Search

Simple Summary: In this phase II trial, patients with advanced hepatocellular carcinoma (HCC) previously treated with lenvatinib were enrolled to receive atezolizumab and bevacizumab every 3 weeks. The primary endpoint was progression-free survival. A total of 26 eligible patients were enrolled. The median progression-free survival from the start of treatment was 9.70 [90% confidence interval, 5.10–14.24] months, with the lower limit above the predefined threshold. The median overall survival was 17.23 [90% confidence interval, 13.18–27.85] months and the objective response rate was 34.6%. Sixteen patients (61.5%) received subsequent therapies. Severe adverse events, adverse events leading to treatment delays, and adverse events leading to treatment discontinuation occurred in eight (30.8%), fourteen (53.8%), and five (19.2%) patients, respectively, and no treatment-related death occurred. This combination therapy is suggested to be effective and safely administered for patients with advanced HCC previously treated with lenvatinib. Background/Objectives: Atezolizumab and bevacizumab combination therapy has been established as a standard of care for first-line treatment; however, its efficacy and safety have not been fully evaluated for patients previously treated with systemic therapy. Methods: In this phase II trial, patients with advanced hepatocellular carcinoma previously treated with lenvatinib were enrolled to receive a dose of 1,200 mg of atezolizumab and 15 mg/kg of bevacizumab every 3 weeks. The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, disease control rate, subsequent therapy, and frequency of adverse events. The threshold and expected progression-free survival were 3 and 6.8 months, respectively. Considering a one-sided significance level of 0.05 and a statistical power of 80%, the minimum required sample size was 26 patients. Results: The median progression-free survival from the start of treatment was 9.70 [90% confidence interval, 5.10–14.24] months, and the lower limit of the 90% CI was above the predefined threshold. The objective response and disease control rates were 34.6% and 73.1%, respectively. Sixteen patients (61.5%) received subsequent therapies, and the median overall survival was 17.23 [90% confidence interval, 13.18–27.85] months. Severe adverse events, adverse events leading to treatment delays, and adverse events leading to treatment discontinuation occurred in eight (30.8%), fourteen (53.8%), and five (19.2%) patients, respectively, and no treatment-related deaths occurred. Conclusions: Atezolizumab and bevacizumab combination therapy is effective and can safely be administered to patients with advanced HCC previously treated with lenvatinib. [ABSTRACT FROM AUTHOR]

Introduction: Cell-free DNA (cfDNA) is expected to contribute to the decision for treatment and prediction of effects with minimally invasion. We investigated the correlation between gene mutations before and after lenvatinib (LEN) treatment and its effectiveness, in order to find advanced hepatocellular carcinoma (HCC) patients who would benefit greatly from the therapy. Methods: We analyzed cfDNA before and 6–8 weeks after the start of treatment in 20 advanced HCC patients who started LEN. A next-generation sequencer was used for CTNNB1 and TP53. Concerning TERT promoter, −124C>T and −146C>T mutations are researched using digital PCR. In addition, we examined liver tumor biopsy tissues by the same method. Computerized tomography evaluation was performed at 6–8 weeks and 3–4 months to assess the efficacy. Results: Frequencies of TERT promoter, CTNNB1, and TP53 mutations in pretreatment cfDNA were 45%, 65%, and 65%, but 53%, 41%, and 47% in HCC tissues, respectively. There were no clear correlations between these gene mutations and the disease-suppressing effect or progression-free survival. Overall, there were many cases showing a decrease in mutations after LEN treatment. Integrating the reduction of CTNNB1 and TP53 genetic mutations increased the potential for disease suppression. Conclusion: This study suggests that analysis of cfDNA in advanced HCC patients may be useful for identifying LEN responders and determining therapeutic efficacy. Furthermore, it has potential for selecting responders for other molecular-targeted drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to understand how specific characteristics of liver cancer, specifically the spread of cancer to blood vessels or other parts of the body, affect treatment outcomes. By analyzing data from 362 patients who received first-line treatment for liver cancer that could not be surgically resected, the researchers identified patterns that could assist in predicting how well patients will respond to treatment. Patients whose cancer had spread only to other parts of the body lived longer than those whose cancer had spread to the blood vessels or both areas. These findings suggest that patients whose cancer had spread only outside the liver may represent a distinct group that could benefit from specific treatment strategies. This new insight may help doctors tailor treatments for liver cancer and improve patient outcomes. Objectives: This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. Methods: We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Results: Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories—patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)—revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariable analysis, including performance status, Child–Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Conclusions: Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment. [ABSTRACT FROM AUTHOR]

Aim: To explore patients' process of living with chronic liver disease while continuing regular healthcare visits for hepatocellular carcinoma surveillance. Methods: Semistructured interviews and participant observations were conducted in this qualitative constructivist grounded theory study. The participants included 11 patients undergoing regular hepatocellular carcinoma surveillance every 1–6 months for 2–30 years. Data were analyzed using coding, memo‐writing, theoretical sampling, and constant comparison. Results: The participants incorporated regular healthcare visits into their living cycle. The cycle's core comprised two categories ("inferring my liver condition" and "desiring status quo"). The cycle underwent a transition described by three phases ("seeking ways to live with my chronic liver disease," "being overwhelmed by living with my chronic liver disease," and "reconstructing my life to live with my chronic liver disease"). This transition involved adjusting to living with chronic liver disease while continuing regular healthcare visits. The relative importance of the cycle's core progressively shifted from "inferring my liver condition" to "desiring status quo." Conclusions: This study revealed the transition phases of patients' living cycles in adjusting to living with chronic liver disease while continuing regular healthcare visits. Understanding the different phases in which patients are and the psychological impact of healthcare visits can help them look forward to recuperative actions. Furthermore, patients who have a sense of ownership experience loneliness because of regular healthcare visits. A support system including nurses as part of regular hepatocellular carcinoma surveillance should be established to help ease patients' sense of loneliness by utilizing their sense of ownership. [ABSTRACT FROM AUTHOR]

Summary: This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child–Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child–Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study. [ABSTRACT FROM AUTHOR]

Aim: The coronavirus disease 2019 (COVID‐19) pandemic has significantly impacted the allocation of medical resources, including cancer screening, diagnosis, and treatment. We aimed to investigate the effects of the pandemic on morbidity and mortality following hepatectomy for hepatocellular carcinoma (HCC). Methods: We identified patients who underwent hepatectomy for HCC between 2018 and 2021 from the Japanese National Clinical Database (NCD). The number of surgical cases, the use of intensive care units, and the incidence of morbidity were assessed. The standardized morbidity / mortality ratio (SMR) was used to evaluate the rates of morbidity (bile leakage and pneumonia) and mortality in each month, which compares the observed incidence to the expected incidence calculated by the NCD's risk calculator. Results: The study included a total of 10 647 cases. The number of patients undergoing hepatectomy for HCC gradually decreased. The proportion of patients aged 80 years or older increased and that of cases with T1 stage decreased. The proportion of patients who were admitted to the intensive care unit did not change between the pre‐ and postpandemic period. The mean actual incidence rates of bile leakage, pneumonia, 30‐day mortality, and surgical mortality were 9.2%, 2.3%, 1.4%, and 2.1%, respectively. The SMR for the mortalities and morbidities in each month did not increase mostly throughout the COVID‐19 pandemic. Conclusions: The present study showed the decreasing number of resected cases for HCC, while the surgical safety for hepatectomy was enough to be maintained by managing medical resources in Japan. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Owing to advances in the multidisciplinary treatment of hepatocellular carcinoma (HCC), a conceptualization and definition for borderline resectable (BR) HCC, which carries a high risk of recurrence, is warranted. In this study, we aimed to define BR-HCC using a prognosis-oriented approach. STUDY DESIGN: The study included an original cohort of 221 patients and an independent validation cohort of 181 patients who had undergone primary hepatic resection for HCC. To define biological BR-HCC, we evaluated the risk factors for early recurrence beyond the Milan criteria within 1 year after hepatic resection using multivariable logistic regression models. Subsequently, we developed high-risk scores using the identified risk factors and defined BR-HCC. The utility of high-risk score was validated in the validation cohort. RESULTS: In the original cohort (hepatitis B virus:hepatitis C virus = 20%:29%), recurrence beyond the Milan criteria within 1 year was observed in 28 patients (13%), with a 5-year survival rate of 25%. Multivariable analysis identified risk factors for recurrence beyond the Milan criteria within 1 year, including serum alpha-fetoprotein levels of 12 ng/mL or more (p = 0.02), tumor diameters less than 5 cm (p = 0.02), tumor number 3 or more (p = 0.001), and macrovascular invasion (p = 0.04). BR-HCC was defined as a tumor with 2 or more identified risk factors, and 42 patients (19%) were diagnosed with BR-HCC, with a 5-year survival rate of 51%. In the validation cohort, 45 (25%) patients had BR-HCC, with a 5-year survival rate of 42%. CONCLUSIONS: The prognosis-oriented definition of BR-HCC enabled us to identify patients who are susceptible to early unresectable recurrence and have poor survival after hepatic resection for HCC. For patients with BR-HCC, preoperative systemic therapy may be a viable option to improve postresection outcomes. [ABSTRACT FROM AUTHOR]

Aim: Coronavirus disease 2019 emerged in December 2019 and spread worldwide. This study aimed to clarify the impact of the coronavirus disease 2019 pandemic on the diagnosis and treatment of hepatocellular carcinoma (HCC) in Japan. Methods: First, we collected the monthly numbers of HCC‐related general medical practices from January 2019 to December 2021 at liver disease‐specific medical institutions in Japan. Next, we collected individual clinical information from patients with newly diagnosed HCC during this period. Results: There was a decrease in the number of HCC‐related medical practices, including referrals, enhanced abdominal ultrasonography and radiofrequency ablation, in Japan's first state of emergency (SOE; April–May 2020) compared with 2019. Fewer patients were diagnosed with new HCC during the first SOE than before or after it. There was no difference in tumor diameter, number of tumors or Barcelona Clinic Liver Cancer stage between patients diagnosed before the first SOE and those diagnosed during or after the first SOE. The median waiting times for treatment of patients diagnosed during and after the first SOE were 31 and 37 days, which were significantly shorter and not longer than that of patients diagnosed before the first SOE (36 days), respectively. Conclusion: The number of HCC‐related general medical practices decreased during the first SOE. However, the coronavirus disease 2019 pandemic did not lead to HCC progression by diagnostic delays or cause HCC treatment delays in Japan. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Macroscopic vascular invasion (MVI) significantly impacts survival in patients with hepatocellular carcinoma (HCC), warranting systemic therapy over locoregional therapy. Despite novel approaches, HCC with MVI has a poor prognosis compared to early-to intermediate-stage HCC. This study aimed to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for HCC characterized by MVI. Methods: This retrospective cohort study evaluated HCC patients with MVI treated using C-ion RT with a dose of 45.0–48.0 Gy/2 fractions or 52.8–60.0 Gy/4 fractions between 1995 and 2020 at our institution in Japan. We analyzed the prognostic factors and rates of local recurrence, survival, and adverse events. The local recurrence rate was determined using the cumulative incidence function, with death as a competing event. Survival rates were determined using the Kaplan–Meier method. The log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis were used to compare subgroups. Results: In total, 76 patients with a median age of 71 years (range, 45–86 years) were evaluated. Among them, 68 had Child–Pugh grade A while eight had grade B disease. In 17 patients, the vascular tumor thrombus reached the inferior vena cava or main trunk of the portal vein. Over a median follow-up period of 27.9 months (range, 1.5–180.4 months), the 2-year overall survival, progression-free survival, and local recurrence rates were 70.0% (95% confidence interval [CI]: 57.7–79.4%), 32.7% (95% CI: 22.0–43.8%), and 8.9% (95% CI: 1.7–23.5%), respectively. A naïve tumor and a single lesion were significant prognostic factors for overall survival in the univariate analysis. Albumin-bilirubin grade 1 and a single lesion were independent prognostic factors in the multivariate analysis. Overall, four patients (5%) experienced grade 3 late adverse events, with no observed grade 4 or 5 acute or late adverse events. Conclusions: C-ion RT for HCC with MVI showed favorable local control and survival benefits with minimal toxicity. [ABSTRACT FROM AUTHOR]

Patient profiles suitable for long-term lenvatinib treatment for unresectable hepatocellular carcinoma (uHCC) are yet to be fully understood. This post-hoc analysis aimed to identify such patient characteristics and explore the impact of treatment duration and relative dose intensity (RDI) on treatment outcomes. The data were obtained from 703 patients in a multicenter, prospective cohort study in Japan. Lenvatinib-naïve patients with uHCC were enrolled between July 2018 and January 2019 and were followed up for 12 months. Moreover, patients were dichotomized using the median treatment duration into the longer- (≥177 days; n = 352) or shorter-treatment (<177 days; n = 351) groups. The longer-treatment group often had better performance status, lower Child-Pugh score and better modified albumin-bilirubin grade than the shorter treatment group (p<0.05 for all). The objective response rate (47.6% vs. 28.2%; p<0.001) and disease control rate (92.4% vs. 60.2%; p<0.001) were both significantly higher in the longer-treatment groups than in the shorter-treatment groups. The proportion of patients with any adverse drug reactions was generally similar between the two treatment groups. Within the longer-treatment group, the disease control rate was high regardless of dose modification (i.e., RDI <100% vs. ≥100% during the initial 177 days) (91.2% vs. 98.0%). In conclusion, patients with longer treatment tended to have better overall conditions. Lenvatinib dose modifications at the physician's discretion, considering the balance between effectiveness and safety, may contribute to the long-term treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma. Human leukocyte antigen (HLA) self-recognition through killer immunoglobulin-like receptor (KIR), a process termed "licensing", raises the NK cell capacity. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy. Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma (HCC). We performed adaptive immunotherapy using donor-liver-derived natural killer (NK) cells after living-donor liver transplantation (LDLT) to prevent HCC recurrence. Dominant inhibitory signals tightly regulate NK cell activity via human leukocyte antigen (HLA)-specific inhibitory receptors, such as killer immunoglobulin-like receptors (KIRs). The functional recognition of HLA through KIR raises the NK cell capacity, which is a process termed "licensing." Here, we investigated the effect of polymorphic KIR-HLA genotypes on the efficacy of NK-cell-based immunotherapy after LDLT. Seventy-seven Japanese recipients with HCC who underwent LDLT and their corresponding donors between 1996 and 2016 were enrolled in this study. The median follow-up period was 8.3 years. The HCC recurrence risk was stratified using radiological and pathological assessments according to the Milan criteria. Of the 77 recipients, 38 received immunotherapy. Immunotherapy improves early post-transplantation survival and lowers the recurrence rate in the intermediate-risk recipients. We analyzed the genotypes of five inhibitory KIRs and HLA using sequence-specific polymorphism-based typing. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy. [ABSTRACT FROM AUTHOR]

Liver cancer is one of the most prevalent cancers in Japan with hepatocellular carcinoma (HCC) as the major histological subtype. Successful novel treatments for HCC have been reported; however, recurrences or metastasis may occur, which results in poor prognoses and high mortality of HCC patients. Fascin, an actin-bundling protein, regulates cell adhesion, migration, and invasion. Its overexpression positively correlates with poor prognosis of malignant tumors, and Fascin is considered as one of the tumor biomarkers and therapeutic target proteins. In this study, we attempted to reveal the relationship between Fascin and HCC using HLE, one of the human HCC cell lines. We performed the study with classical immunocytochemistry and recently developed techniques, such as wound-healing assay, spheroid cultivation, and low-vacuum scanning electron microscopy (LV-SEM). Non-Fascin-knockdown (FKD) cell spheroid had a regular spherical appearance with tight cell–cell connections, while FKD cell spheroid had an irregular shape with loose cell–cell connections. Cells of non-FKD spheroid presented fibrous protrusions on the cell surface, contrarily, cells of FKD spheroids showed bulbous-shaped protrusions. Morphological observation of FKD and non-FKD HLE spheroids were performed using LV-SEM. Our study may help to reveal the roles of Fascin in the process of HCC formation and its malignancy. [ABSTRACT FROM AUTHOR]

Background: Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC. Methods: We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021. Results: During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child–Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7 months. Regarding patients with Child–Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20 mg was lower than those who initialized at 60 mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3 months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%). Conclusions: Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib. The preprint version of this work is available on https://www.researchsquare.com/article/rs-2655181/v1. [ABSTRACT FROM AUTHOR]

This text provides an overview of the current therapeutic strategies for hepatocellular carcinoma (HCC) in Japan. The 5-year survival rate for HCC patients has significantly improved over the past 40 years, thanks to advancements in diagnostic techniques and the development of new therapies. The approval of therapeutic agents such as sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has also contributed to this improvement. The article discusses different treatment strategies for HCC, including the use of molecular-targeted agents after transarterial chemoembolization (TACE) failure and the concept of "TACE unsuitability." Sequential therapies and combination treatments have shown promising results, and ongoing clinical trials are evaluating the combination of TACE with immunotherapy. The article emphasizes the importance of ongoing research in improving treatment outcomes for HCC patients at all stages. [Extracted from the article]

Introduction: Because of recent developments in treatments for hepatocellular carcinoma (HCC), methods for determining suitable therapy for initial or recurrent HCC have become important. This study used artificial intelligence (AI) findings to establish a system for predicting prognosis of HCC patients at time of reoccurrence based on clinical data as a reference for selection of treatment modalities. Methods: As a training cohort, 5,701 observations obtained at the initial and each subsequent treatment for recurrence from 1,985 HCC patients at a single center from 2000 to 2021 were used. The validation cohort included 5,692 observations from patients at multiple centers obtained at the time of the initial treatment. An AI calculating system (PRAID) was constructed based on 25 clinical factors noted at each treatment from the training cohort, and then predictive prognostic values for 1- and 3-year survival in both cohorts were evaluated. Results: After exclusion of patients lacking clinical data regarding albumin-bilirubin (ALBI) grade or tumor-node-metastasis stage of the Liver Cancer Study Group of Japan, 6th edition (TNM-LCSGJ 6th), ALBI-TNM-LCSGJ 6th (ALBI-T) and modified ALBI-T scores confirmed that prognosis for patients in both cohorts was similar. The area under the curve for prediction of both 1- and 3-year survival in the validation cohort was 0.841 (sensitivity 0.933 [95% CI: 0.925–0.940], specificity 0.517 [95% CI: 0.484–0.549]) and 0.796 (sensitivity 0.806 [95% CI: 0.790–0.821], specificity 0.646 [95% CI: 0.624–0.668]), respectively. Conclusion: The present PRAID system might provide useful prognostic information related to short and medium survival for decision-making regarding the best therapeutic modality for both initial and recurrent HCC cases. [ABSTRACT FROM AUTHOR]

For the 23rd Nationwide Follow‐up Survey of Primary Liver Cancer in Japan, data from 20 889 newly registered patients and 42 274 previously registered follow‐up patients were compiled from 516 institutions over a 2‐year period from January 1, 2014 to December 31, 2015. Basic statistics compiled for patients newly registered in the 23rd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment‐related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 22nd survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non‐B non‐C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2004 and 2015 whose final outcome was survival or death. The median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, Child–Pugh grade, or albumin‐bilirubin grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2015 into five time period groups. The data obtained from this nationwide follow‐up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer in the world. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to compare the safety of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma (HCC) in patients with Child-Pugh A (CP-A) and Child-Pugh B (CP-B) and to determine the adverse events (AEs) that cause dose reduction/interruption of treatment in patients with CP-B. Methods: Sixty-six patients with lenvatinib as a first-line treatment for HCC at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and January 2022 were retrospectively evaluated. We analyzed the treatment duration, AEs, and reasons for dose reduction/interruption associated with lenvatinib treatment in patients with CP-A and CP-B HCC. Results: The CP-B group had significantly more cases of grade ≥ 2 fatigue and anorexia than the CP-A group (p = 0.045 and p = 0.042, respectively). Regarding AEs that caused dose reduction/interruption of treatment, the CP-A group had significantly more cases of proteinuria than the CP-B group (p = 0.015), whereas the CP-B group had significantly more cases of hand-foot syndrome (HFS) than the CP-A group (p = 0.013). Conclusion: Patients with CP-B have greater difficulty than patients with CP-A in continuing treatment with repeated dose reductions/interruption of treatment due to intolerable grade ≥ 2 AEs (fatigue and anorexia). HFS is more likely to cause dose reduction/interruption of treatment in CP-B than in CP-A unresectable HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: High intensity of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI imaging (EOB-MRI) in the hepatobiliary phase (HB) is associated with mutations in CTNNB1 and activation of β-catenin, an immune-cold microenvironment, and an unfavorable response to anti-PD-1/PD-L1 monotherapy in patients with hepatocellular carcinoma (HCC). EOB-MRI could serve as a surrogate marker predicting the immune microenvironment and molecular subtype but does not predict the response to atezolizumab + bevacizumab therapy. Our results suggest that this is because the high-intensity group benefits from bevacizumab, while the low-intensity group benefits from atezolizumab. Although EOB-MRI might serve as a surrogate marker for the response to other currently developed immunotherapies, it is not necessary to avoid atezolizumab + bevacizumab treatment for hyperintense HCC. It has been reported that high intensity in the hepatobiliary (HB) phase of Gd-EOB-DTPA-enhanced MRI (EOB-MRI) is associated with an immune-cold microenvironment in HCC. The aim of this study is to reveal whether non-high-intensity HCCs are homogeneous with respect to the immune microenvironment and to investigate the predictive ability of EOB-MRI for the response to atezolizumab + bevacizumab therapy (Atezo/Bev). The association between differences in stepwise signal intensity of HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment was investigated in 65 HCC patients (cohort 1). The association between EOB-MRI and the therapeutic effect of Atezo/Bev was evaluated in the Atezo/Bev cohort (60 patients in cohort 2). The proportion of HCCs having CTNNB1 mutations and classified as Chiang CTNNB1 and Hoshida S3 was high in the high-intensity HB-phase group. Infiltration of tumor-associated macrophages (TAM) and regulatory T-lymphocytes (Treg) was characteristic of the high-intensity and low-intensity groups, respectively. Although EOB-MRI could not predict the response to Atezo/Bev treatment, our results demonstrate that EOB-MRI could serve as a surrogate marker predicting the immune microenvironment. This suggests that Atezo/Bev treatment can be selected regardless of signal intensity in the EOB-MRI HB phase. [ABSTRACT FROM AUTHOR]

Background and Aim: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first‐ or later‐line systemic therapy. Methods: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first‐line therapy for HCC were defined as the first‐line group (n = 268) while those treated with Atezo/Bev as second‐ or later‐line therapy were defined as the later‐line group (n = 162). Results: The median progression‐free survival times in the first‐ and later‐line groups were 7.7 months (95% confidence interval [CI], 6.7–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.021). Regarding treatment‐related adverse events, hypertension of any grade was more common in the first‐line group than in the later‐line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later‐line group (hazard ratio, 1.304; 95% CI, 1.006–1.690; P = 0.045) was significantly associated with progression‐free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression‐free survival times in the first‐ and later‐line groups were 10.5 months (95% CI, 6.8–13.8) and 6.8 months (95% CI, 5.0–9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression‐free survival times in the first‐ and later‐line groups were 7.7 months (95% CI, 6.3–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.022). Conclusion: The use of Atezo/Bev as first‐line systemic therapy in patients with HCC is expected to prolong survival. [ABSTRACT FROM AUTHOR]

Simple Summary: The Barcelona clinic liver cancer (BCLC) system is used widely for staging hepatocellular carcinomas (HCCs). However, it is questionable that for patients classified as BCLC stage C, control of intrahepatic targets using various treatment procedures is not the main topic of discussion, whereas the importance of intrahepatic tumor control in patients with extrahepatic tumor spread is reviewed. Therefore, this study analyzed the data of 64 consecutive BCLC stage C patients with intrahepatic target nodules who received systemic therapy and evaluated the efficacy of the combined use of systemic sequential therapy, including more than two agents, and locoregional treatment administered after initiation of systemic therapy. We showed that the combined use of systemic sequential therapy of more than two agents and locoregional-treatment improved overall survival in BCLC stage C HCC patients with intrahepatic target nodules who had previously received systemic therapy-based treatment. Background: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). Methods: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP). Results: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003). Conclusions: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment. [ABSTRACT FROM AUTHOR]

Introduction: Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or superselective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria. Methods: This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, superselective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone. Results: Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and 3 patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status. Conclusion: The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug-free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread. [ABSTRACT FROM AUTHOR]

Simple Summary: Although sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reported to affect therapeutic efficacy and the occurrence of adverse events in sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC), there is considerably less evidence regarding the relationship between SMI and prognosis in the HCC patients treated with atezolizumab plus bevacizumab (atezo/bev) therapy. Furthermore, there are no reports of muscle strength, including grip strength (GS), which is essential for an accurate diagnosis of sarcopenia. This is the first study to show the relationship between sarcopenia, diagnosed by decreased GS and SMI, and clinical outcomes in atezo/bev therapy, with novel evidence having a strong impact. The presence of sarcopenia is significantly associated with shorter overall survival with the occurrence of adverse events and decreased liver function. Monitoring of both GS and SMI is useful for assessing the general condition and predicting prognosis in HCC patients treated with atezo/bev therapy. Although there have been advances in the prevention and diagnosis of hepatocellular carcinoma (HCC) in recent years, many HCC patients are still diagnosed with advanced stage. Systemic therapy is indicated for unresectable HCC (uHCC) with major vascular invasion and/or extrahepatic metastases, and the atezolizumab plus bevacizumab (atezo/bev) combination is currently recommended as first-line treatment for uHCC. Recently, sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reportedly associated with prognosis in uHCC patients treated with sorafenib or lenvatinib. There are few reports on muscle strength assessments, including grip strength (GS), despite their importance in accurate sarcopenia diagnosis, and furthermore, there is no evidence regarding atezo/bev therapy. In this study, we investigated whether sarcopenia affects the clinical outcome of atezo/bev therapy. This study included 64 uHCC patients on atezo/bev therapy and assessed their GS and SMI, and SMI was measured using bioelectrical impedance analysis (BIA). We diagnosed sarcopenia based on GS and BIA-SMI and compared the clinical outcomes in the sarcopenia and non-sarcopenia groups. Of these patients, 28 had sarcopenia, and 36 had non-sarcopenia. Adverse events (AEs) frequently occurred, and the albumin-bilirubin score significantly decreased after atezo/bev therapy in the sarcopenia group than in the non-sarcopenia group. The median progression-free survival was 4.7 (0.4–26.4) and 10.6 (1.1–24.5) months in the sarcopenia and non-sarcopenia groups, respectively. The median overall survival (OS) was 12.6 (1.4–27.7) months in the sarcopenia group and was not reached in the non-sarcopenia group, indicating a significant difference in the Kaplan-Meier survival curves for both groups (p < 0.01). In multivariate analysis, sarcopenia was significantly associated with OS. In conclusion, sarcopenia was significantly associated with poor clinical outcomes based on the occurrence of AEs and decreased liver function in uHCC patients on atezo/bev therapy. GS and SMI are important parameters for accurately diagnosing sarcopenia. [ABSTRACT FROM AUTHOR]

Background: Lenvatinib was approved for use in unresectable hepatocellular carcinoma (uHCC) in Japan in 2018. Patients with diverse clinical characteristics receive lenvatinib treatment in clinical practice. Thus, it is crucial to evaluate the safety and effectiveness of lenvatinib in real-world clinical settings. Objective: This study aimed to evaluate the real-world safety and effectiveness of lenvatinib for uHCC in clinical practice in Japan. Patients and Methods: Between July 2018 and January 2019, patients with uHCC who were administered lenvatinib for the first time were enrolled in this prospective, multicenter, observational post-marketing study (NCT03663114). Patients were orally administered lenvatinib and followed up for 12 months. For safety, adverse drug reactions (ADRs) were evaluated. For effectiveness, the objective response rate (ORR) was calculated to evaluate tumor response. Overall survival (OS) was estimated using the Kaplan–Meier method. Results: Data of 703 patients (median age, 73 years; 80.2% males) were analyzed. The median (range) treatment duration was 25.3 (0.3–68.9) weeks. The mean ± standard deviation initial dose was 7.37 ± 1.65 mg in patients with body weight < 60 kg and 10.43 ± 2.49 mg in those with body weight ≥ 60 kg. ADRs (any grade) were reported in 84.9% of the patients, with Grade ≥ 3 ADRs reported in 42.5% of the patients. The most common ADRs (> 10%) were decreased appetite, fatigue, hypertension, proteinuria, palmar-plantar erythrodysesthesia, hypothyroidism, and diarrhea. The median OS of the 703 patients was 498.0 days. In 494 patients assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the ORR was 39.5% (95% confidence interval: 35.1–43.9%). Patients with better liver or renal function at baseline achieved significantly higher ORR than those with worse liver or renal function. Conclusions: In patients with uHCC in real-world clinical practice in Japan, treatment with lenvatinib was generally well tolerated, and no new safety concerns were identified. The ORR and median OS were similar to or better than the results of the Japanese subset of the global Phase III REFLECT trial. Our results demonstrated that clinically meaningful treatment responses were achieved with lenvatinib in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Aim: Cabozantinib showed a favorable benefit–risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open‐label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. Methods: Patients with previously treated, advanced HCC received cabozantinib 60 mg/day. Progression‐free survival (PFS) and tumor response rates in prior‐sorafenib and sorafenib‐naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin–bilirubin (ALBI) score. Results: Median cabozantinib exposure was 5.6 months. In the prior‐sorafenib cohort (n = 20), median PFS was 7.4 months per IRC assessment and 5.6 months per investigator assessment. In the sorafenib‐naïve cohort (n = 14), median PFS was 3.6 and 4.4 months per IRC and investigator assessment, respectively. Six‐month PFS rate per IRC and investigator assessment in the prior‐sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib‐naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior‐sorafenib cohort and 64.3% in the sorafenib‐naïve cohort. Median overall survival (Kaplan–Meier estimate) was 19.3 and 9.9 months in the prior‐sorafenib and sorafenib‐naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar–plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. Conclusions: Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Summary: This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04–6.58, P = 0.042) and 2.85 (95% CI: 1.37–5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22–13.84, P < 0.001) and 3.54 (95% CI: 1.83–6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23–0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25–0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223–13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS. [ABSTRACT FROM AUTHOR]

Purpose: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. Methods: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. Results: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6–7.3). Conclusion: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial. [ABSTRACT FROM AUTHOR]

In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33–0.43) for sustained virologic response (SVR) and 1.70 (1.61–1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19–0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19–0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence. [ABSTRACT FROM AUTHOR]

Aim: This study compared the efficacy and safety of atezolizumab and bevacizumab (Atez/Bev) in patients with viral and non‐viral infection in clinical settings. Methods: We conducted the retrospective cohort study of 323 BCLC stage B or C hepatocellular carcinoma (HCC) patients with Child‐Pugh class A, and a performance status of 0 or 1 who started Atez/Bev from September 2020 to December 2021 at 22 institutions in Japan. Patients with viral infection was defined as those who were either serum anti‐HCV‐ Ab or HBs‐Ag‐positive, while patients with non‐viral infection was defined as those who were both serum anti‐HCV Ab‐ and HBs‐Ag‐negative. We constructed a propensity‐score‐matched cohort to minimize the risk of observable potential confounders. Results: Propensity score matching produced 126 matched pairs for patients with viral versus non‐viral infection. After matching, the significant differences in baseline demographic features did not exist between the two groups. The objective response rate was 20.6% and 24.6% in viral‐ and non‐viral‐related HCC patients, respectively, without a significant difference (p = 0.55). The disease control rate was not also significantly different (68.3% vs 69.0%, p = 1.00). The median progression‐free survival was 7.0 months (95% confidence interval [CI] 6.0–9.6) and 6.2 months (95% CI 5.1–7.8) in patients with viral and non‐viral infection, and the 12‐month survival rates were 65.5% (95% CI 50.8–76.8) and 71.7% (95% CI 57.3–81.9) in those with viral and non‐viral infection, respectively, which were not significantly different (p = 0.33, p = 0.38). No significant difference in treatment‐related adverse events was found between the two groups. Conclusions: Our etiology‐based study demonstrated that Atez/Bev showed good efficacy and safety for HCC patient with non‐viral infection as well as those with viral infection. [ABSTRACT FROM AUTHOR]

Introduction: Atezolizumab and bevacizumab (AB) therapy was the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). However, the predictive marker of therapeutic response that can be easily used in clinical practice is still unknown. We prospectively investigated the utility of time-intensity curve (TIC) analysis using contrast-enhanced ultrasound (CEUS) as a predictive indicator of therapeutic response after the start of AB therapy. Methods: Thirty-five patients who received AB therapy for u-HCC were included in this study. TIC analysis was performed in 28 patients who were able to undergo CEUS before and 3–7 days after administration. We analyzed prognostic factors related to the initial therapeutic response and long progression-free survival (PFS). Results: The initial therapeutic response using dynamic computed tomography or Gd-EOB magnetic resonance imaging at 8–12 weeks after administration was partial response/stable disease/progressive disease (PD) in 14/12/9 cases (40/34/26%). Cases with PD (n = 9) had more cases without decreased blood flow in TIC analysis compared with cases with non-PD (100 vs. 18%, p = 0.001). Cases without decreased blood flow in TIC analysis (n = 10) had more cases with PD compared with cases with decreased blood flow (60 vs. 0%, p = 0.001). PFS in patients without decreased blood flow early after the administration was shorter than that in those with decreased blood flow (9.1 vs. 28 weeks, p = 0.0051). Conclusion: Early evaluation by TIC analysis using CEUS may be useful in predicting the therapeutic response in patients treated with AB therapy for u-HCC. [ABSTRACT FROM AUTHOR]

Background: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long‐term efficacy and association with adverse events in real‐world practice are unknown. This study was designed to shed light on these issues. Methods: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. Results: A total of 123 patients were enrolled in this study. The median progression‐free survival (PFS) for the first‐line treatment group was 8.0 months (95% confidence interval [CI], 6.1–9.9), whereas the median PFS for the second‐ or later‐line treatment group was 4.1 months (95% CI, 2.6–5.7), which was significantly worse than that of the first‐line treatment group (p =.005). Twenty‐seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p =.026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p =.013). Conclusions: The PFS of atezolizumab plus bevacizumab as first‐line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long‐term PFS. Plain language summary: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma.With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly.The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus.The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma. This report demonstrated that the cumulative incidence rate of bevacizumab interruption due to anti‐VEGF–related adverse events was significantly higher in patients with comorbid hypertension and/or diabetes mellitus during atezolizumab plus bevacizumab for advanced hepatocellular carcinoma. Interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Introduction: When lenvatinib is administered to people with hepatocellular carcinoma (HCC), tumor blood flow is reduced due to the inhibition of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). Few studies have examined the decrease in tumor blood flow with respect to changes in tumor blood vessels (TBVs) in clinical practice. We investigated the mechanism of tumor blood flow control by investigating changes in the diameter of relatively large TBVs in large-sized lesions with high blood flow. Methods: From January 2011 to October 2021, patients receiving lenvatinib for unresectable intrahepatic HCC at Toranomon Hospital, Tokyo, Japan, were considered for inclusion. We investigated the TBV diameter in the arterial phase of dynamic computed tomography before treatment and its change over time (2–12 weeks after lenvatinib initiation). The relationship between changes in TBV diameter and prognosis was also examined. Results: Of 114 patients treated with lenvatinib for HCC, 26 patients who had intrahepatic lesions with a tumor diameter of 30 mm or more enrolled in the study. The median tumor and TBV diameters before treatment were 58 mm and 2.55 mm, respectively. Twenty-five patients (96%) had a shrinkage in TBV diameter 2–12 weeks after lenvatinib administration. The maximum TBV diameter shrinkage of 20% or more was observed in 19 patients (73%), and progression-free survival was prolonged in these patients compared to the group with less than 20% TBV diameter shrinkage (p = 0.039). Discussion/Conclusion: Due to the antiangiogenic effect of lenvatinib, a shrinkage in the TBV diameter of HCC was observed. The shrinkage of TBV may be regarded as a process of normalization of TBVs. The shrinkage of TBVs in imaging analysis may be associated with improved prognosis; however, additional studies are still required. [ABSTRACT FROM AUTHOR]

Aims: This retrospective study compared the survival between elderly and non‐elderly patients. Methods: A total of 5545 treatment‐naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively. Results: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non‐elderly patients, the median albumin‐bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non‐elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non‐elderly patients did (p = 0.017). Non‐liver‐related death in elderly patients significantly differed among periods (p = 0.023), while liver‐related death did not (p = 0.050). Liver‐ and non‐liver‐related death in non‐elderly patients significantly differed among periods (p < 0.001, p = 0.005). Conclusions: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient. [ABSTRACT FROM AUTHOR]

Recently, non‐B non‐C chronic liver diseases, including alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), have markedly increased worldwide. Liver transplantation (LT) is an effective curative therapy for hepatocellular carcinoma (HCC) as well as decompensated liver cirrhosis. In Japan, where the source of liver grafts is strongly dependent on living donors, efforts have been made to unify the indications for eligibility of HCC patients for LT, leading to the development of 5‐5‐500 criteria. Along with the expansion of eligibility for LT, the current changing trends in underlying liver diseases of LT recipients, which are related to the rising tide of non‐B non‐C cirrhosis and HCC, are highlighting the importance of peri‐transplant management of patients with various comorbidities. The post‐LT prognosis of patients with ALD is significantly affected by de novo malignancies and metabolic syndrome‐related complications as well as posttransplant alcohol relapse. NAFLD/NASH patients often suffer from obesity, type 2 diabetes mellitus, and other metabolic syndrome‐related disorders, and nonneoplastic factors such as cardiovascular events and recurrence of NAFLD/NASH have a significant impact on post‐LT outcomes. Patient management in the peri‐transplant period as well as risk assessment for LT are key to improving post‐LT outcomes in the era of a growing number of cases of LT for non‐B non‐C liver diseases. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC). Methods: Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups. Results: The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03–1.71; p = 0.029), whereas overall survival (OS) was not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group. Conclusions: LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver. [ABSTRACT FROM AUTHOR]

Background: Liver disease remains a significant concern for people living with HIV (PLWH), especially in those with hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection. This study assessed the prevalence of viral hepatitis coinfections and evaluated the current state of hepatitis management by HIV care providers in Japan., Methods: This single-center, retrospective, observational study analyzed data from PLWH treated with antiretroviral therapy between April 1, 2023 and March 31, 2024. Data included demographics, ART regimen, hepatitis status, and screening practices of 811 PLWH treated with antiretroviral therapy., Results: The median age of the study population was 48 years, and 97.8 % were men. The HBV status was as follows: chronic HBV, 6.5 %; clinical remission, 34.0 %; uninfected, 30.9 %; unknown, 14.2 %. The HCV antibody positivity rate was 3.2 %. Substantial gaps in hepatitis screening and monitoring were identified. Specifically, we found inadequate rates of abdominal ultrasound examinations and HCC screening among patients with HIV and viral hepatitis coinfection. Moreover, only 71.7 % of patients chronically infected with HBV and 61.5 % with HCV underwent abdominal ultrasound examinations in the preceding 12 months-only 5.7 % and 3.8 % of the participants in these groups had had received tumor marker testing in the previous 12 months., Conclusion: There are challenges in hepatitis and HCC screening and monitoring among patients with HIV and viral hepatitis coinfection in Japan. These findings underscore the need to improve adherence to clinical practice guidelines and implement integrated care models to enhance hepatitis management in PLWH., Competing Interests: Declaration of interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: Atezolizumab-bevacizumab (AB) is the established first-line systemic therapy for patients with unresectable hepatocellular carcinoma (uHCC). However, the optimal second-line treatment for patients unresponsive to AB remains undefined., Patients and Methods: This multicenter, retrospective study included patients with uHCC who underwent second-line treatment with lenvatinib (LEN) or sorafenib (SOR) after AB failure at two academic centers between June 2018 and November 2023. Treatment response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST. Propensity score matching (PSM) was employed to mitigate confounding bias., Results: A total of 123 were included in the final analysis, 56 patients received LEN, and 67 received SOR. Before PSM, LEN was associated with significantly improved progression-free survival (PFS) compared with SOR (median 4.9 vs. 3.3 months, p < 0.001); however, no significant difference in overall survival (OS) was observed (median 13.2 vs. 11.5 months, p = 0.651). After PSM, in a cohort of 50 patients (25 per each group), LEN maintained its PFS advantage over SOR (median 4.8 vs. 3.3 months, p = 0.046), while the median OS was longer with LEN but not statistically different (median 11.4 vs. 7.9 months, p = 0.197). Response rates were 40% for LEN and 12% for SOR (p = 0.021) based on modified RECIST, and 12% and 8% (p = 0.728) based on RECIST v1.1, respectively., Conclusion: In this real-world study, LEN demonstrated superior PFS and comparable OS to SOR as second-line treatment for uHCC after progression on AB., Competing Interests: Declarations. Ethical approval: This study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. All study protocols were reviewed and approved by the institutional review boards of each participating center (Asan Medical Center, 2021-0064; Kurume University School of Medicine; 23006). Academic investigators were responsible for the study design. The requirement for informed consent from enrolled patients was waived owing to the retrospective nature of the study. Competing interests: J. Cheon received honoraria from Eisai, and Roche, and received research grants from Bayer. C. Yoo received honoraria from Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol Myers Squibb, Ipsen, Novartis, Boryung, Mundipharma, and Roche, and received research grants from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Ipsen, Boryung and Lunit Inc. All other authors declare no competing interests., (© 2025. The Author(s).)

Background and Aim: In recent years, there has been a rise in cryptogenic hepatocellular carcinoma (c-HCC) cases in Japan, posing a detection challenge due to an unknown etiology. This study aims to enhance diagnostic strategies for c-HCC by analyzing its characteristics and exploring current opportunities for detection., Methods: A retrospective study was conducted from April 2012 to March 2022, enrolling 372 newly diagnosed hepatocellular carcinoma (HCC) patients. Excluding cases associated with hepatitis viral infection, alcoholic liver disease, non-alcoholic fatty liver disease/steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and congestive hepatopathy, the study specifically focused on genuine c-HCC. The analysis delved into the characteristics, detection opportunities, and survival outcomes associated with c-HCC., Results: Among the non-viral HCC cases, 55 patients (29.3%) (34 men and 21 women) were diagnosed with c-HCC, making it the second-highest etiology. Notably, individuals with c-HCC, typically aged 60 and above (median age 76.0), exhibited a women predominance and presented with larger tumors (4.5 cm vs. 2.5 cm), correlating with a poorer prognosis. Cirrhosis was notably absent in most c-HCC cases (72.7%), and more than half (56.4%) did not have diabetes mellitus (DM). Diagnostic pathways for c-HCC primarily involved incidental imaging (47%) and symptoms (24%). Within the cohort of c-HCC, the prognosis for symptomatic cases is notably unfavorable compared to other cases [median survival time 19.0 (7.0-45.0) months vs. 47.0 (29.0-76.0) months, p = 0.029]. In the multivariate regression analysis, age and women emerged as independent factors associated with c-HCC. Rather than a significant increase in women, there is a narrowing gender gap., Conclusion: Patients with c-HCC were predominantly elderly, without cirrhosis or diabetes, and exhibited minimal gender differences. Detection often occurred incidentally through abdominal imaging. Considering the limitations of conventional surveillance, it seems reasonable to propose that abdominal imaging be included in cancer screening, particularly for individuals aged 60 and older., Trial Registration: 1610A127., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Transarterial radioembolization (TARE) is effective for unresectable hepatocellular carcinoma; however, it awaits approval in Japan. This study aimed to simulate the cost-effectiveness of TARE over chemoembolization when TARE is approved in Japan and identify the requirements for cost-effectiveness., Materials and Methods: A Markov model was constructed to analyze the costs and effectiveness associated with TARE and transarterial chemoembolization with drug-eluting beads (DEB-TACE) for 2-month cycles over 5 years. In the primary analysis, the intention-to-treat survival data were used to calculate transition probabilities, whereas the ancillary analysis assessed the per-protocol survival data. DEB-TACE costs were calculated using the Japanese nationwide claims Diagnosis Procedure Combination database between April 2018 and March 2022, whereas TARE costs were estimated using database and international sources. The incremental cost-effectiveness ratio (ICER) was determined based on the payer's perspective and compared with the Japanese willingness-to-pay threshold of 5 million Japanese yen (JPY) (31,250 USD) per quality-adjusted life years (QALY)., Results: From the claims database, 6,986 patients with hepatocellular carcinoma who received DEB-TACE were identified. In the primary analysis, the ICER was 5,173,591 JPY (32,334 USD)/QALY, surpassing the Japanese willingness-to-pay threshold. However, the ancillary analysis showed a lower ICER of 4,156,533 JPY (25,978 USD)/QALY, falling below the threshold. The one-way deterministic sensitivity analysis identified progression-free survival associated with TARE and DEB-TACE, DEB-TACE costs, and radioactive microsphere reimbursement price as key ICER influencers. The primary analysis suggested that setting the reimbursement price of radioactive microspheres below 1.399 million JPY (8,744 USD), approximately 2.8% lower than the price in the United Kingdom, would place the ICER below the Japanese willingness-to-pay threshold., Conclusions: Under specific conditions, TARE can be a more cost-effective treatment than DEB-TACE. If the reimbursement price of radioactive microspheres is set approximately 2.8% lower than that in the United Kingdom, TARE could be cost-effective compared with DEB-TACE., Competing Interests: Declarations. Competing interest: The authors have no competing interest to disclose. Ethics approval: We strictly adhered to the ethical guidelines laid out in the Declaration of Helsinki by the World Medical Association. This study was approved by the Ethics Committee of the University of Tokyo (No. 3501-(5)). Consent to participate/publish: Our study fulfilled the necessary conditions to waive the need for informed consent based on the Ethical Guidelines for Medical and Health Research Involving Human Subjects established by the Japanese National Government, which stipulates the requirements for protecting patient anonymity., (© 2024. The Author(s).)

Health state utilities are global measurements of quality of life and have been used to evaluate health outcomes for the cost-utility analysis. This study aimed to estimate the health state utilities of patients with hepatitis B (HB), hepatitis C (HC), and hepatitis-related diseases in Japan. We distributed a self-administered questionnaire, including the EuroQol 5-Dimension 5-Level (EQ-5D-5L), to 9,952 outpatients with several clinical conditions caused by HB or HC virus infection (such as asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis) and estimated the condition-specific utilities of patients with HB or HC. In patients with more severe conditions (patients with acute hepatitis, fulminant hepatitis, and hepatocellular carcinoma and patients undergoing post-liver transplantation), the utilities of these severe conditions were estimated by three hepatitis experts using the EQ-5D-5L. The means of the utilities for acute hepatitis, fulminant hepatitis, asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, compensated cirrhosis, hepatocellular carcinoma stage I/II, hepatocellular carcinoma stage III/IV, and post-liver transplantation were 0.529, − 0.111, 0.904, 0.868, 0.845, 0.722, 0,675, 0,428, and 0.651 and 0.876, 0.821, 0.737, 0.671, 0.675, 0.428, and 0.651 in HB and HC, respectively. To the best of our knowledge, this is the first study that comprehensively assessed the health state utilities of patients with HB, HC and hepatitis-related conditions from a nationwide survey in Japan using the EQ-5D-5L. [ABSTRACT FROM AUTHOR]

Background: The mechanism of copper-induced cell death, which is called cuproptosis, has recently been clarified. However, the integrated role of cuproptosis-related genes in hepatocellular carcinoma (HCC) and its relationship with immune characteristics are still completely unknown. Methods: In this study, the expression, genetic, and transcriptional regulation states of 16 cuproptosis-related genes in HCC were systematically investigated. An unsupervised clustering method was used to identify distinct expression patterns in 370 HCC patients from the TCGA-HCC cohort. Differences in functional characteristics among different expression clusters were clarified by gene set variation analysis (GSVA). The abundances of immune cells in each HCC sample were calculated by the CIBERSORT algorithm. Next, a cuproptosis-related risk score was established based on the significant differentially expressed genes (DEGs) among different expression clusters. Results: A specific cluster of HCC patients with poor prognosis, an inhibitory immune microenvironment, and high expression levels of immune checkpoint molecules was identified based on the expression of the 16 cuproptosis-related genes. This cluster of patients could be well-identified by a cuproptosis-related risk score system. The prognostic value of this risk score was validated in the training and two validation cohorts (TCGA-HCC, China-HCC, and Japan-HCC cohorts). Moreover, the overall expression status of the cuproptosis-related genes and the genes used to establish the cuproptosis-related risk score in specific cell types of the tumor microenvironment were preliminarily clarified by single-cell RNA (scRNA) sequencing data. Conclusion: These results indicated that cuproptosis-related genes play an important role in HCC, and targeting these genes may ameliorate the inhibitory immune microenvironment to improve the efficacy of immunotherapy with immune checkpoint inhibitors (ICIs). [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the leading causes of cancer-related death both in Japan and globally. In the advanced stage, hepatic arterial infusion chemotherapy (HAIC) is one of the most commonly used treatment options for liver cancer in Japan, and implantation of a catheter system (called a port system) in the body is a treatment method that has evolved mainly in Japan. The Guideline Committee of the Japanese Society of Interventional Radiology and the Japanese Society of Implantable Port Assisted Treatment jointly published clinical practice guidelines for HAIC with a port system to ensure its appropriate and safe performance in Japanese in 2018. We have written an updated English version of the guidelines with the aim of making this treatment widely known to experts globally. In this article, the evidence, method, indication, treatment regimen, and maintenance of the system are summarized. [ABSTRACT FROM AUTHOR]

Summary: Background: While surveillance improves the early detection of hepatocellular carcinoma (HCC), it is unclear whether this has improved prognosis in clinical practice. Aims: To investigate the characteristics and prognoses of patients with viral versus non‐viral HCC over the previous two decades in Japan, while HCC surveillance has been active. Methods: This multi‐centre study enrolled 6007 patients initially diagnosed with HCC between 2000 and 2020 at seven high‐volume academic centres. Patients were categorised based on dates of diagnosis: 2000–2006, 2007–2013 and 2014–2020. HCC characteristics and post‐diagnosis survival rates were compared between periods in patients with viral and non‐viral HCC. Results: The percentage of patients with non‐viral HCC increased during the study period. The maximal tumour size and percentage of patients with multinodular HCC decreased significantly over time in the viral HCC group but remained unchanged in the non‐viral HCC group. Liver function at diagnosis improved over time in both groups, but to a greater extent in the viral HCC group. Survival rates increased significantly with time in the viral HCC group, but not in the non‐viral HCC group. Conclusions: The prevalence of non‐viral HCC is increasing. Although the survival of patients with viral HCC improved significantly over the past two decades, there was no improvement in patients with non‐viral HCC. This was presumably due mainly to lower surveillance among patients with non‐viral HCC and failure to diagnose early‐stage HCC. [ABSTRACT FROM AUTHOR]

Since the approval of sorafenib for the treatment of unresectable hepatocellular carcinoma in 2007 (in 2009 in Japan), five more regimens have been approved: lenvatinib, and atezolizumab plus bevacizumab for first-line treatment, and regorafenib, cabozantinib, and ramucirumab for second-line treatment, which are currently available for clinical use. The positive results of durvalumab, a programmed cell death ligand 1 antibody, plus tremelimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, were also presented at the 2022 American Society Clinical Oncology Gastrointestinal Cancers Symposium as superior to sorafenib in prolonging the overall survival; this combination is expected to be approved by the end of 2022. These systemic therapies are changing the treatment paradigm not only for advanced hepatocellular carcinoma but also for intermediate-stage hepatocellular carcinoma. This review focuses on the role of systemic therapy in intermediate-stage hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Ramucirumab has been shown to be effective as a second-line agent after sorafenib in hepatocellular carcinoma (HCC) patients whose α-fetoprotein was ≥400 ng/mL. We performed a retrospective cohort study to investigate ramucirumab efficacy in a real-world setting. Progression-free survival (PFS) was consistent through treatment lines, modified albumin–bilirubin (mALBI) grade, Barcelona Clinic for Liver Cancer (BCLC) stage, and α-fetoprotein (AFP) level. By contrast, ascites was more frequently seen in mALBI 2b/3 patients and, therefore, should be carefully monitored. Background: The present study aimed to clarify the efficacy and safety of ramucirumab in a real-world setting, including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. Methods: In total, 79 patients with hepatocellular carcinoma (HCC) from 14 institutes throughout Japan were retrospectively analyzed. The response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and AEs were recorded according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. Results: Median overall survival (OS) in the total cohort was 7.5 months (m). Median OS was 8.8 m in patients who were administered ramucirumab as a second-line treatment, while it was 7.3 m in third- or later-line treatment. Progression-free survival rates in the second- and third- or later-line therapies were 3.2 m and 3.2 m, respectively. The disease control rate (DCR) in the study was 43%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events (AEs), the development of ascites was observed significantly more frequently in modified albumin–bilirubin (mALBI) 2b/3 patients than in mALBI 1/2a patients (54.5% vs. 25.0%, p = 0.03). Conclusions: Ramucirumab is useful as a second-line therapy and feasible as a third- or later-line treatment for HCC. [ABSTRACT FROM AUTHOR]

Background and Aim: The development of hepatocarcinogenesis after a sustained virological response (SVR) remains an important issue affecting the balance between treatment and occupational life of workers with chronic hepatitis C virus (HCV) infection in Japan. Here, we aimed to evaluate the hepatocellular carcinoma (HCC) reducing effect and risk factors for developing HCC after SVR in patients treated with direct‐acting antiviral agents (DAAs) among the working population. Methods: We studied 2579 working patients with chronic HCV infection who achieved SVR after antiviral treatment. We compared the difference in the cumulative incidence of post‐SVR HCC between the interferon (IFN)‐based n = 1615 and DAA (n = 964) groups. The risk factors for post‐SVR HCC development were determined in the DAA group. Results: After propensity score matching (n = 644 in each group), the HCC development rates were not significantly different between the groups (P = 0.186). Multivariate Cox regression and the cutoff values determined by the receiver operating characteristic curve analyses revealed that age ≥61 years, diabetes, lower serum albumin levels <4.0 g/dL at 24 weeks after the end of treatment (EOT), and higher serum α‐fetoprotein levels ≥4.1 ng/mL at 24 weeks after the EOT were associated with the development of HCC. Conclusion: The HCC suppressing effect after SVR through DAA treatment is equivalent to that of IFN treatment in patients in the working population. Intensive follow‐up is required after SVR with DAA treatment in Japanese workers with these risk factors to ensure the promotion of health and employment support. [ABSTRACT FROM AUTHOR]

Patients with a chronic hepatitis B virus (HBV) infection who are treated with nucleos(t)ide analogues (NAs) are still at risk for hepatocellular carcinoma (HCC), and it has been clinically questioned whether patients with a high risk of HCC can be identified efficiently. We aimed to clarify the risk factors associated with the development of HCC during NA therapies. A total of 611 chronically HBV-infected patients without a history of HCC, who were treated with NAs for more than 6 months (median 72 months), from 2000 to 2021, were included from 16 hospitals in the Tohoku district in Japan. Incidences of HCC occurrence were analyzed with clinical factors, including on-treatment responses. Alanine aminotransferase (ALT) normalization, based on the criteria of three guidelines, was analyzed with other parameters, including the age–male–ALBI–platelets (aMAP) risk score. During the observation period, 48 patients developed HCC, and the cumulative HCC incidence was 10.6% at 10 years. Non-achievement of ALT normalization at 1 year of therapy was mostly associated with HCC development when ALT ≤ 30 U/L was used as the cut-off (cumulative incidence, 19.9% vs. 5.3% at 10 years, p < 0.001). The effectiveness of the aMAP risk score at the start of treatment was validated in this cohort. A combination of an aMAP risk score ≥ 50 and non-achievement of ALT normalization could stratify the risk of HCC significantly, and notably, there was no HCC development in 103 patients without these 2 factors. In conclusion, non-achievement of ALT normalization (≤30 U/L) at 1 year might be useful in predicting HCC during NA therapies and, in combination with the aMAP risk score, could stratify the risk more precisely. [ABSTRACT FROM AUTHOR]

Aim: To compare the total medical costs and treatment outcomes in patients with primary hepatocellular carcinoma (HCC) according to their initial treatment, that is, hepatectomy or radiofrequency ablation (RFA), in real‐world clinical practice in Japan. Methods: This retrospective observational study was conducted using a medical claims database. Patients who underwent hepatectomy or RFA for primary HCC were matched using propensity score matching methods for available baseline characteristics. The average per‐patient total medical costs from the date of initial treatment to up to 3 years were estimated. The 3‐year survival and recurrence rates were estimated using the Kaplan‐Meier method. Results: Data of 1726 patients (863 in each group) were analyzed. The average 3‐year medical costs were USD 8000 lower in the RFA group than in the hepatectomy group (USD 35,000 vs. USD 43,000). Patients in the RFA group had comparable 3‐year overall survival to those in the hepatectomy group (87.6% vs. 90.4%). However, the 3‐year recurrence rate was significantly higher in the RFA group than in the hepatectomy group (41.5% vs. 30.8%; hazard ratio = 1.56, 95% confidence interval: 1.31–1.87). Conclusions: In this 3‐year study, patients achieved similar survival rates irrespective of initial treatment, but the RFA group had a lower total medical cost burden than the hepatectomy group. If both treatments are equally feasible, RFA may be a preferable initial curative treatment for primary HCC. However, careful consideration and adequate treatment should be given due to its higher recurrence risk. [ABSTRACT FROM AUTHOR]

Aim: The present study focused on the association of early bevacizumab (Bev) interruption with the clinical outcome of atezolizumab plus bevacizumab. Methods: This retrospective study included 239 patients with advanced hepatocellular carcinoma receiving atezolizumab/Bev from September 2020 to June 2021 at 16 different institutions in Japan. We conducted a 9‐week landmark analysis to investigate the association of Bev interruption due to adverse events with the therapeutic efficacy. Results: The median age was 73.0 (68.0–80.0) years old, with 195 (81.6%) men. The objective response rate was significantly higher in patients without Bev interruption than in those with it (34.5% vs. 17.3%, p = 0.038). The median progression‐free survival (PFS) was 6.5 months (95% confidence interval [CI] 4.5–9.7) and 9.0 months (95% CI 7.1–not applicable) in patients with and without Bev interruption, respectively, with statistical significance (p = 0.021). The 12‐month overall survival (OS) rates in patients with and without Bev interruption were 49.4% (CI 27.7%–67.9%) and 82.2% (95% CI 70.3%–89.6%), respectively, showing a significant difference (p = 0.004). The presence of Bev interruption was a significant factor associated with the PFS (p = 0.021) and OS (p = 0.008). A multivariate analysis showed that modified albumin–bilirubin 2b (p < 0.001) and later‐line treatment (p = 0.018) were unfavorable factors associated with Bev interruption. Liver injury, appetite loss, protein urea, and ascites or hepatic edema were more frequently found in patients with Bev interruption than in those without it. Conclusions: Early Bev interruption was an unfavorable factor associated with the PFS and OS. Good liver function and treatment settings may be associated with maintaining Bev treatment. [ABSTRACT FROM AUTHOR]