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Simple Summary: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with systemic treatments such as sorafenib. Hepatic arterial infusion chemotherapy (HAIC) is the treatment using an indwelling catheter port system. The regimen of HAIC used in the study is New FP which is consisted of a fine-powder cisplatin and 5-fluorouracil. In the study, for the patients with locally progressed HCC, such as HCC with vascular invasion, initial administration of local hepatic treatment using HAIC was superior to systemic treatment using sorafenib. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Programmed cell death protein 1 (PD−1)/PD-ligand 1 (PD-L1) blockade is becoming a novel therapeutic option for a hepatocellular carcinoma. In this work, we evaluated efficacy and safety of lenvatinib following failure of PD-1/PD-L1 blockade. The median progression-free survival was 10 months (95% confidence interval (CI): 8.3–11.8) and the median overall survival was 15.8 months (95% CI: 8.5–23.2) since lenvatinib therapy initiation. The objective response rate was 55.6%, and the disease control rate was 86.1%. All of efficacy outcomes were better than those by lenvatinib treatment alone as the 1st line treatment therapy. No particular safety concerns were observed. It was speculated that lenvatinib right after failure of PD-1/PD-L1 blockade provided synergistic effect since anti-PD-1 antibodies can remain binding to CD8+T cells for more than several months. Lenvatinib demonstrated considerably high antitumor activity and good survival benefit with acceptable toxicity in patients with unresectable HCC when administered right after failure of PD-1/PD-L1 blockade. Although programmed cell death protein 1 (PD−1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD−1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4–8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5–100.0) mg and 12 (IQR, 64.4–100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3–11.8) and the median overall survival was 15.8 months (95% CI: 8.5–23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure. [ABSTRACT FROM AUTHOR]

Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies, such as radiofrequency ablation or transarterial chemoembolization. Therefore, establishment of response evaluation criteria solely devoted to HCC is needed in clinical practice, as well as in clinical trials of HCC treatment, such as systemic therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2021 by the Liver Cancer Study Group of Japan based on the 2019 version of RECICL, which was commonly used in Japan. The major revised points of the RECICL 2021 is inclusion of RECIST version 1.1 and modified RECIST as response evaluation criteria in systemic therapy for HCC. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of daily clinical practice and clinical trials as well, not only in Japan, but also internationally. [ABSTRACT FROM AUTHOR]

Aim: Both entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are widely used to treat chronic hepatitis B (CHB) in Japan. However, it remains unclear whether the efficacy of TAF in decreasing the hepatitis B surface antigen (HBsAg) level, and its safety, are superior to those of ETV. This study aimed to report the long‐term effects and safety of 96‐week ETV and TAF treatment in patients with CHB. Methods: A prospective comparative observational study was undertaken on the following two groups: patients with CHB who received continuous ETV (n = 32) and patients with CHB who were switched from ETV to TAF upon request (n = 48). The HBsAg, urinary β2‐microglobulin (β2MG)/creatinine (Cr), urinary N‐acetyl‐β‐D‐glucosaminidase (NAG)/Cr, and serum alanine aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR), and bone mineral density (lumbar spine and femur) at 96 weeks were compared. Results: The two groups did not significantly differ with respect to mean age, male / female patient ratio, or rate of hepatitis B e antigen‐positive status. The mean changes in serum HBsAg level and eGFR at 96 weeks were not significantly different between the two groups. The β2MG/Cr and NAG/Cr levels at 96 weeks were similar between the two groups. Additionally, the bone mineral density of the lumbar spine and femur as well as the serum ALT did not significantly differ. Conclusions: When compared with patients who received continuous ETV, those who were introduced to TAF after ETV showed similar effects in terms of the decrease in HBsAg level and safety. [ABSTRACT FROM AUTHOR]

Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child–Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were −2.61 to −2.61 for 30 patients in the lenvatinib group (p = 0.254) and −2.66 to −2.09 in the cTACE group (p < 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%; p < 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child–Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE. [ABSTRACT FROM AUTHOR]

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child–Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1), (2) Child–Pugh score 5 and ALBI grade 2 (group 2), (3) Child–Pugh score 6 (group 3), and (4) Child–Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child–Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment. [ABSTRACT FROM AUTHOR]

Objectives: To assess the clinical feasibility of US-US image overlay fusion with evaluation of the ablative margin in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).Methods: Fifty-three patients with 68 HCCs measuring 0.9-4.0 cm who underwent RFA guided by US-US overlay image fusion were included in this retrospective study. By an overlay of pre-/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. Therefore, the ablative margin three-dimensionally could be shown during the RFA procedure. US-US image overlay was compared to dynamic CT a few days after RFA for assessment of early treatment response. Accuracy of graded response was calculated, and the performance of US-US image overlay fusion was compared with that of CT using a Kappa agreement test.Results: Technically effective ablation was achieved in a single session, and 59 HCCs (86.8 %) succeeded in obtaining a 5-mm margin on CT. The response with US-US image overlay correctly predicted early CT evaluation with an accuracy of 92.6 % (63/68) (k = 0.67; 95 % CI: 0.39-0.95).Conclusion: US-US image overlay fusion can be proposed as a feasible guidance in RFA with a safety margin and predicts early response of treatment assessment with high accuracy.Key Points: • US-US image overlay fusion visualizes the ablative margin during RFA procedure. • Visualizing the margin during the procedure can prompt immediate complementary treatment. • US image fusion correlates with the results of early evaluation CT. [ABSTRACT FROM AUTHOR]

Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies, such as radiofrequency ablation and transarterial chemoembolization. Therefore, establishment of response evaluation criteria solely devoted to HCC is needed in clinical practice, as well as in clinical trials of HCC treatment, such as systemic therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2019 by the Liver Cancer Study Group of Japan based on the 2015 version of RECICL, which was commonly used in Japan. The major revised points of the RECICL 2019 are as follows: (i) CEA and CA19‐9 have been newly added as tumor markers that should be recorded for use as criteria in the response evaluation for intrahepatic cholangiocarcinoma; (ii) the criteria now state that the details of molecular targeted therapy should be specified; and (iii) specific methods for overall evaluation are now described. Also, as an assessment of overall TE4 requires that TE4 is achieved in all nodules (even non‐target lesions), the same calculation methods described above are used. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of daily clinical practice and clinical trials as well, not only in Japan, but also internationally. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that describes the case of a 67-year-old man with compensated cirrhosis caused by hepatitis B virus and the use of radiofrequency ablation (RFA) as treatment for inoperable hepatocellular carcinoma (HCC).

The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence‐based medicine and partly to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance–diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinoma (CCA) is a chemotherapy-resistant cancer. Reportedly, combination chemotherapy that includes immune checkpoint inhibitors (ICIs) showed superior effects compared to conventional chemotherapy for the treatment of advanced CCA. Although the efficacy of ICIs is considered to be affected by the tumor immune microenvironment (TME), the genetic/epigenetic background associated with TME in CCA is unknown. Here, we find that downregulations of genes involved in antigen presentation are associated with a "non-inflamed" tumor; the downregulations are inversely correlated with their DNA methylation levels. All tumors in the "inflamed" group exhibited an upregulation/low-methylation pattern. In contrast, the majority of CCAs in the non-inflamed group represent a downregulation/high-methylation pattern in antigen-presenting machineries. In addition, unique gene mutations of CCA that should induce DNA methylation events, like those in IDH1/2, are exclusively observed in CCAs carrying a non-inflamed tumor phenotype. These results may prove to be a clue to develop novel biomarkers and combination therapies for the treatment of CCA using ICIs. Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a "non-inflamed" tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (p = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the "inflamed" group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (p = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the "non-inflamed" tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA. [ABSTRACT FROM AUTHOR]

Simple Summary: The response rate to immune checkpoint inhibitor (ICI) monotherapy in hepatocellular carcinoma (HCC) is as low as 20%; therefore, it is important to identify the patient subgroups that respond to ICI. β-catenin activation is considered to be a key factor of ICI resistance. β-catenin activation is involved in immunologically cold tumor formation in the tumor microenvironment. Overall, controlling β-catenin activation may improve response rates of HCC tumors to ICI. β-catenin modulators and certain kinase inhibitors can suppress β-catenin activation; therefore, combining these drugs with ICIs is expected to further improve the therapeutic effect of ICIs in HCC. Recently, the therapeutic combination of atezolizumab and bevacizumab was widely used to treat advanced hepatocellular carcinoma (HCC). According to recent clinical trials, immune checkpoint inhibitors (ICIs) and molecular target agents are expected to be key therapeutic strategies in the future. Nonetheless, the mechanisms underlying molecular immune responses and immune evasion remain unclear. The tumor immune microenvironment plays a vital role in HCC progression. The infiltration of CD8-positive cells into tumors and the expression of immune checkpoint molecules are key factors in this immune microenvironment. Specifically, Wnt/β catenin pathway activation causes "immune exclusion", associated with poor infiltration of CD8-positive cells. Some clinical studies suggested an association between ICI resistance and β-catenin activation in HCC. Additionally, several subclassifications of the tumor immune microenvironment were proposed. The HCC immune microenvironment can be broadly divided into inflamed class and non-inflamed class, with several subclasses. β-catenin mutations are important factors in immune subclasses; this may be useful when considering therapeutic strategies as β-catenin activation may serve as a biomarker for ICI. Various types of β-catenin modulators were developed. Several kinases may also be involved in the β-catenin pathway. Therefore, combinations of β-catenin modulators, kinase inhibitors, and ICIs may exert synergistic effects. [ABSTRACT FROM AUTHOR]

Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. Median OS was 21.6 months (95% CI 18.6–24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7–12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49–0.76; p < 0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51–0.72; p < 0.001 and HR 0.50; 95% CI 0.39–0.65; p < 0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49–0.76; p < 0.001), 4-month (HR 0.63; 95% CI 0.51–0.80; p < 0.001), and 6-month (HR 0.68; 95% CI 0.54–0.86; p < 0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44–0.68; p < 0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38–0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. NCT01761266. This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival. [Display omitted] • A post hoc analysis of REFLECT: Is objective response associated with OS in uHCC? • In lenvatinib- or sorafenib-treated patients, OS was assessed by response status using landmark analyses per the Simon-Makuch method. • Responders had longer median OS (21.6 months) vs nonresponders (11.9 months). • Responders had significantly prolonged OS by response status at 2, 4, and 6 months. • Objective response was an independent predictor of OS in individuals with uHCC. [ABSTRACT FROM AUTHOR]

Aim: We report a rare case of immune‐related cholangitis in which the natural course could be demonstrated. Case Presentation: Eight courses of pembrolizumab maintenance therapy were given as first‐line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune‐related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. Conclusion: No previous case reports have described the changes and progression in bile duct images in immune‐related adverse events. Therefore, this case is noteworthy for considering the progression of immune‐related cholangitis. [ABSTRACT FROM AUTHOR]

Simple Summary: New-FP is a regimen of hepatic arterial infusion chemotherapy for hepatocellular carcinoma (HCC). In the study, the regimen significantly prolonged the survival of patients with major portal vein tumor thrombus-HCC. Background: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. Methods: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). Results: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p < 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p < 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. Conclusions: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function. [ABSTRACT FROM AUTHOR]

Simple Summary: The eradication of the hepatitis C virus (HCV) has had a significant impact on the management of patients with HCV-related hepatocellular carcinoma (HCC). However, its eradication has not completely resolved survival issues in patients with HCV-related HCC. Therefore, the present study investigated prognostic factors for survival in patients with HCV-related HCC undergoing molecular targeted therapies. In total, 359 HCC patients treated with first-line chemotherapy were enrolled. The median follow-up duration was 16.0 months (range, 1.0–115.7) and the median duration of first-line systemic therapy was 3.7 months (range, 0.7–86.9). The achievement of a sustained virological response (SVR) (p < 0.001), albumin-bilirubin (ALBI) grade II/III (p < 0.001), Barcelona Clinic Liver Cancer (BCLC) stage C (p  =  0.005), extrahepatic spread (p < 0.001), baseline AFP level ≥ 90 (p = 0.038), baseline DCP level ≥ 500 (p < 0.001), and a fibrosis-4 (FIB-4) index ≥ 4 (p  =  0.003) were identified as independent prognostic factors for overall survival. Background: The treatment of the hepatitis C virus (HCV) has reduced the risk of hepatocellular carcinoma (HCC)-related mortality. Many patients with advanced HCC have achieved longer survival through systemic chemotherapy. However, survivors of HCC may develop liver cancer during and after treatment. Therefore, the present study investigated prognostic factors for survival in patients with HCV-related HCC in the new era of molecular targeted therapy. Methods: A total of 359 patients with HCV-related HCC treated with first-line chemotherapy were reviewed. A Cox proportional hazards model and Kaplan–Meier curve were used to identify prognostic factors associated with survival outcomes. Results: The median follow-up duration was 16.0 months (range, 1.0–115.7) and the median duration of first-line systemic therapy was 3.73 months (range, 0.7–86.9). The achievement of a sustained virological response (SVR) (p  <  0.001), albumin–bilirubin (ALBI) grade II/III (p  <  0.001), Barcelona Clinic Liver Cancer (BCLC) stage C (p  =  0.005), extrahepatic spread (p < 0.001), baseline AFP (alpha-fetoprotein) level ≥ 90 (p = 0.038), baseline DCP (des-γ-carboxy prothrombin) level ≥ 500 (p < 0.001), and a fibrosis-4 (FIB-4) index ≥ 4 (p  =  0.003) were identified as prognostic factors for overall survival. Conclusions: The achievement of SVR was most strongly associated with overall survival. Other factors, such as the BCLC stage, extrahepatic spread, baseline tumor marker (AFP/DCP) levels, ALBI grade, and FIB-4 index need to be considered in the management of patients with HCV-related HCC. [ABSTRACT FROM AUTHOR]

Aim: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. Methods: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. Results: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty‐eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. Conclusion: In rare cases, HBsAg‐positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected. [ABSTRACT FROM AUTHOR]

Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage. [ABSTRACT FROM AUTHOR]

Background: Combination therapy with the oral fluoropyrimidine anticancer drug S1 and interferon is reportedly effective for the treatment of advanced hepatocellular carcinoma (HCC), but selection criteria for this therapy have not been clarified. In this study, we attempted to identify factors predicting the effectiveness of this combination therapy. Methods: Pathological specimens of HCC were collected before treatment from 31 patients with advanced HCC who underwent S1+ pegylated-interferon (PEG-IFN) α-2b therapy between January 2007 and January 2009. In these pathological specimens, the expression levels of CD133, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and interferon-receptor 2 (IFNR2) proteins were determined by Western blot assay. The presence or absence of p53 gene mutations was determined by direct sequencing. The relationships between these protein expression levels and the response rate (RR), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: The CD133 protein expression level was significantly lower in the responder group than in the nonresponder group. Comparing the PFS and OS between high- and low-level CD133 expression groups ( n = 13 and 18, respectively) revealed that both parameters were significantly prolonged in the latter group. The expression levels of TS, DPD, and IFNR2 protein and the presence of p53 gene mutations did not correlate with the RR. Conclusions: CD133 was identified as a predictor of the therapeutic effect of S1+ PEG-IFN α-2b therapy against advanced HCC. [ABSTRACT FROM AUTHOR]

The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group (n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group (n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced. [ABSTRACT FROM AUTHOR]

Developments in image fusion technology made it possible to visualize the ablative margin on ultrasound (US). The purpose of the present study was to assess the ablative area of radiofrequency ablation for hepatocellular carcinoma and compare it with the ablative hyperechoic zone with a non-enhanced area on contrast-enhanced US/contrast-enhanced computed tomography (CEUS/CECT) in the same cross-section. This retrospective study included 25 patients with 27 hepatocellular carcinomas. The long and short dimensions of the ablative hyperechoic zone were measured using B-mode US, and those of the non-enhanced area were assessed with CEUS/CECT on the same cross-section measured with B-mode US, using image fusion techniques. The technical effectiveness of ablation with an adequate ablative margin in a single session was determined in all patients. The long and short dimensions of the ablative hyperechoic zone ranged between 15.0 and 40.7 mm (mean: 27.3 ± 6.9 mm) and between 14.0 and 33.0 mm (mean: 23.3 ± 5.8 mm), respectively. R values for the long and short dimensions were 0.99 and 0.98, respectively, between B-mode US and CEUS, and 0.96 and 0.92, respectively, between B-mode US and CECT. The ablative hyperechoic zone may be regarded as a necrotic lesion after radiofrequency ablation. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs. [ABSTRACT FROM AUTHOR]

Aim: To retrospectively investigate the potential benefit of ultrasound–ultrasound (US‐US) overlay fusion guidance for local controllability of radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). Methods: Patients (n = 101) with 121 HCCs (mean ± SD, 1.8 ± 0.7 cm) who underwent RFA guided by US‐US overlay fusion were included in the retrospective study. By overlaying pre/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. The ablative margin could thereby be evaluated three‐dimensionally during the RFA procedure. As a control group, all 325 patients with 453 HCCs who underwent conventional RFA during the same study period were selected. Results: The total number of RF needle insertions per tumor for ablation was significantly more in the US overlay fusion group (mean 1.9 vs. 1.2; P < 0.01). The technical success rates of ablation after a single session were 100% (101/101) and 96.6% (314/325) for the US overlay fusion group and the control group, respectively. For early assessment of RFA response, 5‐mm safety margins were achieved in 89.3% (108/121) and 47.0% (213/453) of nodules in the US overlay fusion group and the control group, respectively (P < 0.01). During the follow‐up period (median 19 months), the 2‐year local tumor progression rates were 0.8% (1/121) and 6.0% (27/453) in the US overlay fusion group and the control group, respectively (P = 0.022, log–rank test). Conclusions: US‐US overlay fusion guidance can be highly effective for safety margin achievement in RFA for HCC, providing a lower risk of local tumor progression. [ABSTRACT FROM AUTHOR]

Objectives: To assess the clinical feasibility of US-US image overlay fusion with evaluation of the ablative margin in radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).Methods: Fifty-three patients with 68 HCCs measuring 0.9-4.0 cm who underwent RFA guided by US-US overlay image fusion were included in this retrospective study. By an overlay of pre-/postoperative US, the tumor image could be projected onto the ablative hyperechoic zone. Therefore, the ablative margin three-dimensionally could be shown during the RFA procedure. US-US image overlay was compared to dynamic CT a few days after RFA for assessment of early treatment response. Accuracy of graded response was calculated, and the performance of US-US image overlay fusion was compared with that of CT using a Kappa agreement test.Results: Technically effective ablation was achieved in a single session, and 59 HCCs (86.8 %) succeeded in obtaining a 5-mm margin on CT. The response with US-US image overlay correctly predicted early CT evaluation with an accuracy of 92.6 % (63/68) (k = 0.67; 95 % CI: 0.39-0.95).Conclusion: US-US image overlay fusion can be proposed as a feasible guidance in RFA with a safety margin and predicts early response of treatment assessment with high accuracy.Key points: • US-US image overlay fusion visualizes the ablative margin during RFA procedure.• Visualizing the margin during the procedure can prompt immediate complementary treatment.• US image fusion correlates with the results of early evaluation CT. [ABSTRACT FROM AUTHOR]

Aim To investigate whether plain cone-beam computed tomography (CT) immediately after conventional transcatheter arterial chemoembolization (c-TACE) can help to predict tumor response semiquantitatively in patients with hepatocellular carcinoma (HCC). Methods Analysis was carried out retrospectively on 262 targeted HCCs in 169 patients treated with c-TACE. Dynamic CT was performed at baseline and 1-4 months after c-TACE. Receiver-operating characteristic curve analysis was undertaken to evaluate whether voxel values of cone-beam CT could predict a complete response and to identify the cut-off value. Final tumor response assessment and early prediction using the retention pattern of iodized oil, the cut-off value of the density, and the combination of the cut-off density value and retention pattern of iodized oil in HCCs on postprocedural cone-beam CT were compared. Results Complete response was obtained in 72.9% of lesions. According to the pattern of iodized oil uptake, the sensitivity, specificity, and accuracy for predicting complete response were 85.9%, 70.4%, and 81.7%, respectively by excellent uptake on cone-beam CT. The area under the curve was 0.86 with the optimal cut-off at a voxel value of 200.13. According to not only the density but also the homogeneity of iodized oil retention, the sensitivity, specificity, and accuracy values for predicting complete response were 86.4%, 95.8%, and 88.9%, respectively. The predictive accuracy was significantly better than that of the pattern of iodized oil retention only ( P = 0.019). Conclusion The combination of density and visual estimate of homogeneity is superior to either alone in predicting tumor response of c-TACE in HCC patients. [ABSTRACT FROM AUTHOR]

Objective: In order to evaluate the influence of liver inflammation on liver stiffness measurement (LSM) by the simultaneous use of shear wave and strain imaging (combinational elastography), shear wave and strain imaging were compared before and after initial therapy for autoimmune hepatitis (AIH). Methods: Nine AIH patients initially treated with steroid were enrolled. Transient elastography and real-time tissue elastography were performed just before and 1 month after the start of initial steroid treatment. Blood samples, LSM, and the liver fibrosis index (LFI) were compared. Results: Aspartate aminotransferase (p = 0.002) and alanine aminotransferase (ALT) (p = 0.015) were significantly decreased after initial treatment. The LSM was 15.5 ± 9.6 kPa at baseline, decreasing to 7.2 ± 2.3 kPa after initial treatment p = 0.034). The LFI was 1.67 ± 0.67 at baseline and 1.61 ± 0.66after initial treatment; no significant change in LFI was recognized (p = 0.842). Between ▵ ALT and ▵ LSM, a significant regression equation could be calculated as follows: ▵ ALT = -0.55 + 0.654 × ▵ LSM. Conclusions: Combinational elastography was useful in evaluating not only the degree of liver fibrosis, but also the degree of liver inflammation in AIH. [ABSTRACT FROM AUTHOR]

Background: This study examined the effects of peretinoin, an acyclic retinoid, on the survival of patients with hepatitis C virus-related hepatocellular carcinoma (HCC) who had completed curative therapy and participated in a randomized, placebo-controlled trial. Methods: This study was an investigator-initiated retrospective cohort study. Subjects were all patients who were administered the investigational drug (peretinoin 600 mg/day, peretinoin 300 mg/day, or placebo) in the randomized trial. Survivals between the groups were compared using the log-rank test, and hazard ratios were estimated by Cox regression. Results: Survey data were collected from all patients ( n = 392) who participated in the randomized trial, all of whom were then divided into the peretinoin 600 mg/day ( n = 132), peretinoin 300 mg/day ( n = 131), and placebo ( n = 129) groups. At the median follow-up of 4.9 years, 5-year cumulative survival rates for patients in the 600 mg/day, 300 mg/day, and placebo groups were 73.9, 56.8, and 64.3 %, respectively. Comparison of overall survival among patients classified as Child-Pugh A revealed that survival of the 600 mg/day group ( n = 105) was significantly longer than that of the placebo group ( n = 108) (hazard ratio 0.575, 95 % CI 0.341-0.967; P = 0.0347). Conclusions: Administration of 600 mg/day peretinoin to patients with hepatitis C virus-related HCC who have completed curative therapy may improve survival for those classified as Child-Pugh A, for whom liver function is relatively stable. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for the detection of hepatocellular carcinomas (HCCs) and dysplastic nodules (DNs) compared with dynamic multi-detector row computed tomography (MDCT), and to discriminate between HCCs and DNs. Methods: Eighty-six nodules diagnosed as HCC or DNs were retrospectively investigated. Gd-EOB-DTPA-enhanced MRI and dynamic MDCT were compared with respect to their diagnostic ability for hypervascular HCCs and detection sensitivity for hypovascular tumors. The ability of hepatobiliary images of Gd-EOB-DTPA-enhanced MRI to discriminate between these nodules was assessed. We also calculated the EOB enhancement ratio of the tumors. Results: For hypervascular HCCs, the diagnostic ability of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of MDCT for tumors less than 2 cm ( p = 0.048). There was no difference in the detection of hypervascular HCCs between hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI (43/45: 96%) and dynamic MDCT (40/45: 89%), whereas the detection sensitivity of hypovascular tumors by Gd-EOB-DTPA-enhanced MRI was significantly higher than that by dynamic MDCT (39/41: 95% vs. 25/41: 61%, p = 0.001). EOB enhancement ratios were decreased in parallel with the degree of differentiation in DNs and HCCs, although there was no difference between DNs and hypovascular well-differentiated HCCs. Conclusion: The diagnostic ability of Gd-EOB-DTPA-enhanced MRI for hypervascular HCCs less than 2 cm was significantly higher than that of MDCT. For hypovascular tumors, the detection sensitivity of hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of dynamic Gd-EOB-DTPA-enhanced MRI and dynamic MDCT. It was difficult to distinguish between DNs and hypovascular well-differentiated HCCs based on the EOB enhancement ratio. [ABSTRACT FROM AUTHOR]

Aim: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. Hepatic resection is the mainstay of curative treatment for early stage HCC. Although c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte proliferation and HCC development in mice, the extent of involvement of JNK in human HCC development is unknown. The aim of this study is to assess the predictive value of JNK for postoperative recurrence in HCC. Methods: From April 2005 to March 2008, 159 patients underwent curative resection for HCC. From the 159 patients, 20 patients each matched for age, gender and etiology were registered as three groups: (i) without recurrence (no recurrence group), (ii) with recurrence within one year after surgery (early recurrence group), and (iii) with recurrence at one year or more after surgery (late recurrence group) (a cross-sectional control study). We investigated factors contributing to postoperative early and late phase recurrence. Results: Multivariate analysis using a Logistic regression model showed that JNK activity in non-cancerous liver tissue was correlated with postoperative late recurrence. ( P = 0.02, odds ratio; 5.79, 95% confidence interval [CI]; 1.33-25.36). Conclusions: JNK activity in non-cancerous liver tissue is considered as a reliable predictive biomarker for post-operative recurrence in HCC. [ABSTRACT FROM AUTHOR]

Aim: Conventional contrast harmonic sonography has the technical problem of a short enhancement time during targeting of hepatic malignancies for radiofrequency (RF) ablation. This study investigated the effectiveness of contrast harmonic sonographic guidance using perfluorocarbon microbubbles (Sonazoid) during RF ablation of hepatic malignancies. Materials and Methods: Nodules were detected on contrast-enhanced computed tomography, but could not be resolved clearly by B-mode sonography. Sixty-six patients (51 men, 15 women; mean age, 65.8 years) with 108 hepatic malignancies were enrolled. Fifty-one patients with hepatocellular carcinoma and 15 patients with liver metastases were treated by RF ablation guided by contrast harmonic sonography using perfluorocarbon microbubbles for a target lesion identified as a defect image after the administration of contrast medium. Results: The maximal diameters of all tumours ranged from 0.7 to 3.5 cm (mean ± SD, 1.7 cm ± 0.9) on sonography. Complete tumour necrosis was achieved by a single session of RF ablation in 62 (94%) of the 66 patients, while two sessions were required for the remaining four (6%) patients. The average number of treatment sessions was 1.1 ± 0.3. In the post-vascular phase, 105 (97%) of a total of 108 malignant hepatic tumours were depicted as a defect with a margin. Clinical courses have been satisfactory without any signs of local tumour progression during 1–12 months of follow-up (mean, 4.3 months). Conclusion: Using perfluorocarbon microbubbles, contrast harmonic sonographic-guided RF ablation is an efficient approach for guiding further ablation of hepatic malignancies that are not clearly demarcated by B-mode sonography. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapy is becoming a promising approach for unresectable-hepatocellular carcinoma (HCC); the anti-tumor response is affected by the tumor microenvironment (TME). Although Wnt/β-catenin mutations are reported to cause non-inflamed phenotype, their role on TME remains controversial. We aimed to clarify the heterogeneity of immunophenotype in HCC with Wnt/β-catenin mutations., Methods: This study includes 152 resected HCCs; mutations in the catenin beta-1 , adenomatous polyposis coli, or AXIN1 , or AXIN2 genes were defined as Wnt/β-catenin mutations. With hierarchical cluster analyses, TME was classified into inflamed or non-inflamed classes based on the gene expressions associated with T-cell activation. Expression profiles of molecules related to cell differentiation and biliary-stem cell markers were compared between the TME classes to investigate whether differences in tumor traits were associated with TME., Results: Forty of 152 (26.3%) HCCs carried the Wnt/β-catenin mutations. Of these, 33 were classified as non-inflamed (33/40, 82.5%) and 7 as inflamed (7/40, 17.5%). Non-inflamed class was characterized by low number of CD3+, CD4+, and CD8+ cells on immunostaining, and high mRNA expressions of AXIN2 and GLUL, which are involved in the canonical Wnt/β-catenin signaling and hepatocyte differentiation, respectively. Non-inflamed tumors showed higher enhancement on the hepatobiliary-phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) compared to inflamed tumors. HCCs classified as inflamed class are revealed to have high numbers of CD3+, CD4+, and CD8+ tumor infiltrating lymphocytes on immunostaining. This class is associated with increased expression of anti-epithelial cell adhesion molecule and FOXM1 accompanied by upregulation of genes related to interferon-gamma signaling, dendritic cell migration, regulatory T cells, and myeloid-derived suppressor cell activation and recognized as low enhancement nodule on Gd-EOB-DTPA-enhanced MRI., Conclusion: Heterogeneity of tumor traits and TME was observed in HCC with Wnt/β-catenin mutation. The potential was indicated that tumor traits and TME are determined not only by the activation of the HNF4A but also by FOXM1 , both of which are downstream transcription factor of the Wnt/β-catenin signaling pathway., Competing Interests: N.N. is an Editorial Board member of liver cancer. T.A., Y.K., K.S., M.M., H.C., M.T., S.H., H.I., K.U., Y.M. M.T., T.N., and K.N. have no relevant conflicts of interest to disclose. S.M. Michie Sakamoto is an Associate Editor of Liver Cancer. M.K. has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb. M.K. has also received grants and personal lecture fees from Merck Sharpe and Dohme (M.S.D), Eisai, and Bayer, and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, Chugai, AstraZeneca and ONO Pharmaceuticals. Masatoshi Kudo is an Editor-in-Chief of liver cancer., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background and Aim: A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer., Methods: Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m 2 and nab-paclitaxel at 125 mg/m 2 ., Results: Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups., Conclusion: Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events., (© 2023 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074)., Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14-21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0-2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0-1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety., Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1-31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months-NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed., Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy., Competing Interests: Masatoshi Kudo: lecture: Eli Lilly, Bayer, Eisai, Chugai, Takeda, and AstraZeneca; grants: Gilead Sciences, Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, and GE Healthcare; and advisory consulting: Chugai, Roche, AstraZeneca, and Eisai. Masatoshi Kudo is the Editor-in-Chief of Liver Cancer. Kazuomi Ueshima: consulting or advisory roles for Eisai, Lilly Japan, Pfizer, Chugai Pharma, and Takeda and honoraria from Bayer, Eisai, Lilly Japan, Chugai Pharma, Takeda, MSD, EA Pharma, Sumitomo Group, Taiho Pharmaceutical, and Kowa. Issei Saeki: honoraria from Eisai and research funding from Chugai Pharma. Toru Ishikawa, Nobukazu Tanabe, Yoshiyuki Wada, Masahiro Tsuda, Kazuhiko Nakao, Shunsuke Nojiri, Junji Furuse, Keisuke Hino, Chikara Ogawa, and Kenichi Yoshimura: no conflict of interest. Yoshitaka Inaba: Eisai, AstraZeneca, and Chugai. Naoki Morimoto: research funding from Eisai and AbbVie and honoraria from Eisai, AbbVie, and Chugai Pharma. Hiroshi Aikata: honoraria from Eisai and research funding from Eisai. Yasuteru Kondo: consulting or advisory roles for Terumo, Toray Medical, Hanaco Medical, UTM, Japan Lifeline, Century Medical, and Covidien. Takanori Ito: honoraria (speaker fee) from Chugai. Tetsuya Hosaka: honoraria from Gilead Sciences. Yusuke Kawamura: honoraria from Eisai, Chugai Pharma, and Terumo. Teiji Kuzuya: honoraria from Eisai, Takeda Yakuhin, Eli Lilly Japan, and Chugai Pharmaceutical. Hironori Koga: speaker honoraria from Eisai and Chugai Pharma and research grants from Shionogi, Daiichi Sankyo, and Chugai Pharma. Masafumi Ikeda: consulting or advisory roles for Eisai, Novartis, Chugai Pharma, Ono Pharmaceutical, AstraZeneca, Servier, and Takeda and honoraria from Taiho Pharmaceutical, Eisai, Lilly Japan, Chugai Pharma, AstraZeneca, and Servier. Michihisa Moriguchi: consulting or advisory roles for Bayer Yakuhin, Chugai Pharma, Eisai, and Lilly Japan and honoraria from Bayer Yakuhin, Chugai Pharma, Eisai, Lilly Japan, Takeda, and MSD. Takashi Hisai: employee of Eisai Co., Ltd. Yasuaki Arai: royalties from Sumitomo Bakelite and honoraria from Merit Medical Systems, Canon Medical Systems, Terumo International Systems, Sumitomo Bakelite, Boston Scientific, Japan Lifeline, Taiho Pharmaceutical, Guerbet Japan, AstraZeneca plc, Cosmotec, and Toray., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies., Methods: This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4., Results: The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody ( p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group., Conclusion: The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice., Competing Interests: M.K. has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb. He has also received grants and personal lecture fees from Merck Sharpe and Dohme (MSD), Eisai, and Bayer, and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, Chugai, AstraZeneca, and ONO Pharmaceuticals. He is an Editor-in-Chief of LIVER CANCER. K.U. has received Honoraria from: Bayer AG, Eisai Co. Ltd., Merck Sharp and Dohme, Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical. Co. Ltd., EA Pharma Co., Ltd., AbbVie GK and Kowa Co., Ltd. He has received consulting or advisory fees from: Eisai Co. Ltd., Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Inc. T.A., M.M., H.C., M.T., S.H., H.I., Y.M., A.Y., K.S., and M.T., no relevant conflicts of interest to disclose. N.N. is an Editorial Board member of liver cancer., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Aim: Sorafenib was previously considered a first-line treatment for hepatocellular carcinoma (HCC) patients with macroscopic portal vein tumor thrombus (PVTT). This case-matched analysis was performed to evaluate the best first-line treatment for HCC in patients with macroscopic PVTT., Methods: The HCC patients with Vp2 (PVTT invaded into a second-order portal branch), Vp3 (first-order portal branch), and Vp4 (main trunk or contralateral portal vein) PVTT who underwent hepatectomy and those treated with sorafenib were included. Treatment results were compared between the two modalities for each PVTT category, and a propensity analysis was performed for patients with Vp3 and Vp4 (Vp3/4)., Results: The median survival times (MSTs) of patients with Vp2, Vp3, and Vp4 PVTT who underwent hepatectomy were 21.4, 13.6, and 14.9 months, respectively; the MSTs for those with Vp2, Vp3, and Vp4 PVTT who received sorafenib treatment were 6.9, 5.5, and 3.6 months, respectively, with a significant difference. In a propensity-matched cohort of patients with Vp3/4 PVTT (36 patients in each), the MST of patients who underwent hepatectomy (15.1 months) was significantly better than the patients treated with sorafenib (4.5 months)., Conclusion: Hepatectomy can be associated with prolonged survival in HCC patients with macroscopic PVTT., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

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., Competing Interests: Masatoshi Kudo received lecture fee from Eli Lilly, Bayer, Eisai, Chugai, Takeda, and MSD; and grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, and GE Healthcare. Masatoshi Kudo is the editor-in-chief of Liver Cancer. Tomoko Aoki, Kazuomi Ueshima, Masahiro Morita, Hirokazu Chishina, Masahiro Takita, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Naoshi Nishida (Smoking Research Foundation [Research Grant] Chikara Ogawa), Tetsu Tomonari, Noriaki Nakamura, Hidekatsu Kuroda, Atsushi Takebe, Yoshifumi Takeyama, Masaaki Hidaka, and Susumu Eguchi had no conflict of interest. Kaoru Tsuchiya received lecture fee from Eli Lilly, Bayer, Eisai, Chugai, and Takeda. Stephan L Chan is the advisor for Astra-Zeneca, MSD, Eisai, and Ipsen, and received research funding from Bayer, Eisai, Ipsen, Sirtex, and MSD. Masayuki Kurosaki received lecture fee from Gilead, AbbVie, Eli Lilly, Bayer, Eisai, Chugai, Janssen, and Otsuka. Namiki Izumi received lecturer fee from Chugai, Eisai, Takeda, Lily, and Bayer., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS., Patients and Methods: A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis., Results: Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27-0.70; P < 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses., Conclusions: OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies., (©2021 American Association for Cancer Research.)

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes., Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries., Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months)., Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib., Competing Interests: A.C.-G. has received grants and personal fees from MSD, Eisai, and Bayer and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca, and GSK. M.K. has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb; has received grants and personal fees from MSD, Eisai, and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, and ONO Pharmaceutical. Prof. Kudo is the Editor-in-chief of Liver Cancer. K.U.: she is an Editorial Board Member. A.J.: personal fees from Eisai., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

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., Competing Interests: Kazuomi Ueshima received honoraria and consulting or advisory fees from Bayer AG, Eisai Co. Ltd., Merck Sharp & Dohme, Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., and Kowa Co., Ltd. and consulting or advisory fees from Eisai Co., Ltd., Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Inc. Atsushi Komemushi, Takeshi Aramaki, Hideki Iwamoto, Shuntaro Obi, Yozo Sato, Toshihiro Tanaka, Kiyoshi Matsueda, Hiroya Saito, Miyuki Sone, and Yoshitaka Inaba have no relevant conflicts of interest to disclose. Michihisa Moriguchi received honoraria from Bayer, Eisai, Eli Lilly, and Chugai and consulting or advisory fees from Bayer, Eli Lilly, and Chugai. Takuji Yamagami received a research grant from Guerbet Japan, Nihon Medi-Physics, Eisai, Fujifilm Toyama Chemical Co. Ltd., GE Healthcare, Boston Scientific, and Fuji Pharma Co., Ltd. Masatoshi Kudo received honoraria and consulting or advisory fees from Bayer AG and Eisai Co., Ltd.; honoraria from Bayer AG, Bristol Myers Squibb, EA Pharma Co., Ltd., Eisai Co., Ltd., and Merck Sharp & Dohme; and research funding from Bayer AG, Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., and Taiho Pharmaceutical. Yasuaki Arai received honoraria from Merit Medical Systems, Cosmotec, Fuji Pharma, Canon Medical Systems, Canon Medical Systems Asia Pte. Ltd., Canon Medical Systems Malaysia Sdn. Bhd., Sumitomo Bakelite, Boston Scientific Japan, Boston Scientific Corporation, Japan Lifeline, AstraZeneca plc, Guerbet Japan, Guerbet Asia Pacific, Kyorin Pharmaceutical, Daiichi Sankyo Co., Ltd., and Eisai Co., Ltd. Masatoshi Kudo is the Editor-in-Chief of Liver Cancer, and Kazuomi Ueshima is an Editorial Board Member of Liver Cancer., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034)., Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group ( N = 80) or a TACE alone group ( N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE., Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group ( p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria., Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Immune checkpoint inhibitors (ICIs) have become the standard of care for several cancers. However, ICI therapy has also been associated with various immune-related adverse events (irAEs). Clinical manifestations of immune-related colitis resemble those of inflammatory bowel diseases such as ulcerative colitis (UC). The composition of the bowel microflora is thought to influence the development of inflammatory bowel disease and irAE colitis. We profiled the gene expressions and microbe compositions of colonic mucosa from patients with solid cancers receiving anti-PD-L1 antibody treatment; we then compared the expression profiles associated with irAE colitis with those associated with UC. The pathway enrichment analysis revealed functional similarities between inflamed regions of irAE colitis and UC. The common enriched pathways included leukocyte extravasation and immune responses, whereas non-inflamed mucosa from patients with irAE colitis was distinct from patients with UC and was characterized by the recruitment of immune cells. A similarity between the microbiota profiles was also identified. A decreased abundance of Bacteroides species was observed in inflamed regions from both irAE colitis and UC based on a microbiota composition analysis of 16S rDNA sequencing. Pathways associated with molecule transport systems, including fatty acids, were enriched in inflamed and non-inflamed irAE colitis and inflamed UC, similar to Piphillin-inferred KEGG pathways. While UC is characterized by local regions of inflammation, ICI treatment extends to non-inflammatory regions of the colonial mucosa where immune cells are reconstituted. This analysis of the similarity and heterogeneity of irAE colitis and UC provides important information for the management of irAE colitis., Competing Interests: KS reports personal fees from Roche Diagnostics, Bio‐Rad, SRL Diagnostics, AstraZeneca, Chugai Pharmaceutical outside the submitted work. KU has received personal fees and honoraria from Eisai. HH reported grants from the Japan Agency for Medical Research and Development during the conduct of the study and grants and personal fees from AstraZeneca, Boehringer Ingelheim Japan Inc, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb and personal fees from Eli Lilly Japan, Kyorin Pharmaceutical, Merck Biopharma, MSD, Novartis, Pfizer Japan, Shanghai Haihe Biopharma, and Taiho Pharmaceutical outside the submitted work. KNa reports grants from Novartis, Boehringer Ingelheim, Pfizer, Takeda, SymBio Pharmaceuticals, Kyorin Pharmaceutical, CareNet, Nichi-Iko Pharmaceutical, Daiichi-Sankyo, Hisamitsu Pharmaceutical, Yodosha, Clinical Trial, Medicus Shuppan Publishers, Ayumi Pharmaceutical, Nikkei Business Publications, Thermo Fisher Scientific, Nanzando, Medical Review, Yomiuri Telecasting, Reno Medical, MSD, Eli Lilly, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Astellas, and grants from Novartis, Boehringer Ingelheim, Pfizer, Takeda, SymBio Pharmaceuticals, Daiichi-Sankyo, Merck Serono, ICON, Parexel International, IQVIA Services, A2 Healthcare, AbbVie, EP-CRSU, Linical, Otsuka Pharmaceutical, EPS, Quintiles, CMIC Shift Zero, Eisai, Kissei Pharmaceutical, Kyowa Hakko Kirin, Bayer, inVentiv Health, Gritstone Oncology, GlaxoSmithKline, Covance, MSD, Eli Lilly, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Astellas outside the submitted work. MK received fees for advisory role from Eisai, Ono, MSD, Bristol-Myers Squibb, and Roche, lecture fees from Eisai, Bayer, MSD, Bristol-Myers Squibb, Eli Lilly, and EA Pharma, and research funding from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, Abbvie, and Eisai. KNi reports personal fees from Otsuka Pharmaceutical, Life Technologies Japan, Boehringer Ingelheim, Eli Lilly, Chugai Pharmaceutical, Eisai, Pfizer, Novartis, MSD, Ono Pharmaceutical, Bristol‐Myers Squibb, SymBio Pharmaceuticals Limited, Solasia Pharma, Yakult Honsha, Roche Diagnostics, AstraZeneca, Sanofi, Guardant Health, Takeda, Kobayashi Pharmaceutical, and grants from Otsuka Pharmaceutical, Life Technologies Japan, Boehringer Ingelheim, Eli Lilly, Ignyta, Astellas outside the submitted work. The remaining 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., (Copyright © 2021 Sakai, Sakurai, De Velasco, Nagai, Chikugo, Ueshima, Kura, Takahama, Hayashi, Nakagawa, Kudo and Nishio.)

Introduction: Immune checkpoint inhibitors (ICIs) are promising agents for the treatment of hepatocellular carcinoma (HCC). However, the establishment of noninvasive measure that could predict the response to ICIs is challenging. This study aimed to evaluate tumor responses to ICIs using the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), which was shown to reflect Wnt/β-catenin activating mutation., Methods: A total of 68 intrahepatic HCC nodules from 18 patients with unresectable HCC and Child-Pugh class A liver function who received anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy were enrolled in this study. All patients had viable intrahepatic lesions evaluable using the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI within the 6 months prior to the treatment. The relative enhancement ratio was calculated, and the time to nodular progression (TTnP) defined as 20% or more increase in each nodule was compared between higher or hypo-enhancement HCC nodules. Then, the progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) were compared between patients with and without HCC nodules with higher enhancement on hepatobiliary phase images., Results: The median PFS was 2.7 (95% confidence interval [CI]: 1.4-4.0) months in patients with HCC nodules with higher enhancement ( n = 8) and 5.8 (95% CI: 0.0-18.9) months in patients with hypointense HCC nodules ( n = 10) ( p = 0.007). The median TTnP of HCC nodules with higher enhancement ( n = 23) was 1.97 (95% CI: 1.86-2.07) months and that of hypointense HCC nodules ( n = 45) was not reached ( p = 0.003). The ORR was 12.5% (1/8) versus 30.0% (3/10); the disease control rate was 37.5% (3/8) versus 70.0% (7/10), respectively, in patients with or without higher enhancement intrahepatic HCC nodules., Conclusion: The TTnP on HCC nodules with higher enhancement and the median PFS in patients who carried higher enhancement intrahepatic HCC nodules were significantly shorter than those in hypointense HCC nodules with anti-PD-1/PD-L1 monotherapy. The intensity of the nodule on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is a promising imaging biomarker for predicting unfavorable response with anti-PD-1/PD-L1 monotherapy in patients with HCC., Competing Interests: T.A.: no relevant conflicts of interest to disclose. N.N. is an Editorial Board member of LIVER CANCER. K.U. has received Honoraria from Bayer AG, Eisai Co. Ltd., Merck Sharp & Dohme, Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical. Co. Ltd., EA Pharma Co., Ltd., AbbVie GK, and Kowa Co., Ltd. He has received consulting or advisory fees from Eisai Co. Ltd., Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Pfizer Inc. M.M.: no relevant conflicts of interest to disclose. H.C.: no relevant conflicts of interest to disclose. M.T.: no relevant conflicts of interest to disclose. S.H.: no relevant conflicts of interest to disclose. H.I.: no relevant conflicts of interest to disclose. Y.M.: no relevant conflicts of interest to disclose. A.Y.: no relevant conflicts of interest to disclose. K.S.: no relevant conflicts of interest to disclose. M.T.: no relevant conflicts of interest to disclose. M.K. has received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb. He has also received grants and personal lecture fees from Merck Sharpe and Dohme (MSD), Eisai, and Bayer, and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, Chugai, AstraZeneca, and ONO Pharmaceuticals. He is an editor-in-chief of LIVER CANCER., (Copyright © 2021 by The Author(s). Published by S. Karger AG, Basel.)

Introduction: Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC., Methods: Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram., Results: Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein < 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8 + cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8 + tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS ( p < 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells., Discussion/conclusion: The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8 + TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI., Competing Interests: Masatoshi Kudo reports honoraria and consulting or advisory fees from Bayer AG, Roche, and Eisai Co. Ltd.; honoraria from Bayer AG, Bristol Myers Squibb, EA Pharma Co., Ltd., Eisai Co. Ltd., and Merck Sharp & Dohme; and research funding from Bayer AG, Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., and Taiho Pharmaceutical. M.K. is an Editor-in-Chief, and N.N. is an Editorial Board member of Liver Cancer., (Copyright © 2021 by S. Karger AG, Basel.)

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC., Competing Interests: M.K. received honoraria from Eisai, Bayer, MSD, Bristol-Myers Squibb, Lilly, and EA Pharma and grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, Abbvie, and Eisai and has had an advisory role in Eisai, Ono, MSD, Bristol-Myers Squibb, and Roche. Y.K. received honoraria from Esiai. K.H. received honoraria from Taiho, Chugai, and Takeda. R.T. received honoraria from Abbvie, Bayer, Chugai, Eisai, Fujifilm Wako, GE Healthcare, Gilead Sciences, Medtronic, MSD, Otsuka, Shionogi, and Sumitomo Dainippon. K.K. has no conflicts of interest to declare. S.S. has no conflicts of interest to declare. H.T. received honoraria from AbbVie, MSD, and Bayer. Y.I. has no conflicts of interest to declare. A.H. received honoraria from Eisai, Bayer, and Otsuka. M.I. received honoraria from Eisai, Bayer, and Lilly and research funding from Bayer, Eisai, Ono, Bristol Myers Squibb, AstraZeneca, Chugai, Merck Serono, Novartis Pharma, and MSD. N.I. received honoraria from Bayer and Eisai. M.M. received honoraria from Eisai, Bayer, and Lilly. S.O. received honoraria from Bayer, Eisai, and Eli Lilly; consulting or advisory fees from Bayer, Eisai, Merck & Co., Inc., Chugai Pharma, Eli Lilly, and AstraZeneca; and research grants from Bayer, Eisai, and Eli Lilly. Y.M. has no conflicts of interest to declare. K.U. received honoraria from Eisai and Eli Lilly. T.M. has no conflicts of interest to declare. S.M. received honoraria from Eisai, Bayer, Guerbet, Asahi Intecc, Philips, Canon, Piolax, Daiichi-Sankyo, Fujiyakuhin, and Eli Lilly. O.N. has no conflicts of interest to declare. H.Y. has no conflicts of interest to declare. M.S. received grants from Eisai, Olympus, Fujifilm, and CYTLIMIC. E.H. has no conflicts of interest to declare. M.S. received grants from EA Pharma, Eisai, Covidien Japan, Novartis Pharma, Taiho, Chugai, Bayer, Astellas, Ono, and Takeda. N.K. has no conflicts of interest to declare. S.M. has no conflicts of interest to declare. T.T. received honoraria from Gilead Sciences, AbbVie, and MAD and grant/research support from Gilead Sciences, AbbVie, MSD, Janssen, Eisai, EA Pharma, and Otsuka., (Copyright © 2021 by S. Karger AG, Basel.)

Although programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD-1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4-8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5-100.0) mg and 12 (IQR, 64.4-100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3-11.8) and the median overall survival was 15.8 months (95% CI: 8.5-23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.

A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c-Met inhibitor tivantinib as second-line treatment significantly prolonged progression-free survival in a subpopulation whose tumor samples highly expressed c-Met (MET-high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. This randomized, double-blind, placebo-controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET-high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice-a-day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression-free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression-free survival was 2.8 (95% confidence interval: 2.7-2.9) and 2.3 (1.5-2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52-1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1-11.6) and 8.5 (6.2-11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58-1.15). The most common tivantinib-related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second-line treatment for Japanese patients with MET-high hepatocellular carcinoma. (NCT02029157)., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Prior to the approval of sorafenib, hepatic arterial infusion chemotherapy (HAIC) was offered to patients with advanced hepatocellular carcinoma (HCC) in East Asia, particularly Japan. According to the Japanese guidelines, HAIC is recommended as one of the treatment options in patients without extrahepatic metastasis (EHM)., Methods: The present cohort study compared the use of HAIC and sorafenib on outcomes of patients with advanced HCC. Consecutive patients with advanced HCC who received HAIC or sorafenib as a first-line systemic therapy were enrolled from 10 Japanese institutions. The primary outcomes were overall survival (OS) in patients with macrovascular invasion (MVI), but without EHM, and OS in patients without both MVI and EHM., Results: Between 2009 and 2016, 2,006 patients were enrolled (541 HAIC patients, 1,465 sorafenib patients). After propensity score matching, the OS of patients with MVI but without EHM was significantly longer in the HAIC group compared with the sorafenib group (10.1 vs. 9.1 months for the HAIC and sorafenib groups, respectively; n = 170 for each group; hazard ratio [HR] 0.668; 95% confidence interval [95% CI] 0.475-0.935; p = 0.018). There was no significant difference in OS between patients without both MVI and EHM (12.2 vs. 15.4 months for the HAIC and sorafenib groups, respectively; n = 76 in each cohort after propensity score matching; HR 1.227; 95% CI 0.699-2.155; p = 0.475)., Conclusion: HAIC is a potential front-line treatment choice in a subpopulation of patients with advanced HCC with MVI but without EHM., Competing Interests: K.U. received honoraria from Bayer and Eisai, and consulting or advisory fees from Eisai and Eli Lilly. S. Ogasawara received honoraria from Bayer, Eisai, Eli Lilly, consulting or advisory fees from Bayer, Eisai, Merck & Co. Inc., Chugai Pharma, Eli Lilly, and research grants from Bayer and Eisai. M.I. received consulting or advisory fees from Bayer Yakuhin, Eisai, Novartis Pharma, Shire, and MSD, and research grants from Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Baxalta Japan Limited, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Nano Carrier, ASLAN Pharmaceuticals, Novartis Pharma, and Takara Bio. Y.Y. received honoraria from Bayer and an Overseas Research Fellowship from the Uehara Memorial Foundation. T.T. received a consulting or advisory role, speakers bureau, and research funding from Bayer and Eisai. T.Y. received consulting or advisory roles, speakers' bureau, and research funding from Bayer and Eisai. S. Obi received research funding from Eisai, Otsuka pharmaceutical, and Mochida pharmaceutical. T. Ohmura received honoraria from Eisai and Bayer and speakers bureau from Bayer. T. Ohki received speakers bureau from Bayer, Eisai, STARmed, Abbvie, Shionogi, Otsuka Pharmaceutical, and Sumitomo Dainippon Pharma. K.N. received a lecture fee from Pfizer. Y.O. received honoraria from Bayer, Eisai, and Sumitomo Dainippon Pharma. M. Kurosaki received speakers bureau from Eisai and Bayer. K.C. received a consulting or advisory fee from Abbvie, Asuka, Glaxo Smithkline, and speakers bureau from Astellas, Abbvie, Abbot, Eisai, Merck & Co. Inc., Otuka, Olympus Medical Systems, Gilead Sciences, JIMRO, ZERIA Pharmaceutical, Daiichi Sankyo, Taisho Pharmaceutical, Sumitomo Dainippon Pharma, Takeda, Tanabe Pharmaceutical, Chugai Pharmaceutical, Bayer, Pfizer, Bristol-Myers Squibb, Miyarisan Pharmaceutical, and Yakult Pharmaceutical Industry. S.K. received a consulting or advisory role, speakers bureau, and research funding from Bayer and Eisai. N.I. received speakers bureau from Eisai and Bayer. N.K. received honoraria, a consulting or advisory role, and research funding from Bayer and Eisai. M. Kudo received honoraria from Bayer, Eisai, Merck & Co. Inc., and Ajinomoto, consulting or advisory frees from Kowa, Merck & Co. Inc., Bristol-Myers Squibb, Chugai Pharmaceutical, and Taiho Pharmaceutical, and research grants from Chugai Pharmaceutical, Otuka, Takeda, Sumitomo Dainippon Pharma, Daiichi Sankyo, Merck & Co., Eisai, Bayer, and Abbvie. M.O. received honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Otsuka, Astellas, Gilead Science, Chugai Pharmaceutical, Mitsubishi Tanabe, Kyorin, Merck Sharp and Dohme, Sumitomo Dainippon, Vertex Pharmaceutical, Takeda, Merck Serono, and Zeria. The other authors involved in this study have nothing to declare regarding funding or conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)

Background and Aim: Immune checkpoint inhibitors are promising agents for the treatment of hepatocellular carcinomas (HCC) refractory to conventional therapies. To enhance the efficacy of this treatment, immunological and molecular characteristics of HCC with programmed cell death ligand 1 (PD-L1) should be explored., Methods: Clinical backgrounds, PD-L1 expression, and the amount of CD8+ tumor-infiltrating mononuclear cells (TIMCs) were analyzed in 154 HCCs. The expression of 3 stem cell markers and co-inhibitory receptors on tumor cells and TIMCs, respectively, were examined by immunohistochemical analysis. Somatic mutations in the 409 cancer-associated genes and TERT promoter were determined; HCCs were classified based on the presence of gene alterations affecting the 8 oncogenic pathways. The results were validated using the dataset from the Cancer Genome Atlas., Results: The expression of PD-L1 in the HCCs was positively correlated with progressive tumor features, the presence of cytokeratin 19 (CK19), Sal-like protein 4 (SALL4), and the mutations of genes involving the phosphatidyl inositol 3-kinase (PI3K)-Akt pathway. Although CD8+ cells were densely infiltrated in PD-L1-positive tumors, these TIMCs frequently expressed multiple co-inhibitory receptors. However, a subset of PD-L1-positive tumors characterized by activating mutations of the PI3K-Akt pathway showed a low degree of TIMCs. Conversely, PD-L1-negative HCCs were associated with mutations in the β-catenin pathway and a small number of TIMCs, although the expression of co-inhibitory receptors was rare., Conclusions: PD-L1-positive HCCs frequently showed an inflamed phenotype with stem cell features; a subset of PD-L1-positive HCCs with mutations in the PI3K-Akt pathway showed a non-inflamed phenotype. In HCCs with dense infiltration of TIMCs, CD8+ cells expressed multiple co-inhibitory receptors, suggesting T cell exhaustion. On the other hand, PD-L1-negative HCCs showed mutations leading to β-catenin activation and exhibited a non-inflamed background. These characteristics should be taken into consideration for developing novel combination therapies using immune checkpoint inhibitors., Competing Interests: N.N. received research grants from Gilead Sciences. M.K. received research grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, Sumitomo Dainippon-Sumitomo, Daiichi Sankyo, AbbVie, Astellas Pharma, and Bristol-Myers Squibb; grants and personal fees from MSD, Eisai, and Bayer; and is an adviser for MSD, Eisai, Bayer, Bristol-Myers Squibb, Eli Lilly, and ONO Pharmaceutical. All other authors have nothing to declare., (Copyright © 2020 by S. Karger AG, Basel.)