.582-0.761; P<0.001), and serum zinc concentration <60 µg/dL (OR, 5.930; 95% CI: 1.480-23.80; P=0.01) were factors associated with presarcopenia. The OR for serum zinc concentration between 60 and 80 µg/dL was 1.910 (95% CI: 0.824-4.420; P=0.13). Conclusions: Low serum zinc levels may be an independent predictor of presarcopenia in patients with chronic liver disease.

Incidence and Predictors of Esophagogastric Varices Bleeding in Patients with Hepatocellular Carcinoma in Lenvatinib.

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients' survival. Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23-21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08-4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40-4.61, p = 0.002), and platelets <150,000/µL (OR: 2.47; 95% CI: 1.35-4.50, p = 0.003). Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.

Outcomes of patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab in real-world clinical practice who met or did not meet the inclusion criteria for the phase 3 IMbrave150 trial.

BACKGROUND: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC). AIMS: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real-world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial. METHODS: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non-IMbrave150 group). RESULTS: Median progression-free survival (PFS) in the IMbrave150 and non-IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non-B, non-C HCC aetiology (hazard ratio [HR], 1.173), α-fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin-bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non-Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α-fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a. CONCLUSIONS: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival.

ALBI score predicts morphological changes in esophageal varices following direct-acting antiviral-induced sustained virological response in patients with liver cirrhosis.

BACKGROUND: This study aimed to clarify the morphological changes in esophageal varices after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) in patients with cirrhosis. METHODS: A total of 243 patients underwent esophagogastroduodenoscopy before DAA treatment and after achieving SVR. Morphological changes in esophageal varices were investigated using esophagogastroduodenoscopy. RESULTS: This study comprised 125 males and 118 females with a median age of 68 years. Esophageal varices at baseline were classified into no varix in 155 (63.8%), F1 in 59 (24.3%), F2 in 25 (10.3%) and F3 in 4 (1.6%) patients. The improvement, unchanged, and aggravation rates of esophageal varices after SVR were 11.9%, 73.3%, and 14.8%, respectively. High ALBI score at SVR12 was an independent factor associated with post-SVR esophageal varices aggravation (p = 0.045). Time-dependent receiver operating characteristic (ROC) curve analysis revealed a cut-off value of - 2.33 for ALBI score at SVR12 in predicting post-SVR esophageal varices aggravation. Of the 155 patients without esophageal varices at baseline, 17 developed de novo post-SVR esophageal varices. High ALBI score at SVR12 was a significant independent factor associated with de novo post-SVR esophageal varices (p = 0.046). ROC curve analysis revealed a cut-off value of - 2.65 for ALBI score at SVR12 in predicting de novo post-SVR esophageal varices. CONCLUSIONS: Patients with cirrhosis can experience esophageal varices aggravation or de novo esophageal varices, despite achieving SVR. In particular, patients with high ALBI score at SVR12 have a high likelihood of developing post-SVR esophageal varices aggravation or de novo post-SVR esophageal varices.

Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma.

AIMS: The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment. METHODS: A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression-free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c-index) and Akaike information criterion (AIC) results. RESULTS: Cox-hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI-De) scoring system. For IMABALI-De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p < .001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c-index 0.606). PFS periods for those IMABALI-De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c-index 0.574). As compared with CRAFITY score, IMABALI-De score had better AIC and c-index results for both OS and PFS. CONCLUSION: The present results indicated that the proposed IMABALI-De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy.

Kinetics of the hepatitis B core-related antigen and treatment responses in chronic hepatitis B patients treated with tenofovir alafenamide.

AIM: An association between hepatitis B core-related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment-naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. METHODS: Patients were treated with TAF monotherapy for 96 weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of -1 log IU/mL from baseline) were evaluated. RESULTS: The study population comprised 241 patients, 36.9% of whom were HBeAg-positive. The median baseline HBcrAg level was 4.7 log IU/mL. The median change in HBcrAg from baseline was -1.1 log IU/mL at 96 weeks after treatment. The HBcrAg response rate at 96 weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96 weeks of treatment (p = 4.53 × 10-6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. CONCLUSIONS: In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment.

Changes in clinical outcomes in Japanese patients with hepatocellular carcinoma due to hepatitis C virus following the development of direct-acting antiviral agents.

BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development. METHODS: A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n = 1169) and post-DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed. RESULTS: Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/µL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P < 0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P < 0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P = 1.0). CONCLUSION: The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients.

Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab.

BACKGROUND: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors. OBJECTIVE: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting. PATIENTS AND METHODS: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea). RESULTS: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival. CONCLUSIONS: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma: TACTICS-L Trial.

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14-21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0-2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0-1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1-31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months-NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

Clinical Efficacy and Body Composition Changes with Sodium Glucose Cotransporter 2 Inhibitor/Glucagon-like Peptide-1 Antagonist Combination Therapy in Patients with Type 2 Diabetes Mellitus-associated Nonalcoholic Fatty Liver Disease.

Objective Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) treatment guidelines recommend sodium glucose cotransporter 2 inhibitor (SGLT2I) and glucagon-like peptide-1 agonist (GLP-1A) therapy in patients with type 2 diabetes mellitus (T2DM). SGLT2I improves the pathological condition of NAFLD/NASH in T2DM patients. However, cases of rebound during long-term SGLT2I treatment have been reported. This study investigated the efficacy of SGLT2I and GLP-1A combination therapy in diabetic patients with NAFLD by examining changes in computed tomography (CT)-based body composition and clinical outcomes. Methods Fifteen patients (5 men/10 women) with T2DM-associated NAFLD who had not responded to SGLT2I treatment and were being treated with GLP-1A combination therapy were included. Changes in the liver function, visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI) were compared using CT to evaluate the body composition. Results SGLT2I significantly improved alanine aminotransferase (28.0 to 13.0 IU/L), alkaline phosphatase (250.0 to 77.0 IU/L), and gamma glutamyl transpeptidase (23.0 to 12.0 IU/L) levels. The body mass index (BMI) decreased from 25.7 to 25.2 kg/m2. A CT-based analysis showed a significant improvement in SATI (80.9 to 66.1, p=0.002), with no significant change in VATI (53.2 to 51.5). GLP-1A addition improved the BMI (25.2 to 23.5 kg/m2) and hemoglobin A1c (6.5% to 6.2%, p=0.001). A further analysis revealed additional improvement in SATI (66.1 to 56.6, p=0.007) and a significant decrease in VATI (51.5 to 48.3, p=0.001). Conclusion SGLT2I and GLP-1A combination therapy improved the liver function, body composition, and glycemic control in diabetic patients with NAFLD/NASH, as well as SATI and VATI. The optimal timing of combination therapy remains to be determined.

Comparison of six hepatocellular carcinoma prediction models in Japanese patients after sustained virologic response undergoing rigorous surveillance for hepatocellular carcinoma.

BACKGROUND AND AIM: While several predictive models for the development of hepatocellular carcinoma (HCC) have been proposed, including those for patients with chronic hepatitis C virus (HCV) infection who have achieved sustained virologic response (SVR), the best model may differ between regions. We compared the ability of six reported models to stratify the risk of post-SVR HCC in Japan, where rigorous surveillance and early detection of HCC is common. METHODS: A total of 6048 patients with no history of HCC who achieved SVR by oral direct-acting antiviral drugs were enrolled in this nationwide study. Patients continued HCC surveillance every 6 months after SVR. The incidence of post-SVR HCC was compared between risk groups using the aMAP score, FIB-4 index, Tahata model, GAF4 criteria, GES score, and ADRES score. RESULTS: During the observation period with a median duration of 4.0 years after SVR, post-SVR HCC developed in 332 patients (5.5%). All six models performed significantly at stratifying the incidence of HCC. However, Harrell's C-index was below 0.8 for all models (range, 0.660-0.748), indicating insufficient stratification ability. CONCLUSION: Although all six proposed models demonstrated a good ability to predict the development of post-SVR HCC, their ability to stratify the risk of post-SVRHCC was unsatisfactory. Further studies are necessary to identify the best model for assessing the risk of post-SVR HCC in regions where early detection of HCC is common.

Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. OBJECTIVE: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC. PATIENTS AND METHODS: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years). RESULTS: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). CONCLUSIONS: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.

Comparison of prognostic impact of atezolizumab plus bevacizumab versus lenvatinib in patients with intermediate-stage hepatocellular carcinoma.

BACKGROUND & AIMS: The study goal was to compare the outcomes of patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC]-B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic therapy. METHODS: A total of 358 patients with BCLC-B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first-line systemic therapy were included. RESULTS: The median progression-free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8-12.6) and 7.3 months (95% CI, 6.3-8.5), respectively (p = .019). In the propensity score-matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0-12.3) and 6.9 months (95% CI, 5.9-8.1), respectively (p = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up-to-seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0-11.8) and 6.3 months (95% CI, 5.5-7.3), respectively (p = .044). CONCLUSIONS: The use of Atezo/Bev as first-line systemic therapy in patients with BCLC-B HCC is expected to result in good PFS.

Treatment options for solitary hepatocellular carcinoma ≤5 cm: surgery vs. ablation: a multicenter retrospective study.

BACKGROUND/AIM: The aim of this study was to compare the therapeutic efficacy of ablation and surgery in solitary hepatocellular carcinoma (HCC) measuring ≤5 cm with a large HCC cohort database. METHODS: The study included consecutive 2,067 patients with solitary HCC who were treated with either ablation (n=1,248) or surgery (n=819). Th e patients were divided into three groups based on the tumor size and compared the outcomes of the two therapies using propensity score matching. RESULTS: No significant difference in recurrence-free survival (RFS) or overall survival (OS) was found between surgery and ablation groups for tumors measuring ≤2 cm or >2 cm but ≤3 cm. For tumors measuring >3 cm but ≤5 cm, RFS was significantly better with surgery than with ablation (3.6 and 2.0 years, respectively, P=0.0297). However, no significant difference in OS was found between surgery and ablation in this group (6.7 and 6.0 years, respectively, P=0.668). CONCLUSION: The study suggests that surgery and ablation can be equally used as a treatment for solitary HCC no more than 3 cm in diameter. For HCCs measuring 3-5 cm, the OS was not different between therapies; thus, ablation and less invasive therapy can be considered a treatment option; however, special caution should be taken to prevent recurrence.