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This retrospective study aimed to evaluate the impact of atezolizumab plus bevacizumab-transcatheter arterial chemoembolization (TACE) sequential therapy in unresectable hepatocellular carcinoma (HCC), especially in patients with intermediate-stage HCC. A total of 212 patients were enrolled and categorized into the Atez/Bev-TACE sequential therapy ( n = 23) or Atez/Bev monotherapy group ( n = 189) between 2020 and 2024. Of these, patients with intermediate-stage HCC were categorized into the Atez/Bev-TACE sequential ( n = 18) or Atez/Bev monotherapy group ( n = 91). The best objective response rate, disease control rate, and median progression-free survival (PFS) after TACE were 73.9%, 82.6%, and 6.1 months, respectively. The PFS after TACE was significantly higher in the Atez/Bev sequential therapy group than in the no-Atez/Bev-administration group after TACE (6.9 months vs. 5.0 months, p = 0.025). The median overall survival (OS) was significantly higher in the Atez/Bev-TACE sequential therapy group than in the Atez/Bev monotherapy group for intermediate-stage HCC (34.9 months vs. 17.8 months; p = 0.016). Independent factors associated with OS were low alpha-fetoprotein levels, modified albumin-bilirubin 1 or 2a levels, and Atez/Bev-TACE sequential therapy. Atez/Bev-TACE sequential therapy improved prognosis compared with Atez/Bev monotherapy in patients with intermediate-stage HCC. Moreover, Atez/Bev should be readministered after TACE.

Introduction: Atezolizumab (ATZ) and bevacizumab (BEV) combination therapy is widely used in patients with unresectable hepatocellular carcinoma (HCC). However, combination therapy is typically interrupted or discontinued owing to BEV-related adverse events. In this study, we examined the effects of BEV dose-reduction on the treatment of unresectable HCC using propensity score matching (PSM)., Method: Overall, 119 patients with HCC who were treated with ATZ + BEV between November 2020 and October 2022 were enrolled retrospectively at our institute. The therapeutic effects and safety of BEV dose-reduction and non-dose reduction after PSM were compared. Decision-tree analysis was used to investigate treatment duration in the patients., Results: Significant differences were not observed between the two groups after PSM. The objective response rate (ORR) and disease control rate (DCR) assessed by modified RECIST did not differ significantly between the two groups (BEV non-dose-reduction/dose-reduction: ORR; 46/34%, DCR; 80/91%). Progression-free survival (PFS) and overall survival (OS) also did not differ significantly between the two groups (BEV non-dose-reduction/dose-reduction: PFS; 5.6/8.6 months, OS; 18.6/15.5 months). The median duration of treatment in the BEV dose-reduction group was significantly longer than that in the non-dose-reduction group (BEV non-dose-reduction/dose-reduction: 4.8/9.1 months, p = 0.038). Decision-tree analysis revealed that dose-reduction of BEV was the first distinguish factor for the extension of treatment duration with ATZ + BEV., Conclusion: BEV dose-reduction can be effectively used in maintaining the treatment duration of ATZ + BEV while maintaining therapeutic effects and safety in real-world clinical practice., (© 2024 S. Karger AG, Basel.)

Aim: This study aimed to establish the shear wave measurement (SWM) cut-off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard., Methods: We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61 kPa), F1 (≥2.61 kPa, <2.97 kPa, any fibrosis), F2 (≥2.97 kPa, <3.62 kPa, significant fibrosis), F3 (≥3.62 kPa, <4.62 kPa, advanced fibrosis), or F4 (≥4.62 kPa, cirrhosis)., Results: The median SWM values increased significantly with increasing fibrosis stage (p < 0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761-0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin-capsular distance; skin-capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut-off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89 kPa, respectively., Conclusions: This multicenter study in a large number of patients established SWM cut-off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut-off values will be applied to liver diseases in the future., (© 2024 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Ultrasonography is a noninvasive and widely accessible modality in clinical practice. Recently, ultrasonography has been used to evaluate tissue stiffness; the two representative techniques are transient elastography (FibroScan ® ) and shear wave elastography. These modalities are now generally used for the assessment of liver fibrosis, the prediction of hepatocarcinogenesis, and determining prognosis. In addition, shear wave elastography is available, not only for the liver but also for various other organs, including the breast and brain. In the breast and brain, shear wave elastography distinguishes malignant lesions from benign ones. Moreover, shear wave elastography can be useful for differentiating between ischemic and hemorrhagic strokes. This review summarizes the recent progress in transient elastography and shear wave elastography of the liver and introduces the advantages of ultrasonographic assessment of tissue stiffness in various organs, including the breast, brain, kidney, heart, thyroid, pancreas, muscle, and bone.

Background: Several preliminary reports have suggested the utility of ultrasound attenuation coefficient measurements based on B-mode ultrasound, such as iATT, for diagnosing steatotic liver disease. Nonetheless, evidence supporting such utility is lacking. This prospective study aimed to investigate whether iATT is highly concordant with magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF) and could well distinguish between steatosis grades., Methods: A cohort of 846 individuals underwent both iATT and MRI-PDFF assessments. Steatosis grade was defined as grade 0 with MRI-PDFF < 5.2%, grade 1 with 5.2% MRI-PDFF < 11.3%, grade 2 with 11.3% MRI-PDFF < 17.1%, and grade 3 with MRI-PDFF of 17.1%. The reproducibility of iATT and MRI-PDFF was evaluated using the Bland-Altman analysis and intraclass correlation coefficients, whereas the diagnostic performance of each steatosis grade was examined using receiver operating characteristic analysis., Results: The Bland-Altman analysis indicated excellent reproducibility with minimal fixed bias between iATT and MRI-PDFF. The area under the curve for distinguishing steatosis grades 1, 2, and 3 were 0.887, 0.882, and 0.867, respectively. A skin-to-capsula distance of ≥ 25 mm was identified as the only significant factor causing the discrepancy. No interaction between MRI-logPDFF and MRE-LSM on iATT values was observed., Conclusions: Compared to MRI-PDFF, iATT showed excellent diagnostic accuracy in grading steatosis. iATT could be used as a diagnostic tool instead of MRI in clinical practice and trials. Trial registration This study was registered in the UMIN Clinical Trials Registry (UMIN000047411)., (© 2024. The Author(s).)

This study aimed to evaluate the effect of lenvatinib (LEN) combined with transcatheter intra-arterial therapy (TIT) for advanced-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 115 patients with advanced-stage HCC who received LEN treatment. The patients were categorized into the LEN combined with TIT group ( n = 30) or the LEN monotherapy group ( n = 85). After PSM, 38 patients (LEN + TIT group, n = 19; LEN monotherapy group, n = 19) were analyzed. The median overall survival (OS) in the LEN + TIT group was significantly higher than that in the LEN monotherapy group (median survival time (MST): 28.1 months vs. 11.6 months, p = 0.014). The OS in the LEN combined with transcatheter arterial chemoembolization and LEN combined with hepatic arterial infusion chemotherapy groups was significantly higher than that in the LEN monotherapy group (MST 20.0 vs. 11.6 months, 30.2 vs. 11.6 months, p = 0.048, and p = 0.029, respectively). Independent factors associated with OS were alpha-fetoprotein and LEN combined with TIT. The indications for LEN combined with TIT were age <75 years and modified albumin bilirubin (m-ALBI) grade 1. We concluded that LEN combined with TIT may improve prognosis compared with LEN monotherapy in patients with advanced-stage HCC.

Background and Aim: This study aimed to investigate whether telephone follow-up by clinical pharmacists for unresectable hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN) contributes to improved adherence and treatment duration for LEN., Methods: This retrospective study enrolled 132 patients with HCC who were treated with LEN. The patients were classified into non-telephone follow-up (n = 32) or telephone follow-up groups (n = 100) [the latter group was further classified into family-pharmacist (FP) telephone follow-up (n = 18), or hospital family-pharmacist (HFP) telephone follow-up (n = 82) groups]., Results: The progression-free survival (PFS) in the telephone follow-up group was significantly higher than that in the non-telephone follow-up group (PFS 6.1 months vs 3.7 months, P = 0.001, respectively). Although treatment duration was significantly longer in the telephone follow-up group than in the non-telephone follow-up group [median treatment duration: 10.4 months vs 4.1 months, P = 0.001, respectively.], no significant differences were noted between the HFP telephone follow-up group and FP telephone follow-up groups (10.3 months vs 13.3 months, P = 0.543). Self-interruption and adverse-event discontinuation in the HFP-telephone follow-up group were significantly lower than those in the FP-telephone and non-telephone groups (0% vs 11.1% vs 18.8%; P < 0.001, 25.6% vs 33.3% vs 53.1%; P = 0.022, respectively)., Conclusions: Telephone follow-up contributes to prolonged treatment duration for LEN in patients with HCC treated. Moreover, telephone follow-up with an HFP may further improve treatment adherence., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: We aimed to validate the predictive factors for tumor response and the prognostic impact of conversion therapy aimed at cancer- and drug-free states in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing atezolizumab plus bevacizumab (Atez/Bev) therapy., Methods: This retrospective study enrolled 156 patients who were Child-Pugh class A with u-HCC treated using Atez/Beva. The profile of objective response was investigated using decision-tree analysis. Progression-free, recurrence-free, and overall survival were assessed., Results: The progression-free and overall survival were 6.1 and 18.0 months, respectively. Objective response and disease control rates were 32.0% and 84.0%, respectively. Decision-tree analysis revealed that neutrophil-to-lymphocyte ratio (NLR) <3, modified albumin-bilirubin grade (m-ALBI) 1 or 2a, and age < 75 were sequential splitting variables for the objective response, respectively. In the multivariate analysis, NLR <3 and m-ALBI grade 1 or 2a were identified as predictive factors for objective response. We successfully achieved eligibility for conversion therapy in 17 patients after Atez/Bev therapy significant response. Following conversion therapy, the curative therapy group, including surgical resection or radiofrequency ablation (RFA), had significantly higher recurrence-free survival than did the transcatheter arterial chemoembolization (TACE) and Atez/Bev discontinuation (surgical resection or RFA; not reached vs. TACE; 5.3 months, p = 0.008, Atez/Bev discontinuation; 3.9 months, p = 0.048, respectively) groups., Conclusions: NLR <3 and m-ALBI grade 1 or 2a were predictive factors for conversion therapy, leading to cancer- and drug-free states in patients with u-HCC undergoing Atez/Bev therapy. Moreover, surgery or RFA may be suitable for conversion therapy for cancer-free status., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC., Methods: We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed., Results: In the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5β1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment., Conclusions: Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors., (© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Aim: Few studies have reported the efficacy and safety of ramucirumab (RAM) after atezolizumab plus bevacizumab (Atezo/Beva) treatment and the overall associated outcomes. Thus, we aimed to evaluate the therapeutic effects and safety of RAM post-treatment with Atezo/Beva., Methods: This retrospective study enrolled 46 patients with unresectable hepatocellular carcinoma who were treated with RAM. The patients were classified into the RAM administered following Atezo/Beva failure (n = 12) or RAM administered following other drug failure (n = 34) groups. Progression-free survival (PFS), overall survival (OS), and adverse event (AE) rates were assessed., Results: There were significant differences in the objective response rates and disease control rates between the RAM administered following Atezo/Beva and RAM administered following others groups (objective response rate 33.3%. vs. 0.0%, p = 0.001; disease control rate 83.3% vs. 32.3, p = 0.001). Although there was no significant difference in the OS rates, the median PFS rates in the RAM administered following Atezo/Beva group was significantly higher than in the RAM administered following others group (PFS 3.9 months. vs. 1.9 months, p = 0.047). The AE rates were comparable between the two groups; ascites was the most common AE (45.6%). Using decision tree analysis, the presence of splenomegaly and body mass index (BMI) < 19.8 were the first and second splitting variables for RAM-related ascites, respectively., Conclusions: The therapeutic effect of RAM increased in patients with Atezo/Beva failure. Patients with splenomegaly and low BMI should be monitored for ascites during RAM treatment., (© 2022 Japan Society of Hepatology.)

Aim: Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib., Methods: We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n = 155) and non-MAFLD (n = 165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n = 115) or viral HCC (n = 205)., Results: The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1 months, p = 0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p = 0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1 months, p = 0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P < 0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC., Conclusions: MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD., (© 2022 Japan Society of Hepatology.)

This study aimed to investigate the clinical characteristics of patients with unresectable hepatocellular carcinoma (HCC), who were eligible for sequential systemic therapy. We evaluated 365 patients with HCC who underwent systemic therapy after 2017. The overall survival (OS) was 13.7 months, 19.2 months, and 35.6 months in the first-line, second-line, and third-line or later therapy groups, respectively. Multivariate analysis revealed that the modified-albumin-bilirubin (m-ALBI) grade, macrovascular invasion, extrahepatic spread, discontinuation due to adverse events (AEs), and sequential therapy were independent factors for OS. At the end of each therapy, the ALBI score was significantly worse among patients with discontinuation due to AEs than among those without. The conversion rate to second-line and third-line therapy among patients with discontinuation due to AEs was significantly lower than that among patients without (30.4% vs. 69.2%, p < 0.001; 6.7% vs. 58.3%; p < 0.001, respectively). In the decision tree analysis, m-ALBI grade 1 or 2a and non-advanced age were selected splitting variables, respectively, for sequential systemic therapy. In conclusion, sequential therapy prolonged the OS of unresectable HCC. Additionally, good hepatic function and non-advanced age were clinically eligible characteristics for sequential systemic therapy., (© 2022. The Author(s).)

This study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab (atezo/beva). This was a multicenter study in which 130 patients were enrolled. Hypertension and skin disorders had a significant correlation with longer survival (median survival time (MST): not reached vs. 14.3 months and not reached vs. 14.8 months, p = 0.001 and p = 0.047, respectively). In contrast, liver injuries were significantly correlated with shorter survival (MST: 14.7 months vs. not reached, p = 0.036), and the median development time was 21 days. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin-bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. The OS in the no discontinuation due to AE group was significantly longer than that in the discontinuation due to AEs group (MST not reached vs. 11.2 months, p = 0.001). We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.

In 2013 and 2014, the development of microcatheters with balloons for the 4-Fr system and new embolization materials provided various options for transarterial chemoembolization (TACE), expanding the range of treatment strategies. At our hospital, balloon-occluded TACE (B-TACE), conventional TACE (C-TACE), and drug-eluting bead TACE (DEB-TACE) have been actively performed for hepatocellular carcinoma (HCC). This study compared the local recurrence-free (LRF) periods of nodules with complete necrosis (TE4) obtained using each treatment method by extracting the nodules evaluated as complete response by the modified Response Evaluation Criteria in Solid Tumors. We performed 580 TACE procedures between June 2013 and April 2019. Among them, 58 HCC nodules in 43 patients, 33 nodules in 30 patients, and 45 nodules in 25 patients were evaluated as having complete necrosis after C-TACE, DEB-TACE, and B-TACE, respectively. The time to local recurrence for each nodule was defined as the LRF period, and the quality of TE4 for each TACE was examined. Factors related to overall survival and the LRF period were determined by univariate and multivariate analyses, and overall survival and the LRF period were analyzed using the Kaplan-Meier method. Multivariate analysis of the LRF period showed that B-TACE was an independent factor. The median LRF periods were 39.3, 13, and 9.1 months for B-TACE, C-TACE, and DEB-TACE, respectively. Moreover, B-TACE had a significantly longer LRF period than C-TACE and DEB-TACE. Conclusion: There was no significant difference between C-TACE and DEB-TACE. The LRF period of nodules with TE4 was the longest with B-TACE, suggesting that B-TACE should be used to achieve a radical cure in patients with HCC., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Invasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure., Aim: As there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external-beam radiation therapy (EBRT)., Methods and Results: The "New FP" was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin-Lipiodol suspension combined with continuous infusion of 5-fluorouracil (5-FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors-based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months)., Conclusion: The combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular-targeted drugs may prolong survival in such patients., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Recently, a combined regimen of atezolizumab and bevacizumab (AB) treatment has been approved as a first-line treatment in patients with advanced hepatocellular carcinoma (HCC), contributing to prolonged survival. However, we often encounter cases where treatment must be discontinued due to the occurrence of adverse events. One of these events, which is often fatal, is gastrointestinal bleeding. To clarify the clinical effects of gastrointestinal bleeding after AB treatment, we evaluated patients with HCC who were treated with AB at our institution. Of the 105 patients, five treated with AB developed gastrointestinal bleeding, necessitating treatment discontinuation. Additionally, we encountered two cases where exacerbation of varicose veins was observed, and AB therapy could be continued by preventive treatment of varices. In conclusion, an appropriate follow-up is required during treatment with AB to prevent possible exacerbation of varicose veins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor TK declared a shared Research Group Japanese Society of Hepatology with the author(s) at the time of review., (Copyright © 2022 Suzuki, Iwamoto, Shimose, Niizeki, Shirono, Noda, Kamachi, Yamaguchi, Nakano, Kuromatsu, Koga and Kawaguchi.)

Background and Aims: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) progresses with a highly multicentric occurrence (MO) even after radical hepatectomy. Despite several efforts to clarify the pathogenesis of MO, the underlying molecular mechanism remains elusive. The aim of this study was to evaluate alterations in DNA methylation in noncancerous liver tissues in the MO of HCC., Methods: A total of 203 patients with HCV-related HCC who underwent radical hepatectomy at our hospital between January 2008 and January 2012 were recruited. We defined a group of nonearly recurrence of HCC (NR) for ≥3 years after radical hepatectomy and a group of early recurrence of HCC (ER) with MO within 2 years after radical hepatectomy., Results: Three patients each were selected in the NR and ER groups in the first set, and 13 patients in the NR group and 17 patients in the ER group were selected in the second set. Genome-wide DNA methylation profiles were obtained from noncancerous liver tissues using a Human Methylation 450 BeadChip, and the differences between the groups were analyzed for each set. After excluding single nucleotide polymorphism-associated methylation sites and low-call sites, 401,282 sites were assessed using a generalized linear model without any adjustments. Nine gene regions, APBB1P , CLSTN3 , DLG5 , IRX5 , OAS1 , SOX12 , SNX19 , TENM2 , and TRIM54 , exhibiting a significant difference ( P < .001) in DNA methylation levels were identified in the common direction between the 2 analysis sets., Conclusion: Alterations in DNA methylation of 9 genes in noncancerous liver tissues appear to be involved in MO after radical hepatectomy for HCV-related HCC., (© 2022 The Authors.)

It remains unclear whether hepatocellular carcinoma (HCC) recurrence in hepatitis C virus (HCV)-infected patients can be suppressed by the elimination of the virus using direct-acting antivirals (DAAs) after radical HCC treatment. We evaluated the sustained inhibitory effect of DAAs on HCC recurrence after curative treatment. This multicenter retrospective study included 190 HCV-positive patients after radical treatment for early-stage HCC. Patients were classified into the DAA treatment group (n = 70) and the non-DAA treatment group (n = 120) after HCC treatment. After propensity score matching (PSM), 112 patients were assessed for first and second recurrences using the Kaplan-Meier method and analyzed using a log-rank test. The first recurrence rates at 1 and 3 years were 3.6% and 42.1% in the DAA treatment group and 21.7% and 61.9% in the non-DAA treatment group, respectively ( p = 0.0026). Among 85 patients who received radical treatment, the second recurrence rate at 3 years was 2.2% in the DAA treatment group and 33.9% in the non-DAA treatment group ( p = 0.0128). In HCV-positive patients with early-stage HCC, the first and second recurrences were suppressed by DAA therapy after radical treatment, suggesting that the inhibitory effect of DAA therapy on HCC recurrence was sustained.

Fontan-associated liver disease (FALD) caused by long-term systemic venous congestion following the Fontan procedure may eventually lead to hepatocellular carcinoma (HCC). Treatment strategies for HCC due to FALD (FALD-HCC) remain unclear. We herein report a 35-year-old man with FALD-HCC that was well controlled by 3 cycles of continuous infusion of 5-fluorouracil and low-dose cisplatin (low-dose FP therapy) combined with 60 Gy of radiation therapy. However, the patient ultimately died of extrahepatic metastases. A pathological autopsy revealed more than 90% necrosis in the primary HCC lesion. This case suggests that low-dose FP therapy might be effective in FALD-HCC.

Background: The antitumor effect of a drug is considered to be associated with a decrease in tumor blood flow., Aims: We investigated whether the efficacy of lenvatinib (LEN) could be accurately assessed by measuring blood flow in hepatocellular carcinoma (HCC) during early treatment stages., Methods and Results: Blood flow changes and treatment results of 19 patients who underwent contrast-enhanced ultrasound (CEUS), before and after LEN administration, in Kurume University Hospital from July 2018 to June 2020 were examined. Blood flow was evaluated after the intravenous administration of perflubutane (0.015 ml/kg). The vascular phase was photographed and used as RAW data, and time-intensity curve analysis was used to obtain the region of interest (ROI) on the entire tumor nodule and quantify tumor blood flow. The evaluation was performed before and 1 and 4 weeks after LEN administration. Mean ± standard deviation (SD) values of the brightness of blood flow in the background liver before and 1 and 4 weeks after LEN administration were 2.84 × 10 -4 ± 2.94 × 10 -4 , 3.07 × 10 -4 ± 3.79 × 10 -4 , and 10.0 × 10 -4 ± 20.8 × 10 -4 dB, respectively. Blood flow in the background liver did not significantly decrease at 1 and 4 weeks compared with that before treatment. Mean ± SD values of the brightness of blood flow in HCC before and 1 and 4 weeks after administration were 3.49 × 10 -3 ± 4.58 × 10 -3 , 1.16 × 10 -3 ± 1.57 × 10 -3 , and 6.39 × 10 -3 ± 22.8 × 10 -3 dB, respectively. Blood flow in HCC after 1 week was significantly lower than that before administration (p = .0192). The therapeutic effects were significantly higher in the group with ≥50% blood flow reduction in HCC at 1 week after administration (p = .0038) and the group with reduced blood flow in HCC at 4 weeks after administration (p = .0051) than those before administration., Conclusion: Early blood flow evaluation by CEUS may be useful in predicting the therapeutic effect of LEN for unresectable advanced HCC., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

The aim of the present study was to investigate whether the degree of contrast enhancement on contrast-enhanced (CE)-CT can predict the prognosis of patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN). A total of 67 consecutive patients with LEN-treated HCC were retrospectively analysed. In the pretreatment CE-CT, the CT values were measured using a region of interest within the main nodule and the liver parenchyma in the arterial phase, and the macroscopic degree of contrast enhancement of the tumour area was quantified by calculating the enhancement ratio (ER) of the liver parenchyma. The associations of pretreatment ER with progression-free survival (PFS) and overall survival (OS) were then investigated. There were 20, 27 and 20 patients in the ER ≥1.5, 1.0≤ ER <1.5 and ER <1.0 groups, respectively. There was no significant difference in the PFS and OS among the three ER groups (PFS, P=0.63; OS, P=0.455). The ER <1.0 group had significantly more patients with larger tumour diameters, Barcelona Clinic Liver Cancer (BCLC) stage C with extrahepatic metastases, and higher des-γ-carboxy prothrombin values compared with the ER ≥1.0 group, suggesting that ER <1.0 reflected more aggressive types of HCC. The multivariate analysis revealed tumour size and α-fetoprotein as independent predictors of shorter PFS. Albumin-bilirubin grade 2 and BCLC stage C were significant predictors of poor OS, whereas the ER was confirmed as a non-significant predictor of both PFS and OS. Only non-alternating LEN and transarterial therapy (AT) were identified as independent predictors of unfavourable OS in patients with BCLC stage B HCC. Therefore, LEN has a strong therapeutic effect on HCC, regardless of the degree of contrast enhancement. Furthermore, AT may prolong the OS of LEN-treated patients with BCLC stage B HCC, regardless of tumour vascularity., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Okamura et al.)

Objective: Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To explore the potential for augmenting its antitumor effect, we assessed the preclinical and clinical efficacy and tolerability of S-1 metronomic chemotherapy (MC) plus sorafenib., Methods: Antitumor effects and toxicity of this combination were tested with HAK-1B xenograft and spontaneous HCC mouse models, and a prospective pilot study was performed to compare therapeutic effects and safety between sorafenib plus MC S-1 for 12 advanced HCC cases and the historical control of 363 sorafenib-treated advanced HCC patients at our hospital from July 2011 to June 2015., Results: In mice, the combination chemotherapy enhanced anti-angiogenic effects, resulting in a stronger tumor hypoxic environment and increased tumor cell apoptosis. Clinically, the objective response rate of the combination chemotherapy was higher than that of sorafenib mono therapy (16.7%; 2/12 vs 5.2%; 19/363, p < 0.05); however, there were no significant differences in overall survival and time to progression. Adverse events including alopecia, thrombocytopenia, and pancreatic enzymes elevation in the combination chemotherapy were higher than those of sorafenib. No patient treated with the combination chemotherapy discontinued treatment due to severe adverse events., Conclusions: Sorafenib plus MC S-1 seems to be effective and tolerable for patients with advanced HCC and could be considered a treatment option for these patients., (Copyright © 2021. Published by Elsevier Inc.)

Given that the outcome of hepatic arterial infusion chemotherapy (HAIC) with cisplatin for intrahepatic advanced hepatocellular carcinoma (HCC) is unclear, we aimed to compare prognostic factors for overall survival (OS) following HAIC with cisplatin versus sorafenib for intrahepatic advanced HCC using propensity score-matched analysis. We enrolled 331 patients with intrahepatic advanced HCC who received HAIC with cisplatin (n = 88) or sorafenib (n = 243) between June 2006 and March 2020. No significant difference was observed in OS between HAIC with cisplatin and sorafenib cohorts (median survival time [MST]: 14.0 vs. 12.3 months; p = 0.0721). To reduce confounding effects, 166 patients were selected using propensity score-matched analysis (n = 83 for each treatment). HAIC with cisplatin significantly prolonged OS compared with sorafenib (MST: 15.6 vs. 11.0 months; p = 0.0157). Following stratification according to the Child-Pugh classification, for patients with class A (MST: 24.0 vs. 15.0 months; p = 0.0145), HAIC with cisplatin rather than sorafenib significantly prolonged OS. Our findings suggest that HAIC with cisplatin demonstrates longer prognostic effects than sorafenib in intrahepatic advanced HCC.

Macroscopic vascular invasion (MVI) is a poor prognostic factor in hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) is a promising treatment in MVI-HCC. However, it is not clear which regimens are suitable for HAIC. In this study, we aimed to compare the therapeutic effects between New FP (a fine-powder cisplatin suspended with lipiodol plus 5-fluorouracil) and low dose FP (LFP/cisplatin plus 5-fluorouracil) in the treatment of MVI-HCC patients with Child-Pugh class A. New FP is a regimen that consists of a fine-powder cisplatin suspended with lipiodol and 5-fluorouracil. Fifty-one patients were treated with LFP, and 99 patients were New FP. We compared the therapeutic effects of LFP and New FP and assessed factors that associated with the therapeutic effects. The median survival and progression-free survival times of LFP and New FP were 16.1/24.7 and 5.4/8.8 months, respectively ( p < 0.05, p < 0.05). The complete response (29%) and objective response rate (76%) of New FP were significantly higher than those of LFP ( p < 0.001, p < 0.01). Factors associated with better therapeutic response were better ALBI-grade and New FP treatment choice. New FP is a more powerful regimen than LFP in HAIC for MVI-HCC. New FP represents a recommended HAIC regimen for the treatment of patients with MVI-HCC.

Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status., Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0., Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC., Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC., Lay Summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population., Clinical Trial Number: NCT01658878., Competing Interests: Conflict of interest MK reports receiving personal fees from Bristol Myers Squibb, Bayer, Eisai, MSD, and Ono Pharmaceutical Co., Ltd., and receiving grants from Eisai, Otsuka, Taiho Pharmaceutical, EA Pharma, Takeda, AbbVie, and Gilead Sciences. AM reports receiving personal fees from Bayer, BTG, and Bristol Myers Squibb and receiving grants and other funding from Bayer. AS reports receiving personal fees from Bristol Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Takeda, Roche, AbbVie, Amgen, Celgene, ArQule, Lilly, Sandoz, and Novartis. IM reports receiving personal fees from Alligator Bioscience, Bristol Myers Squibb, EMD Serono, F-Star Biotechnology, Genmab, Roche, Bayer, MSD, Numab, Lilly, AstraZeneca/MedImmune, Incyte, and Tusk Therapeutics and receiving grants from Pfizer, Alligator Bioscience, Bristol Myers Squibb, and Roche. SP reports receiving personal fees from Celgene, Novartis, Eisai, Bristol Myers Squibb, Shire, and Sirtex Medical; receiving grants from Bristol Myers Squibb; and receiving non-financial support from Bristol Myers Squibb, Amgen, and Merck. ABE reports receiving personal fees from CytomX Therapeutics, Bristol Myers Squibb, Bayer, Eisai, Roche/Genentech, EMD Serono, Exelixis, Pieris Pharmaceuticals, Agenus, and Merck and receiving grants from AstraZeneca, Merck, and Astex Pharmaceuticals. RK reports receiving research funding from Bristol Myers Squibb, Eisai, Ono Pharmaceutical Co., Ltd., MSD KK, AstraZeneca plc, EA Pharma Co., Ltd, Takeda Pharmaceutical Company Limited, CHUGAI Pharmaceutical Co, LTD and honoraria from MSD, Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd, GE Healthcare Japan, Daiichi Sankyo Company, Limited. BE reports receiving personal fees from Bayer, Lexicon, RTI Health Solutions, BTG, Loxo, Merrimack, and Bristol Myers Squibb; receiving grants from AVEO, Boston Biomedical, Bristol Myers Squibb, Cleave Biosciences, Five Prime Therapeutics, Genentech, Hoosier Cancer Research Network, ICON Clinical Research, Merck, Novartis, Pfizer, PPD, Taiho Pharmaceutical, Xencor, and AstraZeneca/MedImmune; and receiving other funding from Exelixis and ERYTECH Pharma. YI reports receiving personal fees from Gilead Sciences Inc, AbbVie Inc, Merck Sharp & Dohme, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., funding from Takeda Pharmaceutical Company Limited, EA Pharma Co, Ltd, Eisai Co Ltd, AbbVie Inc, Merck Sharp & Dohme, Bayer Yakuhin Ltd, Bristol Myers Squibb, Astellas Pharma Inc, Nissan Chemical Industries, Ltd, FUJIREBIO Inc, Ono Pharmaceutical Co., Ltd., Gilead Sciences Inc, and Nichinichi Pharmaceutical Co Ltd. MR reports receiving personal fees from Bayer, Bristol Myers Squibb, AstraZeneca, Ipsen, Lilly, BTG, and Roche; receiving grants from Bayer and Lilly; and receiving non-financial support from Bayer and Bristol Myers Squibb. YS reports receiving personal fees from Bristol Myers Squibb; and receiving other funding from Bristol Myers Squibb and Sanofi. JN reports receiving personal fees and other funding from Bristol Myers Squibb. JA reports receiving personal fees and other funding from Bristol Myers Squibb. TW reports receiving personal fees, grants, and other funding from Bristol Myers Squibb. BS has served in a consulting or advisory role for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, and Roche; has served on speakers’ bureaus for Bayer, Bristol Myers Squibb, Sirtex Medical, TERUMO, and Ipsen; and has received research funding from Bristol Myers Squibb and Sirtex Medical. ACG, MA, KN, FD, and OC report no disclosures. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Atezolizumab plus bevacizumab was approved for patients with hepatocellular carcinoma (HCC). Although clinical trials have revealed its efficacy, the outcomes in the real-world clinical practice are unclear. We retrospectively evaluated the efficacy and safety of atezolizumab plus bevacizumab for HCC., Materials and Methods: This is a multicenter study conducted between November 2020 and March 2021. Among the 61 patients, 51 were assessed for progression-free survival (PFS), therapeutic response, and adverse events (AEs)., Results: The median PFS was 5.4 months. The objective response rate (ORR) was 35.3%. The disease control rate (DCR) was 86.3%. The incidence rates of AEs at any grade and grade >3 were 98.0% and 29.4%, respectively. The most frequent AE at any grade and grade >3 was hepatic disorder. In patients with a previous history of molecular targeted agent (MTA) or the degree of albumin-bilirubin (ALBI) grade, there were no significant differences in the PFS, ORR, DCR, and incidence rates of AEs., Conclusion: The study demonstrated that atezolizumab plus bevacizumab was effective and safe for patients with HCC even in the real-world setting including patients with a previous MTA history or other than ALBI grade 1.

Backround: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC., Methods: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed ( n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment., Results: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2., Conclusions: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

We aimed to evaluate the impact of alternating lenvatinib (LEN) and trans-arterial therapy (AT) in patients with intermediate-stage hepatocellular carcinoma (HCC) after propensity score matching (PSM). This retrospective study enrolled 113 patients with intermediate-stage HCC treated LEN. Patients were classified into the AT ( n = 41) or non-AT group ( n = 72) according to the post LEN treatment. Overall survival (OS) was calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM. Factors associated with AT were evaluated using a decision tree analysis. After PSM, there were no significant differences in age, sex, etiology, or albumin-bilirubin (ALBI) score/grade between groups. The survival rate of the AT group was significantly higher than that of the non-AT group (median survival time; not reached vs. 16.3 months, P = 0.01). Independent factors associated with OS were AT and ALBI grade 1 in the Cox regression analysis. In the decision tree analysis, age and ALBI were the first and second splitting variables for AT. In this study, we show that AT may improve prognosis in patients with intermediate-stage HCC. Moreover, alternating LEN and trans-arterial therapy may be recommended for patients below 70 years of age with ALBI grade 1.

Background & Aims: Intermediate hepatocellular carcinoma (HCC) treatment has become complicated due to the development of various molecular-targeted agents (MTAs). We aimed to determine whether the administration of MTAs in patients with intermediate-stage HCC contributed to the prevention of progression to an advanced stage., Methods: We enrolled and retrospectively examined 289 patients with Child-Pugh class A who had been diagnosed with intermediate-stage HCC and underwent initial trans-arterial chemoembolization (TACE). Patients were classified into 2 groups: a group in which MTAs were administered to patients whose condition was refractory to TACE (n = 65) and a group in which MTAs were not administered (n = 65) at intermediate-stage HCC after propensity score matching (PSM). Time to stage progression (TTSP) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed using a log-rank test after PSM., Results: TTSP and OS of the group with MTA administration were significantly longer than those of the group without MTA administration (TTSP: 36.4 vs. 17.9 months, p < 0.001; median survival time [MST]: 44.6 vs. 26.6 months, p = 0.001). Within the up-to-seven criteria and administration of MTAs at the intermediate-stage HCC were identified as independent factors for TTSP and OS in the multivariate analysis. TTSP and OS in the era of the multi-MTA group were significantly longer than those in the era of the mono-MTA group (TTSP: 44.8 vs. 27.4 months, p = 0.01; MST: 53.4 vs. 33.3 months, p = 0.01)., Conclusion: The administration of MTAs in patients with intermediate-stage HCC contributes to the prevention of stage progression and prolongs OS., (© 2021 S. Karger AG, Basel.)

The aim of the present study was to evaluate the effects of switching to tenofovir alafenamide (TAF) in patients who had received a nucleos(t)ide analog (NA) for the treatment of chronic hepatitis B (CHB). The data from 33 Japanese patients with CHB who received TAF therapy after using NA [adefovir dipivoxil (ADV) and/or tenofovir disoproxil fumarate (TDF)] were retrospectively analyzed. Specifically, the biochemical and virological markers from the start of the TAF treatment to 6 months later were assessed. Comparative evaluation was performed by dividing patients into two groups: Long-term (n=19) and short-term administration groups (n=14), with a cutoff administration duration of 10 years. In all 33 patients, the levels of serum hepatitis B surface antigen (HBsAg; 1,126±1,724 to 1,001±1,591 IU/ml; P<0.0001), serum alkaline phosphatase (ALP) (320±126 to 283±124 U/l; P=0.028), serum bone specific alkaline phosphatase (19.7±9.0 to 17.7±8.0 µg/l; P=0.0006) and urine β2-microglobulin-creatinine ratio (U-BMG/Cr; 5,224±17,471 to 3,547±14,652 µg/g·Cre; P=0.002) significantly decreased from baseline after 6 months. Serum HBsAg, serum ALP and U-BMG/Cr showed a significant reduction in both groups. In conclusion, switching from ADV or TDF to TAF resulted in a decrease in serum HBsAg and improvement in serum ALP and U-BMG/Cr after 6 months of treatment in patients regardless of history of treatment with NA., (Copyright: © Sano et al.)

We sought to investigate the clinical profile(s) associated with the discontinuation of lenvatinib (LEN) due to severe adverse events (DLSAE) in patients with unresectable hepatocellular carcinoma (HCC). This retrospective study enrolled 177 patients with HCC treated with LEN. Independent factors associated with DLSAE were advanced age, albumin-bilirubin (ALBI) grade 2, fatigue grade ≥ 3, and appetite loss ≥ 2. The overall survival (OS) in the group that did not require DLSAE was significantly longer compared to the group that did require DLSAE (median survival time (MST): not reached vs. 12.8 months, p < 0.001). Moreover, advanced age was the most important variable for DLSAE in a decision tree analysis. Hypertension and hand-foot-skin-reaction (HFSR) were also significantly associated with longer survival, and the occurrence of hypertension was the earliest predictor for improved prognosis, while appetite loss and development of grade ≥ 3 fatigue were predictive of a poor prognosis. We concluded that the appearance of hypertension has potential as an early surrogate marker to predict improved prognosis. Moreover, careful management to avoid discontinuation of treatment leads to longer survival in patients receiving LEN.

Background/aim: Assessment of the biological behavior of tumors is important for choosing an appropriate cancer therapy. In hepatocellular carcinoma (HCC), the biological behaviour can be assessed by tumor morphology and molecular biology. This study investigated the usefulness of tumor tissue biopsy for predicting the biological behavior of HCC., Patients and Methods: We studied 43 patients who underwent hepatectomy and preoperative liver tumor biopsy for HCC. We performed clinicopathological and immunohistochemical (IHC) analyses. The expression of the following molecules was examined: regulator of G-protein signaling 5 (RGS5), glypican-3 (GPC3), keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), protein induced by vitamin K absence or antagonist-II (PIVKA-II), β-Catenin, and p53., Results: There was an overall 83.7% agreement regarding tumor differentiation between the preoperative biopsy specimens and the resected specimens. The accuracy of IHC analysis was more than 70% for all molecules between the preoperative biopsy specimens and the resected specimens. The RGS5-positive biopsy cases had higher serum α-fetoprotein levels (p=0.04), a higher rate of moderately or poorly differentiated tumors (p=0.02) and portal vein invasion (p=0.0003) than the RGS5-negative biopsy cases. The GPC3-positive biopsy cases were younger (p=0.04), had higher serum PIVKA-II levels (p=0.01), and a higher rate of portal vein invasion (p=0.03) than the GPC3-negative biopsy cases. The PIVKA-II-positive biopsy cases had significantly higher serum PIVKA-II levels than the PIVKA-II-negative biopsy cases (p=0.02). The other molecular markers showed no significantly different clinical findings between the positive and negative cases., Conclusion: In HCC, there was a high agreement rate of both the histopathological and IHC findings between preoperative biopsy specimens and resected specimens. In the biopsy specimens of HCC, RGS5 and GPC3 expression were useful molecular makers for predicting portal vein invasion. Liver tumor biopsy is useful for predicting the biological behavior of HCC through histopathological and immunohistochemical findings., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Sorafenib and lenvatinib, as molecular-targeted agents, constitute effective primary treatment options for advanced hepatocellular carcinoma (HCC). However, the choice of optimal primary treatment agent remains controversial. Here, we aimed to assess the respective outcomes between these agents as primary treatment in patients with advanced HCC through use of propensity score-matching analysis (PSMA). We enrolled 670 consecutive patients who were diagnosed with advanced HCC and received sorafenib (n = 524) or lenvatinib (n = 146) as the primary treatment among 18 participating institutions between May 2009 and October 2019. To reduce confounding, we used PSMA regarding seven variables related to advanced HCC prognosis, resulting in the selection of 292 patients (n = 146 for each agent). Following PSMA, no significant difference was observed in the outcome of overall survival time between patients treated with sorafenib or lenvatinib (median survival time 15.3 or 14.9 months, respectively; P  = 0.2358). Patients treated with lenvatinib exhibited significantly greater therapeutic effects (response rate: 5% and 31%; disease control rate: 46% and 69% for sorafenib and lenvatinib, respectively; P  < 0.0001), but showed significantly lower probability of transition to secondary treatment (sorafenib, 60%; lenvatinib, 45%; P  < 0.0269) and higher any adverse events rate (sorafenib, 86%; lenvatinib, 95%; P  = 0.0207). Conclusion : As a primary molecular-targeted agent-based treatment for advanced HCC, our findings suggested that sorafenib is generally appropriate as it offers significantly lower frequency of adverse events and higher probability of transition to secondary treatment, in consideration of the enhanced postprogression survival mediated by sequential treatment. Alternatively, lenvatinib affords a significantly higher therapeutic effect and should be used when immediate tumor reduction is required., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background : Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results : The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival ( p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion : Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs., Competing Interests: The authors declare no potential conflicts of interest.

Background and Aims: Conventional transcatheter arterial chemoembolization (C-TACE) and drug-eluting bead (DEB)-based TACE are current treatments for hepatocellular carcinoma (HCC). We compared the therapeutic efficacies and adverse events of these methods in a single-center retrospective cohort study., Methods: We enrolled 174 patients treated between January 2010 and October 2016; 98 and 76 underwent C-TACE and DEB-TACE, respectively, with 76 and 22 of the former group and 49 and 27 of the latter group classified as Child-Pugh class A and B, respectively. Therapeutic outcomes, progression-free survival (PFS), and adverse events were evaluated., Results: The PFS rates in the C-TACE and DEB-TACE groups were 8.1 and 6.1 months, respectively (p = 0.79). The response and disease control rates were 64 and 71% in C-TACE patients and 69 and 78% in DEB-TACE patients, respectively (p = 0.25). Postprocedural pain, vomiting, and fever were more frequent following C-TACE than DEB-TACE (p < 0.001). In contrast, the incidences of bilomas and arterio-portal shunts were significantly higher following DEB-TACE (p < 0.001); the incident rates of arterio-portal shunt formation were 8.1 and 48.7% in patients undergoing C-TACE and DEB-TACE, respectively. Child-Pugh class A was significantly associated with arterio-portal shunt formation after DEB-TACE on multivariate analysis., Conclusions: There were no significant differences in the therapeutic efficacies of C-TACE and DEB-TACE. However, the frequency of arterio-portal shunt formation was significantly higher in HCC patients with Child-Pugh class A undergoing DEB-TACE. Our findings imply that C-TACE should be selected for HCC patients with Child-Pugh class A and DEB-TACE should be chosen for those with Child-Pugh class B., (© 2020 S. Karger AG, Basel.)

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

Background & Aims: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040., Methods: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018., Results: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations., Conclusion: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients., Lay Summary: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aims: The prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) is still poor. We aimed to evaluate the impact of TACE combined with radiofrequency ablation (TACE+RFA) on the prognosis of HCC patients using decision-tree analysis after propensity score matching., Methods: This was a retrospective study. We enrolled 420 patients with HCC treated with TACE alone (n = 311) or TACE+RFA (n = 109) between 1998 and 2016 (median age, 72 years; male / female, 272/148; Barcelona Clinic Liver Cancer (BCLC) stage A / B, 215/205). The prognosis of patients who underwent TACE+RFA was compared to patients who underwent TACE alone after propensity score matching. Decision-tree analysis was used to investigate the profile for prognosis of the patients., Results: After propensity score matching, there was no significant difference in age, sex, BCLC stage, or albumin-bilirubin (ALBI) score between both groups. The survival rate of the TACE+RFA group was significantly higher than the TACE alone group (median survival time [MST] 57.9 months vs. 33.1 months, P < 0.001). In a stratification analysis according to BCLC stage, the overall survival rate of the TACE+RFA group was significantly higher than the TACE alone group in BCLC stage A and B (MST 57.9 and 50.7 months vs. 39.8 and 24.5 months [P = 0.007 and 0.001], respectively). Decision-tree analysis showed that TACE+RFA was the third distinguishable factor for survival in patients with α-fetoprotein level >7 ng/mL and ALBI <-2.08., Conclusion: Decision-tree analysis after propensity score matching showed that TACE+RFA could prolong the survival of HCC patients compared to TACE alone., (© 2019 The Japan Society of Hepatology.)

Various factors are associated with the prognosis of patients with non-viral hepatocellular carcinoma (HCC). The present study aimed to investigate the prognosis of patients with non-viral HCC compared with that of patients with hepatitis C virus-related (HCV)-HCC and the features associated with prognosis of patients with non-viral HCC using data mining analyses. Patients with non-viral HCC (n=182, age 70.4±8.9 years) and HCV-HCC (n=612, age 70±8.4 years) were enrolled and the overall survival was compared between the non-viral HCC and HCV-HCC groups. The present study performed random forest and decision tree analyses to identify features that distinguish prognosis between the non-viral HCC and HCV-HCC groups. The median survival of the non-viral HCC group was significantly shorter than the HCV-HCC group (1,553 vs. 2,304 days, P<0.01). In the multivariate analysis, the non-viral HCC group was an independent risk factor for survival (HR 1.42, 95% CI 1.08-1.87, P=0.013). In the random forest analysis, the high-ranking distinguishable factors were 'number of tumors' and 'HCC stage' in the non-viral HCC group and 'albumin' and 'total bilirubin' in the HCV-HCC group. The decision tree analysis revealed that, in patients with HCC stage >I, the survival period in the non-viral HCC group was significantly shorter than the HCV-HCC group (HR 1.39, 95% CI 1.07-1.81, P=0.0132). The prognosis of patients with non-viral HCC was poorer than patients with HCV-HCC. In addition, data mining analysis revealed that tumor-related variables had the highest importance for survival in patients with non-viral HCC.

Background: Previous studies have suggested an association between the use of direct-acting antiviral agents (DAAs) for treating hepatitis C virus (HCV) infection and the resulting decrease in the incidence of hepatocellular carcinoma (HCC); however, it is unclear whether DAAs prevent the recurrence of HCC after curative treatment for HCC. This study aimed to prospectively investigate HCC recurrence and its predictors after curative treatment for HCC., Methods: A total of 3012 patients with chronic HCV infection, with or without cirrhosis, who were treated with DAAs were enrolled between January 1, 2015 and January 31, 2017 as per the institutional review board approved study protocol at 15 institutions, including 10 university hospitals and five high-volume centers in the Kyusyu area of Japan. Of the 3012 patients, 459 patients who had HCC but were cured with surgery or ablation therapy (curative treatment) before the use of DAAs were included in the analysis., Results: During a mean follow-up period of 29.4 months, 217 (47.2%) patients developed HCC recurrence. The median time to recurrence was 34.0 months, and the 1-, 2-, and 3-year cumulative HCC recurrence rates were 27.1%, 43.4%, and 50.8%, respectively. The risk factors for HCC recurrence were the α-fetoprotein (AFP) level before DAA therapy (P = 0.0047) and the number of curative treatments for HCC before DAA therapy (P < 0.0001)., Conclusions: A high AFP level and multiple occurrences of HCC before DAA therapy are associated with a high risk for HCC recurrence after curative treatment. Follow-up after DAA therapy should include special attention to the abovementioned risk factors., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: Prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) is extremely poor. However, proper therapeutic strategies have not been established yet. The purpose of this study is to identify the effects of external beam radiation therapy (EBRT) for MVI of HCC., Methods: We have analyzed and evaluated 80 consecutive patients with HCC with MVI who underwent EBRT, and factors associated with enhanced survival in EBRT were evaluated by univariate and multivariate analysis., Results: The local response rate of radiotherapy for the irradiated MVI was 66.2%. The time to progression of the irradiated MVI was 5.8 months. Univariate and multivariate analyses showed that the higher irradiation dose (over 45 Gy) and the irradiation location (hepatic vein tumor thrombus - HVTT) were significant factors associated with survival benefits of EBRT. The response of EBRT for HVTT was significantly superior to that for portal vein or bile duct tumor thrombus., Conclusion: We conclude that a multidisciplinary therapeutic strategy based on EBRT should be proactively selected in the treatment of advanced HCC with MVI., (© 2019 S. Karger AG, Basel.)

Background: Transcatheter arterial chemoembolization (TACE) is a standard therapy used in the treatment of intermediate hepatocellular carcinoma (HCC). Recently, balloon-occluded TACE (B-TACE) has been developed., Purpose: This study aimed to clarify the effects of B-TACE in patients with HCC, with a focus on which drug is suitable to suspend in Lipiodol for B-TACE., Methods: We retrospectively evaluated 35 patients with HCC treated with B-TACE. Factors associated with enhanced time to progression (TTP) after B-TACE were evaluated using univariate and multivariate analyses., Results: A total of 35 patients with HCC (40 nodules) were treated with B-TACE between June 2013 and August 2016. Epirubicin was used in 25 nodules and miriplatin was used in 15 nodules. Epirubicin (15.1 months) was significantly better than miriplatin (3.2 months) in prolonging the local TTP after B-TACE (p = 0.0293). Epirubicin showed a positive tendency in TE4 (100% tumor necrosis) rate when compared with miriplatin (p = 0.058). Achievement of TE4 was the only significant factor associated with better TTP after B-TACE. Epirubicin- and TACE-naïve statuses were significant factors in achieving TE4 with B-TACE., Conclusion: To enhance the TTP with B-TACE, TE4 should be achieved. Epirubicin is a more optimal anticancer drug (as a Lipiodol suspension) than miriplatin for achieving TE4 with B-TACE., (© 2018 S. Karger AG, Basel.)

We report on a 62-year-old man with chronic hepatitis C who developed rapidly growing hepatocellular carcinoma (HCC) after achieving sustained virological response at post-treatment week 24 (SVR 24) by direct-acting antiviral (DAA) treatment. In 2008, he failed interferon therapy at 56 years of age. He received daclatasvir plus asunaprevir for 24 weeks after confirmation of no liver tumor by abdominal ultrasonography. He had no advanced liver fibrosis. Three months after initiation of DAA treatment, a liver tumor measuring 6 mm in diameter was detected by ultrasonography and confirmed with magnetic resonance imaging. After achieving SVR 24, the tumor increased in size to 16 mm. Two months later, a tumor biopsy was performed, and histology revealed moderately to poorly differentiated HCC. The patient's alpha-fetoprotein (AFP) level was within the normal range, but the Lens culinaris agglutinin-reactive fraction of AFP level was elevated. The diameter of the tumor increased to 32 mm at 2 months after diagnosis. Lymph node metastasis in porta hepatis was found by positron emission tomography at 4 months after diagnosis. The patient received hepatic arterial infusion chemotherapy and radiation therapy, but died later. Careful monitoring is required during and after DAA treatment because HCC can grow fast even in patients with normal AFP and no advanced liver fibrosis.

We review 6 cases of diaphragmatic perforation, with and without herniation, treated in our institution. All patients with diaphragmatic perforation underwent radiofrequency ablation (RFA) treatments for hepatocellular carcinoma (HCC) performed at Kurume University Hospital and Tobata Kyoritsu Hospital. We investigated the clinical profiles of the 6 patients between January 2003 and December 2013. We further describe the clinical presentation, diagnosis, and treatment of diaphragmatic perforation. The change in the volume of liver and the change in the Child-Pugh score from just after the RFA to the onset of perforation was evaluated using a paired t -test. At the time of perforation, 4 patients had herniation of the viscera, while the other 2 patients had no herniation. The majority of ablated tumors were located adjacent to the diaphragm, in segments 4, 6, and 8. The average interval from RFA to the onset of perforation was 12.8 mo (range, 6-21 mo). The median Child-Pugh score at the onset of perforation (8.2) was significantly higher compared to the median Child-Pugh score just after RFA (6.5) ( P = 0.031). All patients underwent laparotomy and direct suture of the diaphragm defect, with uneventful post-surgical recovery. Diaphragmatic perforation after RFA is not a matter that can be ignored. Clinicians should carefully address this complication by performing RFA for HCC adjacent to diaphragm., Competing Interests: Conflict-of-interest statement: No conflict-of-interest was available.

Although sorafenib and hepatic arterial infusion chemotherapy (HAIC) have been proven to improve prognosis in hepatocellular carcinoma (HCC) patients with macroscopic vascular invasion (MVI), the most appropriate approach remains unclear. The present multicenter, non-randomized, prospective cohort study aimed to compare the efficacy and safety of HAIC and sorafenib in patients with advanced HCC and MVI, without extra-hepatic spread (EHS) and Child-Pugh class A disease. The present study was performed between April 2008 and March 2014, and 64 HCC patients with MVI, without EHS and Child-Pugh class A disease were registered. Of these patients, 44 were treated with HAIC and 20 with sorafenib. HAIC involved cisplatin (50 mg fine powder in 5-10 ml lipiodol) and a continuous infusion of 5-fluorouracil (FU) (1,500 mg/5 days), which is referred to as new 5-FU and cisplatin therapy (NFP). The primary outcome was progression-free survival, and the secondary outcome was overall survival (OS). Clinical factors influencing OS and the therapeutic effect were identified using univariate and multivariate analyses. There were no differences in clinical factors between the two groups. The median progression-free survival was 5.1 and 9.5 months in the sorafenib and NFP groups, respectively (P=0.001). The complete response (CR) or partial response (PR) rates were 10 and 71% in the sorafenib and NFP groups, respectively (P<0.001). The median OS in the sorafenib and NFP groups was 13.2 and 30.4 months, respectively (P=0.013). Multivariate analysis revealed that the independent predictors of survival were Child-Pugh score (5, P=0.022, 95% CI, 0.191-0.892), grade of portal vein invasion (brunch, P=0.009, 95% CI, 0.220-0.752), and therapeutic effect (CR or PR, P<0.001, 95% CI, 0.220-0.752), and the independent predictor of therapeutic effect was therapeutic regimen (NFP, P<0.001, 95% CI, 0.006-0.199). NFP should be the first choice for patients with advanced HCC and MVI, without EHS and Child-Pugh A disease.