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Aim Methods Results Conclusions Clinical trial registration Recent genome‐wide association studies of European populations have identified rs16906115, a single‐nucleotide polymorphism in the interleukin‐7 gene, as a predictor of immune‐related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single‐nucleotide polymorphism in a Japanese population.From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow‐up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non‐responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non‐responders.In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non‐responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis.In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome.UMIN Clinical Trials Registry with the number UMIN000043798. [ABSTRACT FROM AUTHOR]

Alternative treatment modalities are necessary because of the low response rates and unsuitability of molecular-targeted agents (MTA) and/or immune checkpoint inhibitors (iCIs) in HCC patients. Therefore, we analyzed whether drug-eluting beads (DEB)-transcatheter arterial chemoembolization (TACE) with low-dose-FP (Ultra-FP) therapy could improve the efficacy and safety of treatment in difficult-to-treat HCC patients, especially those with advanced stage HCC. From November 2017 to April 2021, 118 consecutive patients with non-resectable difficult-to-treat HCC were included in this study. All patients were treated with Ultra-FP therapy. After the weak DEB-TACE procedure, we administered low-dose FP for 2 weeks followed by resting for 4 weeks. The numbers of HCC patients CR/PR/SD/PD induced by Ultra-FP therapy were 36/52/17/13 (Modified RECIST) patients, respectively. The objective response rate of Ultra-FP therapy was 74.6% (88/118 patients). Tumor marker reduction was observed in 81.4% (96/118 patients). The objective response rate (ORR) in the HCC patients with portal vein tumor thrombosis (PVTT) was 75% (18/24 patients). Median overall survival (mOS) of all included HCC patients was 738 days. The mOS of HCC patients with PVTT (−)/PVTT (+) was 816 days/718 days. The proportion of patients based on ALBI grade system was not significantly different between pre- and after 3 course Ultra-FP therapy. Ultra-FP therapy might be an affordable treatment option for difficult-to-treat advanced HCC. ORR and overall survival after receiving Ultra-FP therapy were remarkable in comparison to various kinds of systemic therapy including MTA and iCIs. [ABSTRACT FROM AUTHOR]

Background: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. Methods: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. Results: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin–bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child–Pugh C. Conclusions: The long-term rifaximin treatment was effective and safe for patients with HE, including Child–Pugh C. [ABSTRACT FROM AUTHOR]

It has been reported that various kinds of immune checkpoint inhibitors (iCIs) could induce immune-related liver damage. We should focus on the programmed cell death-receptor-1 (PD-1) antibody and non-small cell lung cancer (NSCLC) to analyze the characteristics of hepatitis related to iCIs and find factors that could be useful biomarkers for the diagnosis. A single-center retrospective study of 252 NSCLC patients who received PD-1 antibody (nivolumab or pembrolizumab). Some of the biochemical markers and immunological markers were analyzed during PD-1-antibody treatment with or without ALT elevation. Histopathological features were reviewed by a single expert of hepatic pathology focusing on the following features: fibrosis, portal inflammation, lobular inflammation, lobular necrosis. The formation of macro- and micro-granulomas was also evaluated. The frequency of liver damage induced by nivolumab including grade 1 to 4 (ALT) was 41.9% (78/186 patients). The positive rate of anti-nuclear antibody in the nivolumab group with iCIs-related hepatitis was significantly higher than that in the nivolumab group without iCIs-related hepatitis (p = 0.00112). Granulomatous changes were significantly increased in patients with iCIs-related hepatitis compared with DILI and AIH patients (p < 0.05). The ratios of inflammatory cells CD4/CD8, and CD138/CD3 in ICIs-related hepatitis were significantly lower than those in AIH or DILI patients (p < 0.05). We demonstrated that the pre-existing ANA and characteristic liver histology including CD8+ cells dominancy and granulomatous hepatitis could be biomarkers for the diagnosis of iCIs-related hepatitis in the NSCLC with anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

Aim: Despite its relevant clinical impact and high prevalence, covert hepatic encephalopathy (HE) still remains underdiagnosed. As patients with liver cirrhosis tend to be older in Japan, more suitable tests for the elderly and cut‐off values based on this attribute are needed. Recently, a Stroop test has been developed and validated for the screening and diagnosis of covert HE in the United States. The present study aims to establish the cut‐off values of the Stroop test to screen covert HE. Methods: This study was a prospective multicenter cross‐sectional endeavor. We undertook a survey of 311 cirrhotic patients, administering the number connection test (NCT)‐A and ‐B and the Stroop‐off and ‐on test. Results: We determined the cut‐off values of Stroop test results for cirrhotic patients in a variety of age ranges. The cut‐off value of the Stroop test was strongly correlated with age. There was a significant correlation between the results of NCT‐B and age, and Stroop‐on test results showed a correlation with serum albumin (Alb) levels. Serum Alb ≤3.2 g/dl could have the potential to be an objective biomarker of covert HE. In addition, stepwise logistic regression analysis revealed a relationship between the results of the Stroop‐on test and plasma ammonia levels. Conclusions: We established the cut‐off values of Stroop test results and confirmed the efficacy of the Stroop test as a simple tool for assessing cognitive alterations. The Stroop test could be suitable as a necessary minimum for the diagnosis of covert HE. [ABSTRACT FROM AUTHOR]

Aims: Previously, our group reported that lymphotropic hepatitis C virus (HCV) could induce various kinds of immune dysfunctions. The immune dysfunctions could cause vascular disease by inducing cryoglobulinemia. It has been reported that ischemic heart diseases might be caused by HCV. However, the infectious rate of HCV in patients with ischemic heart disease has not been clarified in northern Japan. Therefore, we tried to determine the rate of HCV infectivity in patients with ischemic heart disease. Methods: The target patients of this study were automatically selected using an electronic medical record system to exclude selection bias. The system identified 16 484 patients with ischemic heart disease who were included in this study. In addition, 12 902 subjects who had received medical checkups were included as the control group. Results: The positive rate of HCV antibody among the patients with ischemic disease in our hospital was 2.58%, which was significantly higher (P < 0.01) than in the medical checkup patients (0.84%). The positive rate of HCV antibody in the patients with ischemic heart disease in each age group was significantly higher than in the corresponding age groups of the medical checkup patients. The rate of chronic kidney disease in HCV antibody‐positive patients treated by percutaneous coronary intervention (PCI) was significantly higher than in HCV antibody‐negative patients treated by PCI (P = 0.02). Conclusions: Hepatitis C virus infection might be associated with the pathogenesis of ischemic heart disease and HCV antibody positivity might be a risk factor for ischemic heart disease in northern Japan. [ABSTRACT FROM AUTHOR]

Aim: Epithelial-mesenchymal transition (EMT) is a crucial process during cancer invasion and metastasis, which is accompanied by the suppressed expression of E-cadherin initiated by stimuli such as transforming growth factor (TGF)-ß. Recent studies have shown that the epigenetic regulation of E-cadherin could be an alternate mechanism of EMT induction in hepatocellular carcinoma (HCC). miRNA-29a (miR-29a) is involved in the epigenetic regulation of genes by targeting DNA methyltransferases (DNMT), which methylate CpG islands to suppress the transcription of genes. We studied the involvement of miR-29a in TGF-ß-induced EMT in HCC cells. Methods: We treated human HCC cell lines with TGF-β to induce EMT. To investigate DNA methylation in EMT, cells were treated with a methylation inhibitor, 5-Aza-2'- deoxycytidine (5-Aza) and methylation status of CpG islands in the E-cadherin promoter was examined using methylationspecific PCR. Precursor miR-29a (pre-miR-29a) was electroporated to force the expression of miR-29a in HCC cells in order to study the role of miR-29a in EMT. Results: TGF-β transformed HCC cells into a spindle-shaped morphology accompanied by a decrease of E-cadherin with the induction of methylation of its promoter. Pretreatment of the cells with 5-Aza blocked this suppression of E-cadherin, indicating the involvement of DNA methylation. TGF-β increased DNMT3B and DNMT1 and decreased miR-29a expression. The forced expression of miR-29a abrogated the suppression of E-cadherin induced by TGF-β. Conclusion: miR-29a could regulate TGF-β-induced EMT by affecting DNA methylation via the suppression of DNMT. These observations reveal the epigenetic regulation of genes by miRNA as a unique mechanism of EMT in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: We aimed to evaluate the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev) in the case of intolerable adverse events on the prognosis of patients with unresectable hepatocellular carcinoma. Therapeutic modifications included the interruption or discontinuation of both Atezo and Bev, and the reduction, interruption, or discontinuation of Bev alone. Patients with therapeutic modifications other than the discontinuation of both Atezo and Bev had favorable overall survival and time to progression. In contrast, those with the discontinuation of both Atezo and Bev without other therapeutic modifications were associated with unfavorable overall survival and time to progression. Modified albumin–bilirubin grade 2b liver function at the initiation of Atezo/Bev or experience of immune-related adverse events could increase the risk of discontinuation of both Atezo and Bev without other therapeutic modifications. Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of unresectable hepatocellular carcinoma. We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) (median observation period: 9.40 months). One hundred uHCC from five hospitals were included. Therapeutic modifications without discontinuation of both Atezo and Bev (n = 46) were associated with favorable overall survival (median not reached; hazard ratio (HR): 0.23) and time to progression (median: 10.00 months; HR: 0.23) with no therapeutic modification defined as the reference. In contrast, the discontinuation of both Atezo and Bev without other therapeutic modifications (n = 20) was associated with unfavorable overall survival (median: 9.63 months; HR: 2.72) and time to progression (median: 2.53 months; HR: 2.78). Patients with modified albumin–bilirubin grade 2b liver function (n = 43) or immune-related adverse events (irAEs) (n = 31) discontinued both Atezo and Bev without other therapeutic modifications more frequently (30.2% and 35.5%, respectively) than those with modified albumin–bilirubin grade 1 (10.2%) and without irAEs (13.0%). Patients with objective response (n = 48) experienced irAEs more frequently (n = 21) than those without (n = 10) (p = 0.027). Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of uHCC. [ABSTRACT FROM AUTHOR]

It has been reported that various kinds of miRNAs could affect the pathogenesis of hepatitis C virus infection. Recently, our group reported that deep-sequencing analysis was useful to detect disease-specific miRNAs. The aim of this study is to identify the HCV-specific miRNAs that could contribute to the immunopathogenesis of HCV by using clinical samples and in vitro analysis. Five miRNAs (hsa-miR181a-2-3p, hsa-miR-374a-3p, hsa-miR374a-5p, hsa-miR-204-5p and hsa-miR146b-5p) were shown to be significantly downregulated in CH-C by deep sequence analysis. The average ratio (PBMCs miRNAs/serum miRNAs) of hsa-miR146b-5p was highest among all the miRNAs. Moreover, serum hsa-miR146b-5p was significantly down-regulated in CH-C patients in comparison to CH-B patients and healthy subjects. The expression of hsa-miR146b-5p in CD3+ T cells and CD14+ monocytes of CH-C patients was significantly lower than that of the other groups. The hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with Peg-IFN/RBV was significantly higher than in those of non-SVR patients treated with Peg IFN/RBV. However, the hsa-miR146b-5p expression in CD14+ monocytes of SVR patients treated with DCV and ASV was comparable to that in monocytes of non-SVR patients treated with DCV and ASV. Moreover, the expression levels of hsa-miR146b-5p in CD14+ monocytes were significantly increased after achieving SVR and 1(OH)Vitamin D3 treatment. Further, the expression of HCV-Core could suppress miR146b-5p expression in immune cells and affect the expression of various kinds of cytokines by affecting the NF-κB signaling. In conclusion, the reduction of miR146b-5p in monocytes and T cells could contribute to the immunopathogenesis of hepatitis C virus infection. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) could have important roles in immune regulation, and MDSCs can be induced in patients with various malignant tumors. The immune-suppressive functions of MDSCs in hepatocellular carcinoma (HCC) patients have not been clarified. Therefore, we tried to analyze the biological significance of MDSCs in HCC patients. We quantified PD-L1+MDSCs of HCC patients in various conditions by using multi-color flow cytometry analysis. PBMCs from HCC patients contained significantly higher percentages of PD-L1+MDSCs in comparison to those from healthy subjects (p < 0.001). The percentages of PD-L1+MDSCs were reduced by curative treatment for HCC (p < 0.05), and the percentages of PD-L1+MDSCs before treatment were inversely correlated with disease-free survival time. After we cocultivated PBMCs and several liver cancer cell lines in a transwell coculture system, the percentages of PD-L1+MDSCs were significantly increased compared with control (p < 0.05). The expression of M-CSF and VEGFA was higher in the cell lines that strongly induced PD-L1+MDSCs. Peripheral blood from HCC patients had significantly higher percentages of PD-L1+MDSCs in comparison to those of healthy subjects, and the percentages of PD-L1+MDSCs were reduced by HCC treatment, suggesting that we might use PD-L1+MDSCs as a new biomarker of HCC. [ABSTRACT FROM AUTHOR]

Histology B Recommendations: b The typical histology of AIH is the chronic active hepatitis, along with characteristic to AIH histological findings, such as interface hepatitis, hepatocellular rosette, large numbers of plasma cells, and emperipolesis.52 However, all these findings have low disease specificity, making it difficult to diagnose AIH based on histology alone. SUPPORTING INFORMATION MEMO: PATHOLOGICAL FINDINGS OF ACUTE HEPATITIS PHASE AIH Some cases of acute hepatitis phase AIH have clinical presentations that resemble acute hepatitis. SUPPORTING INFORMATION MEMO: CLINICAL CHARACTERISTICS OF ACUTE HEPATITIS PHASE AIH Among AIH cases which develop like acute hepatitis, are the "acute hepatitis phase AIH" lacking any chronic findings in the liver tissue. B Recommendations: b Some cases of AIH exhibit an "acute presentation" with clinical courses and liver function test patterns that resemble acute hepatitis, severe hepatitis, or acute liver failure (fulminant hepatitis/late-onset hepatic failure (LOHF)) (recommendation grade: 1, evidence strength: B). [Extracted from the article]

Aim: The microRNA (miR) clusters miR‐183/96/182 and miR‐217/216a/216b are significantly upregulated in nonviral hepatocellular carcinoma (NBNC‐HCC). Here, we investigate the impact of each member of these clusters on the clinical outcome of NBNC‐HCC and analyze the antitumor effects of miR‐96‐5p. Methods: The association between recurrence‐free survival of 111 NBNC‐HCC patients and the levels of miR‐183‐5p, miR‐96‐5p, miR‐182‐5p, miR‐217‐5p, miR‐216a‐5p, and miR‐216b‐5p in tumor and adjacent tissues was investigated. The impact of miR‐96‐5p on apoptosis and invasion of a hepatoma cell line, HepG2, was investigated by cell counting, Transwell assay, and flow cytometry, respectively. Results: MicroRNA‐183‐5p, miR‐96‐5p, miR‐182‐5p, miR‐217‐5p, and miR‐216b‐5p were significantly upregulated in tumor tissues compared to the adjacent tissues (p = 0.0005, p = 0.0030, p = 0.0002, p = 0.0011, and p = 0.0288, respectively). By multivariate Cox regression analysis, high tumor/adjacent ratios of miR‐182‐5p (p = 0.007) and miR‐217‐5p (p = 0.008) were associated with poor recurrence‐free survival. In contrast, a low tumor/adjacent ratio of miR‐96‐5p (p < 0.001) was associated with poor recurrence‐free survival. It suggested that further upregulation of miR‐96‐5p in tumors might have an inhibitory effect on recurrence. Transfection of miR‐96‐5p mimic significantly induced apoptosis of HepG2 cells, in association with downregulation of Nucleophosmin 1 (NPM1) and a decrease of phosphorylated AKT protein. Interestingly, simultaneous knockdown of the NPM1 and AKT genes induced apoptosis. MicroRNA‐96‐5p also suppressed proliferation and invasion, which inhibited epithelial‐to‐mesenchymal transition of HCC cells. Conclusion: MicroRNA‐96‐5p as a tumor suppressor would be valuable to stratify NBNC‐HCC patients at high risk of recurrence. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multi-systemic disease of unknown etiology that results in the development of non-caseating epithelioid granulomas. The liver is the third most frequently involved organ after the lymph nodes and the lungs. Most cases of liver sarcoidosis do not present with symptoms and involve minimal liver dysfunction, but some cases display progression to portal hypertension and liver cirrhosis, and finally to liver failure. The mechanism and the risk of progression in liver sarcoidosis are still unknown because of the diagnostic difficulty associated with this condition, and because follow-up examinations can only be done in an invasive manner. Here, we present an informative case of liver sarcoidosis with rapid progression of esophagogastric varices. Four months prior to the definitive diagnosis, no signs of varices were observed on endoscopy, and developmentof esophagogastric varices, rapid progression, and eventual rupture occurred in a short period of time. A liver biopsy, carried out after endoscopic sclerotherapy, revealed that granulomas primarily affected the portal area without fibrotic and cirrhotic changes, which is considered a primary cause of portal hypertension and esophagogastric varices. Following the liver biopsy, the patient was given systemic steroids and is currently receiving outpatient care. Thus, we should consider the possibility that liver sarcoidosis, even in the absence of cirrhotic changes, can cause serious events such as esophagogastric variceal rupture following rapid progression as a result of portal hypertension. [ABSTRACT FROM AUTHOR]

Resistance-associated substitutions (RASs) in hepatitis C virus (HCV) appear upon failure of treatment with direct-acting antivirals (DAAs). However, their origin has not been clarified in detail. Among 11 HCV genotype 1b patients who experienced virologic failure with asunaprevir (ASV)/daclatasvir (DCV), 10 had major NS5A L31M/V-Y93H variants after treatment. L31M/V-Y93H variants were detected as a minor clone before therapy in 6 patients and were the most closely related to the post-treatment variants by phylogenetic tree analysis in 4 patients. Next, to consider the involvement of a trace amount of pre-existing variants below the detection limit, we analysed human hepatocyte chimeric mice infected with DAA-naïve patient serum. L31V-Y93H variants emerged after treatment with ledipasvir (LDV)/GS-558093 (nucleotide NS5B inhibitor) and decreased under the detection limit, but these variants were dissimilar to the L31V-Y93H variants reappearing after ASV/DCV re-treatment. Finally, to develop an infection derived from a single HCV clone, we intrahepatically injected full-genome HCV RNA (engineered based on the wild-type genotype 1b sequence) into chimeric mice. A new Y93H mutation actually occurred in this model after LDV monotherapy failure. In conclusion, post-treatment RASs appear by 2 mechanisms: the selection of pre-existing substitutions among quasispecies and the generation of novel mutations during therapy. [ABSTRACT FROM AUTHOR]