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DOI： 10.1016/j.gastha.2024.07.018

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12328-023-01892-w

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Other Link： https://link.springer.com/article/10.1007/s12328-023-01892-w/fulltext.html

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BACKGROUND AND AIMS: The IMbrave 150 trial revealed the usefulness of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (HCC), making it now considered the first-line systemic chemotherapy agent for HCC. The present study investigated factors associated with early tumor progression of atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice. METHODS: A total of 184 HCC patients who received atezolizumab plus bevacizumab therapy were studied. We investigated the frequency of early progressive disease (e-PD; PD within 9 weeks) and analyzed the risk factors for e-PD. RESULTS: There were 47 patients (25.5%) diagnosed as e-PD. Patients with e-PD had a worse performance status (PS) and albumin-bilirubin (ALBI) and Child-Pugh (C-P) scores and a significantly higher rate of a systemic therapy than those with non-e-PD. A multivariate analysis showed that PS ≥1 (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.9-10, p < 0.001), ALBI score ≥-2.30 (OR = 2.1, 95% CI = 1.0-4.5, p = 0.044) and the history of a systemic therapy (OR = 3.0, 95% CI = 1.4-6.4, p = 0.0038) were significant and independent determinants of e-PD. When examining the liver function trends in e-PD patients, the ALBI scores at 3 and 6 weeks after starting therapy were significantly higher than before the treatment (p < 0.001). CONCLUSIONS: The liver function and systemic therapy are useful predictors of e-PD in HCC patients treated with atezolizumab plus bevacizumab in real-world clinical practice.

DOI： 10.1002/cam4.6369

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Liver fibrosis is an important phenomenon in non-alcoholic fatty liver disease (NAFLD) progression. Standard markers reflecting liver fibrosis, including the FIB-4 index, increase with age. This study aimed to identify fibrosis progression-related markers that are diagnostically beneficial even in aged individuals. Serum levels of pro- and anti-inflammatory cytokines were measured by multiple enzyme-linked immunosorbent assay. Two standard NAFLD or fibrosis progression-related markers - the FIB-4 index and APRI score - were analyzed along with cytokine levels to define the best approach to discriminate advanced fibrosis. Ninety-eight NAFLD patients were enrolled: 59 and 39 patients with fibrosis stages 1-2 and 3-4 respectively. In addition to the FIB-4 index and APRI score, the following factors showed significant differences between stages 1-2 and stages 3-4 in a multivariate analysis: platelet counts, IP-10, and RANTES. The fibrosis stage, FIB-4, APRI, PDGF-BB, and RANTES were related to the prognosis. In aged patients, IP-10, GM-CSF, and RANTES differed between stages 1-2 and stages 3-4. FIB-4 and APRI were beneficial for their correlation with fibrosis. However, to stratify either young or elderly advanced fibrosis patients, and to identify patients likely to have a bad outcome, RANTES was the best marker.

DOI： 10.18926/AMO/65748

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BACKGROUND/PURPOSE: Primary sclerosing cholangitis (PSC) is a rare chronic liver disease. The mechanisms and prediction of PSC progression are unclear. Recent investigations have shown that general conditions, such as oxidative stress, affect the course of chronic diseases. We investigated the clinical course and oxidative stress-related condition of PSC to determine prognostic factors. METHODS: We recruited 58 patients with PSC (mean age; 37.4 years, mean observation period; 1382 days) who visited our department from 2003 to 2021. Clinical characteristics were investigated to define prognostic factors. Oxidative stress status was evaluated using two types of markers: an oxidative stress marker (serum reactive oxygen metabolite; dROM) and an antioxidant marker (serum OXY adsorbent test; OXY). RESULTS: The revised Mayo risk, Child-Pugh, model for end-stage liver disease-sodium (MELD-Na) scores or fibrosis-related FIB-4 index significantly predicted poor overall survival. High intestinal immunoglobulin A (IgA) levels predicted poor survival. Among patients with high and intermediate revised Mayo risk scores, those with physiologically high dROM levels showed better survival than those with lower dROM levels. In this population, dROM was negatively correlated with AST and IgA, which are both correlated with survival. CONCLUSIONS: High and intermediate revised Mayo risk score group predicted a poor clinical course in PSC. Additionally, the Child-Pugh score, MELD-Na score, FIB-4 index, and serum IgA were significantly correlated with survival. In patients with high and intermediate revised Mayo risk scores, physiologically high oxidative stress status correlated with low IgA levels and a good prognosis.

DOI： 10.1007/s12072-023-10557-2

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Language：Japanese   Publisher：日本消化器病学会-中国支部  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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This study sought to identify factors that are predictive of a therapeutic response to hepatic arterial infusion chemotherapy (HAIC) by focusing on the number of prior transcatheter arterial chemoembolization (TACE) sessions. To determine the parameters predicting a good response to HAIC, we retrospectively analyzed 170 patients with hepatocellular carcinoma (HCC) who received HAIC regimens comprising low-dose cisplatin combined with 5-fluorouracil (LFP) or cisplatin (CDDP) for the first time. In both the LFP and CDDP regimens, the response rates were significantly lower in patients with three or more prior TACE sessions than in those with two or fewer prior TACE sessions (LFP 57% versus 28%; p=0.01, CDDP 27% versus 6%; p=0.01). Multivariable logistic regression analysis revealed that the number of prior TACE sessions (≥ 3) was significantly associated with non-responder status (odds ratio 4.17, 95% Confidence Interval (CI) 1.76-9.86) in addition to the HAIC regimen. Multivariable analysis using the Cox proportional hazards model revealed that a larger number of prior TACE sessions (≥ 3) was a significant risk factor for survival (hazard ratio 1.60, 95% CI 1.12-2.29) in addition to Child-Pugh class, serum alpha-fetoprotein concentration, and maximum diameter of HCC. HCC patients who receive fewer prior TACE sessions (≤ 2) were found to be better responders to HAIC.

DOI： 10.18926/AMO/64120

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Anorexia nervosa (AN) can cause severe protein energy malnutrition and the consequent development of various organ disorders. AN is known to cause hepatic complications. We report two cases of starvation and refeeding-induced liver injury in patients with AN, and review the literature on the hepatic complications of AN. Acute liver injury can be induced by both starvation and refeeding, although the underlying pathomechanisms and management of liver injury differ between these two conditions. Clinicians should carefully identify the clinical features to ensure an accurate diagnosis and appropriate management of these conditions.

DOI： 10.2739/kurumemedj.MS6723011

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：日本消化器病学会-中国支部  

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Language：Japanese   Publisher：日本消化器病学会-中国支部  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: Some autoimmune hepatitis (AIH) patients experience relapse during their clinical course, and some risk factors for relapse have been identified previously using a relatively small sample size. The aim of the present study was to identify the risk factors for relapse in recently diagnosed AIH patients using a nationwide survey in Japan. METHODS: The nationwide survey performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017 was re-evaluated. A total of 614 patients who received corticosteroids were enrolled in the present study. Associations between relapse and patients' characteristics at diagnosis were evaluated using logistic regression analysis. RESULTS: Relapse was identified in 143 (23.3%) patients after remission. At the time of diagnosis of the disease, there were significant differences in the γ-glutamyl transpeptidase (γ-GTP) level, prevalence of liver cirrhosis, and degree of liver fibrosis. Multivariable logistic regression analysis showed that γ-GTP elevation and liver cirrhosis were significantly associated with relapse. CONCLUSION: The γ-GTP level at diagnosis could help identify AIH patients at higher risk of relapse. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13766

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS: Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS: The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS: Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

DOI： 10.1007/s11605-021-05197-6

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Language：Japanese   Publisher：(一社)日本成人先天性心疾患学会  

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BACKGROUND: The number of patients with non-functional neuroendocrine tumors (NETs) has increased recently, and the rate of liver metastasis of NETs is about 20% in patients at the first diagnosis. Transcatheter arterial embolization (TAE) and everolimus are therapies with reported efficacy, but few reports have described their combined treatment. We therefore aim to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastasis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in a prospective study. METHODS: We design a single-arm, open-label, prospective study to evaluate the efficacy and safety of combination therapy with everolimus and TAE in patients with liver metastases of GEP-NETs. The study started in June 2021 at Okayama University Hospital and is expected to enroll 18 patients over a 2-year period. DISCUSSION: This study is a prospective study investigating a new treatment method for a rare disease called GEP-NETs. We may obtain useful information that contributes to the treatment guidelines in this study. However, NET is a rare disease, and although the number of cases is statistically established, it may not be possible to accurately assess causality.TRIAL REGISTRATION NUMBER: jRCT1061210015.

DOI： 10.1177/11795549221127750

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Focal nodular hyperplasia (FNH) is a benign nodular lesion, but because of its feature of portal tract vessel abnormality, it may induce portal hypertension. A 27-year-old woman was admitted with a fever. A large nodule with satellite lesions was found in the liver and cotton wool-like feature of arteries were detected on angiography. Technetium galactosyl serum albumin scintigraphy and diagnostic laparoscopy showed that the tumor site was functional, while the surrounding area was a non-functional fibrotic area. A biopsy specimen indicated that the nodular lesion was an FNH-like lesion. She experienced several instances of variceal rupture and suffered liver failure, receiving liver transplantation. The excised liver showed a centrally scarred area in the nodule, indicating that the diagnosis was FNH. We herein report this case as a rare case of FNH that progressed to liver failure.

DOI： 10.1007/s12328-021-01529-w

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BACKGROUND: It remains unclear which factors, such as tumor volume and tumor invasion, influence circulating tumor DNA (ctDNA), and the origin of ctDNA in liquid biopsy is always problematic. To use liquid biopsies clinically, it will be very important to address these questions. AIM: To assess the origin of ctDNA, clarify the dynamics of ctDNA levels, assess ctDNA levels by using a xenograft mouse after treatment, and to determine whether tumor volume and invasion are related to ctDNA levels. METHODS: Tumor xenotransplants were established by inoculating BALB/c-nu/nu mice with the TE11 cell line. Groups of mice were injected with xenografts at two or four sites and sacrificed at the appropriate time point after xenotransplantation for ctDNA analysis. Analysis of ctDNA was performed by droplet digital PCR, using the human telomerase reverse transcriptase (hTERT) gene. RESULTS: Mice given two-site xenografts were sacrificed for ctDNA at week 4 and week 8. No hTERT was detected at week 4, but it was detected at week 8. However, in four-site xenograft mice, hTERT was detected both at week 4 and week 6. These experiments revealed that both tumor invasion and tumor volume were associated with the detection of ctDNA. In resection experiments, hTERT was detected at resection, but had decreased by 6 h, and was no longer detected 1 and 3 d after resection. CONCLUSION: We clarified the origin and dynamics of ctDNA, showing that tumor volume is an important factor. We also found that when the tumor was completely resected, ctDNA was absent after one or more days.

DOI： 10.3748/wjg.v27.i41.7134

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Language：Japanese   Publisher：日本消化器病学会-中国支部  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.

DOI： 10.1007/s12185-021-03157-z

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20210811100004&doc_link_id=10.2957%2Fkanzo.62.463&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.62.463&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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AIM: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin is beneficial to patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. This study aimed to examine the effect of HAIC with cisplatin before radiofrequency ablation (RFA) in patients with HCC. METHODS: This was a multicenter, single-blinded, randomized controlled study (UMIN000007267). Early-stage HCC patients were randomly assigned (1:1) to receive HAIC with cisplatin before RFA therapy (HAIC group) or RFA monotherapy (non-HAIC group). The primary end-point was recurrence-free survival. Efficacy analysis and safety analysis followed the intention-to-treat principle. RESULTS: Between August 2012 and July 2016, 74 patients were recruited. A total of 70 eligible patients were randomly assigned to the HAIC group (n = 35) and non-HAIC group (n = 35). Recurrence-free survival rates at 1 (3) year in the HAIC group and non-HAIC group were 82.9% (54.3%) and 74.3% (34.3%), respectively (hazard ratio [HR], 0.597; 95% confidence interval [CI], 0.320-1.091; p = 0.094]. Subgroup analysis showed that the beneficial effect of HAIC was observed in patients with a single nodule and Child-Pugh score 5. Intrahepatic distant recurrence-free survival rate in the HAIC group was significantly better than that in the non-HAIC group (HR, 0.468; 95% CI, 0.235-0.896; p = 0.022). Adverse events were observed in just two patients in the HAIC group (6%) - grade 2 cholecystitis and grade 2 hyperkalemia. CONCLUSIONS: HAIC with cisplatin before RFA did not significantly decrease recurrence in patients with early-stage HCC. However, it might be effective in preventing intrahepatic distant recurrence.

DOI： 10.1111/hepr.13633

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Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume.

DOI： 10.3390/ijms22115582

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AIM: Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development. METHODS: Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH). RESULTS: Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval, 3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p < 0.001); however, no difference in the positive rate of AFP-L3 was observed between patients with and without fatty livers and between patients with normal and abnormal transaminase. The same relationship was also observed in the validation cohort. CONCLUSION: Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.

DOI： 10.1111/hepr.13626

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Language：Japanese   Publisher：日本消化器病学会-中国支部  

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BACKGROUND ANDAIM: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. METHODS: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. RESULTS: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were -124bp G > A and 10 were -146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. CONCLUSIONS: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

DOI： 10.1111/jgh.15227

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

DOI： 10.1007/s00795-020-00255-5

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Other Link： https://link.springer.com/article/10.1007/s00795-020-00255-5/fulltext.html

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BACKGROUND: We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC). METHODS: Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases. RESULTS: In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased. CONCLUSIONS: Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.

DOI： 10.1007/s00535-020-01748-x

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DOI： 10.2957/kanzo.62.463

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/hepr.13573

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13573

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Health-related quality of life (HRQOL) is lower in individuals with autoimmune hepatitis (AIH) than in the general population. However, previous evaluations of HRQOL for AIH have included a broad range of disease activities. The aim of this study was to clarify HRQOL among patients with AIH in remission.We assessed HRQOL in patients with AIH in remission, patients with chronic hepatitis C (CHC) with eradicated hepatitis C virus (HCV) and patients with primary biliary cholangitis (PBC) using the Japanese version of the Chronic Liver Disease Questionnaire (CLDQ).Participants comprised 62 patients with AIH in remission, 39 patients with CHC with eradicated HCV and 66 patients with PBC. Median ages of patients were 63, 69, and 64 years, respectively. Overall score (5.6 vs 5.9, P = .02) and fatigue (5.2 vs 5.6, P = .01) and worry (5.6 vs 6.0, P = .01) domain scores of the CLDQ were significantly lower in patients with AIH in remission than in CHC with eradicated HCV, and similar to scores except for the systemic symptoms domain in patients with PBC. Disease duration was associated with lower scores on systemic symptoms and activity domains of the CLDQ in patients with AIH in remission.Patients with AIH in remission show impaired HRQOL associated with disease duration.

DOI： 10.1097/md.0000000000022764

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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The Japanese diagnostic guidelines for autoimmune hepatitis (AIH) were proposed in 2014. This study aimed to determine the trends and characteristics of AIH based on a Japanese nationwide survey. Data for 796 patients who were newly diagnosed with AIH from 2014 to 2017 were collected from January to March, 2019 from 54 hospitals throughout Japan. Clinical characteristics, including treatment, were compared with those reported in a prior 2015 survey. The population had a median age of 63 years at diagnosis, and the male to female ratio was 1:5.3. The numbers of women was significantly lower in this survey than in the 2015 survey. Moreover, the incidence of AIH with histological acute hepatitis increased significantly from 11.0 to 21.7%. The changes in the laboratory findings, such as in transaminase and immunoglobulin G levels and antinuclear antibody titers, as well as in prednisolone treatment, reflected an increasing incidence of acute AIH. The clinical characteristics of AIH changed rapidly, in parallel with the increasing incidence of acute AIH. The elucidation and diagnosis of AIH with acute hepatitis are important in the management of AIH.

DOI： 10.1038/s41598-020-71296-0

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Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is a promising method for controlling tumors, although it does not entirely eliminate recurrence. Oxidative stress is associated with the progression of hepatocarcinogenesis, while also acting as an anticancer response. The objective of the present study was to investigate the factors influencing post-RFA outcomes. We recruited 235 newly diagnosed HCC patients who received RFA for single tumors. The patients with recurrence were sub-grouped into early and segmental recurrence groups. The characteristics of the sub-grouped patients were evaluated, including by measuring oxidative stress marker reactive oxygen metabolites and antioxidant marker OXY-adsorbent tests. The factors associated with poor survival were a high Child-Pugh score and early recurrence within 2 years in the same segment. The patients who experienced recurrence within 2 years in the same segment showed a larger tumor diameter than did others. According to a multivariate analysis, the OXY values were also significantly low in these patients. In conclusion, maintaining the antioxidant reservoir function with a high OXY value might be necessary to prevent early recurrence within the RFA-treated segment.

DOI： 10.18926/AMO/60364

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Introduction: Molecular targeting drugs are recommended as second-line treatment for intrahepatic advanced hepatocellular carcinoma (HCC). However, in Asia, hepatic arterial infusion chemotherapy (HAIC) is also considered as a second-line treatment because it improves the survival of responders. The aim of this study was to predict responders and non-responders to HAIC with low-dose cisplatin plus 5-fluorouracil (LFP) using tumor markers. Objective and Methods: The data of 47 patients who received LFP for the first time in our hospital were analyzed retrospectively. We evaluated the association between treatment response by Response Evaluation Criteria in Solid Tumors and the changing ratio of the serum concentration of α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxy prothrombin (DCP) 2 weeks after LFP initiation. Results: The number of patients showing a complete response (CR), a partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 20 (43%), 18 (38%), and 9 (19%), respectively. The AFP ratio showed significant positive correlations for PR vs. SD (p = 0.004) and PR vs. PD (p = 0.003). The DCP ratio correlated significantly for PR vs. SD (p = 0.02). The optimal cutoff values for responders were 0.79 for the AFP ratio and 0.53 for the DCP ratio. Prediction using both or either cutoff value showed 93% sensitivity, 53% specificity, a 94% negative predictive value, and a 57% positive predictive value. Conclusion: Optimal cutoff values for AFP and DCP ratios enable prediction of nonresponders to HAIC with LFP. This simple and early assessment method allows the use of HAIC and molecular targeting drugs for HCC treatment.

DOI： 10.1159/000506941

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients' disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis.

DOI： 10.3390/nu12061576

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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DOI： 10.1007/s00535-019-01645-y

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A 78-year-old man with chronic hepatitis C underwent hepatectomy for hepatocellular carcinoma (HCC) 11 years prior to presentation. He was diagnosed with multiple intrahepatic recurrences of HCC with portal vein invasion and received hepatic arterial infusion chemotherapy (HAIC) with cisplatin. He developed abdominal pain, diarrhea, and blood-stained stool following treatment. Computed tomography revealed significant bowel wall thickening throughout the colon. Colonoscopy revealed reddish edematous mucosa with a reduced vascular pattern without ischemic changes. Conservative treatment with total parenteral nutrition improved his condition and his imaging findings. This is the first report of severe colitis following HAIC with cisplatin.

DOI： 10.2169/internalmedicine.3340-19

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BACKGROUND: Mutations in the human telomerase reverse transcriptase (hTERT) gene promoter have been reported in hepatocellular carcinoma (HCC); however, analyses of these mutations in liquid biopsies have been technically difficult because of the high GC content of the regions of interest within this promoter. We evaluated the feasibility and prognostic value of hTERT promoter mutations identified in circulating cell-free DNA (cfDNA) from the serum of patients with HCC. OBJECTIVE: A cohort of HCC patients (n = 36) who were curatively treated by surgical resection between June 2003 and September 2014 were enrolled in this study. METHODS: The presence of hTERT promoter mutations in cfDNA from the patients' serum was analyzed via modified droplet digital polymerase chain reaction, and associations were sought between specific promoter mutations and patients' disease-free survival (DFS). RESULTS: The G>A hTERT mutation at -124 bp was detected in the serum of 25 patients (69%). Although no marked differences were observed between the characteristics of the serum mutation-positive and serum mutation-negative patient groups, the DFS of patients with the mutation was significantly shorter than that of the serum mutation-negative patients (p = 0.02). Among 18 clinicopathologic and background liver factors examined, the presence of the -124 bp G>A mutation was an independent and significant predictor of patients' DFS (hazard ratio = 3.01, 95% confidence interval 1.11-10.5, p = 0.03) in multivariate analyses. CONCLUSIONS: The -124 bp G>A hTERT promoter mutation was observed in the serum of 69% of HCC patients who underwent surgical resection and was an independent predictor of disease progression in HCC.

DOI： 10.1159/000506135

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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This study will assess the safety and efficacy of the administration of adenoviral vector expressing the human-reduced expression in immortalized cells (Ad-REIC) to a liver tumor in patients with hepatocellular carcinoma (HCC) or liver metastasis of pancreatic cancer. A Phase I clinical study of Ad-REIC administration to a liver tumor in a patient with HCC or liver metastasis of pancreatic cancer will be conducted. The study is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed in Okayama University Hospital, Okayama, Japan. Ad-REIC will be injected into the liver tumor under ultrasound guidance. Ad-REIC administration will be repeated a total of three-times every 2 weeks. The primary end point is the dose-limiting toxicity and incidence of adverse events. The secondary end points are the objective response rate and disease control rate. This study aims to expand the indication of Ad-REIC by assessing its safety and efficacy in patients with HCC or liver metastasis of pancreatic cancer.

DOI： 10.2217/fon-2019-0115

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DOI： 10.1007/s00535-019-01586-6

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本消化器病学会-中国支部  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Steroids are often administered at the time of transcatheter arterial chemoembolization (TACE), a standard treatment of hepatocellular carcinoma (HCC), with the expectation of preventing postembolization syndrome. Here we investigated the precise effects of steroids on TACE. We prospectively enrolled 144 HCC patients from 10 hospitals who underwent TACE. Three hospitals used steroids (steroid group, n=77) and the rest did not routinely use steroids (control group, n=67). The occurrence of adverse events and the algetic degree at 1-5 days post-treatment were compared between the groups. Fever (grades 0-2) after TACE was significantly less in the steroid group (56/21/0) compared to the control group (35/29/3, p=0.005, Cochran-Armitage test for trend). The suppressive effect of steroids against fever was prominent in females (p=0.001). Vomiting (G0/G1/ G2-) was also less frequent in the steroid group (70/5/2) versus the control group (53/10/3), but not significantly (p=0.106). The algetic degree and the grade of hematological adverse events, including hyperglycemia, did not differ between the groups. We conclude that the administration of steroids was useful for the prevention of adverse events after TACE in patients with HCC.

DOI： 10.18926/AMO/56935

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BACKGROUND AND AIM: Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment. METHODS: We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. RESULTS: Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen. CONCLUSIONS: Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib.

DOI： 10.1111/jgh.14535

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Language：Japanese   Publisher：日本消化器病学会-四国支部  

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Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as "cancer-eliminating agents" or as products to improve one's health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.

DOI： 10.3390/cancers11020213

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Post-orthotopic liver transplantation (OLT) hepatitis B recurrence is well-controlled with a nucleos(t)ide analogue and hepatitis B immunoglobulin (HBIG) combination, but the high cost and the potential risk of unknown infection associated with HBIG remain unresolved issues. Low-cost recombinant hepatitis B virus (HBV) vaccine administration is a potential solution to these problems. We retrospectively analyzed the rate and predictive factors of HBV vaccine success in 49 post-OLT patients: liver cirrhosis-type B (LC-B), n=28 patients; acute liver failure-type B (ALF-B), n=8; and non-HBV-related end-stage liver disease (non-B ESLD) who received a liver from anti-hepatitis B core antibody-positive donors, n=13. A positive anti-hepatitis B surface antibody response was achieved in 29% (8/28) of the LC-B group, 88% (7/8) of the ALF-B group, and 44% (4/9) of the adult non-B ESLD group. All four non-B ESLD infants showed vaccine success. The predictive factors for a good response in LC-B were young age, marital donor, and high donor age. ALF-B and non-B ESLD infants are thus good vaccination candidates. LC-B patients with marital donors are also good candidates, perhaps because the donated liver maintains an efficient immune memory to HBV, as the donors had already been infected in adulthood and showed adequate anti-HBV immune responses.

DOI： 10.18926/AMO/56457

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.13288

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DOI： 10.1248/yakushi.18-00170

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The herbal medicine berberine (BBR) has been recently shown to be an AMP-activated protein kinase (AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4+T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). We examined the favorable effects of BBR in vitro, using lamina propria (LP) CD4+ T cells in T cell transfer IBD models in which SCID mice had been injected with CD4+CD45RBhigh T cells. BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4+ T cells. This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. We then examined the effects of BBR on the same IBD models in vivo. BBR-fed mice showed AMPK activation in the LPCD4+ T cells and an improvement of colitis. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4+ T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation.

DOI： 10.1038/s41598-019-48331-w

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DOI： 10.1186/s13256-018-1901-y

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Gastroenterological Endoscopy Society  

DOI： 10.11280/gee.60.2297

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BACKGROUND: Autoimmune hepatitis (AIH) is characterized by progressive inflammation and necrosis of hepatocytes and eventually leads to a variety of phenotypes, including acute liver dysfunction, chronic progressive liver disease, and fulminant hepatic failure. Although the precise mechanisms of AIH are unknown, environmental factors may trigger disease onset in genetically predisposed individuals. Patients with the recently established entity of AIH with acute presentation often display atypical clinical features that mimic those of acute hepatitis forms even though AIH is categorized as a chronic liver disease. The aim of this study was to identify the precise clinical features of AIH with acute presentation. METHODS: Eighty-six AIH patients with acute presentation were retrospectively enrolled from facilities across Japan and analyzed for clinical features, histopathological findings, and disease outcomes. RESULTS: Seventy-five patients were female and 11 were male. Patient age ranged from adolescent to over 80 years old, with a median age of 55 years. Median alanine transaminase (ALT) was 776 U/L and median immunoglobulin G (IgG) was 1671 mg/dL. There were no significant differences between genders in terms of ALT (P = 0.27) or IgG (P = 0.51). The number of patients without and with histopathological fibrosis was 29 and 57, respectively. The patients with fibrosis were significantly older than those without (P = 0.015), but no other differences in clinical or histopathological findings were observed. Moreover, antinuclear antibody (ANA)-positive (defined as × 40, N = 63) and -negative (N = 23) patients showed no significant differences in clinical or histopathological findings or disease outcomes. Twenty-five patients experienced disease relapse and two patients died during the study period. ALP ≥ 500 U/L [odds ratio (OR) 3.20; 95% confidence interval (CI) 1.12-9.10; P < 0.030] and GGT ≥ 200 U/L (OR 2.98; 95% CI 1.01-8.77; P = 0.047) were identified as independent risk factors of disease relapse. CONCLUSIONS: AIH with acute presentation is a newly recognized disease entity for which diagnostic hallmarks, such as ALT, fibrosis, and ANA, are needed. Further investigation is also required on the mechanisms of this disorder. Clinicians should be mindful of disease relapse during patient care.

DOI： 10.1007/s00535-018-1444-4

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Language：Japanese   Publisher：(一社)日本移植学会  

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DOI： 10.1038/s41598-018-31063-8

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Daclatasvir (DCV) + asunaprevir (ASV) combination therapy has become available for patients with hepatitis C virus (HCV) serogroup 1 infection. We studied the efficacy of this therapy by focusing on the factors associated with sustained virological responses (SVR) including resistance-associated variants (RAVs) and mixed infection of different HCV genotypes. We enrolled 951 HCV serogroup 1-positive patients who received this combination therapy at our hospital or affiliated hospitals. The presence of RAVs in non-structural (NS) regions 3 and 5A was analyzed by direct sequencing. HCV genotypes were determined by PCR with genotype-specific primers targeting HCV core and NS5B regions. SVR was achieved in 91.1% of patients. Female sex, age > 70 years, and RAVs were significantly associated with non-SVR (p<0.01 for all). Propensity score-matching results among the patients without RAVs regarding sex, age, and fibrosis revealed that mixed HCV infection determined by HCV NS5B genotyping showed significantly lower SVR rates than 1B-mono infection (p=0.02). Female sex and RAVs were significant factors associated with treatment failure of this combination therapy for patients with HCV serogroup 1 infection. Mixed HCV infection other than 1B-mono infection would be useful for predicting treatment failure.

DOI： 10.18926/AMO/56178

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Oxidative stress is being recognized as a key factor in the progression of chronic liver disease (CLD), especially non-alcoholic fatty liver disease (NAFLD). Many NAFLD treatment guidelines recommend the use of antioxidants, especially vitamin E. Many prospective studies have described the beneficial effects of such agents for the clinical course of NAFLD. However, as these studies are usually short-term evaluations, lasting only a few years, whether or not antioxidants continue to exert favorable long-term effects, including in cases of concomitant hepatocellular carcinoma, remains unclear. Antioxidants are generally believed to be beneficial for human health and are often commercially available as health-food products. Patients with lifestyle-related diseases often use such products to try to be healthier without practicing lifestyle intervention. However, under some experimental NAFLD conditions, antioxidants have been shown to encourage the progression of hepatocellular carcinoma, as oxidative stress is toxic for cancer cells, just as for normal cells. In this review, we will highlight the paradoxical effects of antioxidants against NAFLD and related hepatocellular carcinoma.

DOI： 10.3390/nu10080977

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier USA  

DOI： 10.1016/j.transproceed.2017.11.078

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Unfortunately, in the original publication of this article, the copyright line was incorrectly published in PDF as "© The Author(s) 2017" instead of "©The Author(s) 2017 This article is an open access publication" and also the CC-BY description was not included. The description should be as follows.

DOI： 10.1007/s00535-017-1409-z

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BACKGROUND: Portopulmonary hypertension (POPH) is characterized by pulmonary vasoconstriction, while hepatopulmonary syndrome (HPS) is characterized by vasodilation. Definite POPH is a risk factor for the survival after orthotopic liver transplantation (OLT), as the congestive pressure affects the grafted liver, while subclinical pulmonary hypertension (PH) has been acknowledged as a non-risk factor for deceased donor OLT. Given that PH measurement requires cardiac catheterization, the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography is used to screen for PH and congestive pressure to the liver. We investigated the impact of a subclinical high TRPG on the survival of small grafted living donor liver transplantation (LDLT). METHODS: We retrospectively analyzed 84 LDLT candidates. Patients exhibiting a TRPG ≥25 mmHg on echocardiography were categorized as potentially having liver congestion (subclinical high TRPG; n = 34). The mean pulmonary artery pressure (mPAP) measured after general anesthesia with FIO20.6 (mPAP-FIO20.6) was also assessed. Patients exhibiting pO2 < 80 mmHg and an alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg were categorized as potentially having HPS (subclinical HPS; n = 29). The clinical course after LDLT was investigated according to subclinical high TRPG. RESULTS: A subclinical high TRPG (p = 0.012) and older donor age (p = 0.008) were correlated with a poor 40-month survival. Although a higher mPAP-FIO20.6 was expected to correlate with a worse survival, a high mPAP-FIO20.6 with a low TRPG was associated with high frequency complicating subclinical HPS and a good survival, suggesting a reduction in the PH pressure via pulmonary shunt. CONCLUSION: In cirrhosis patients, mPAP-FIO20.6 may not accurately reflect the congestive pressure to the liver, as the pressure might escape via pulmonary shunt. A subclinical high TRPG is an important marker for predicting a worse survival after LDLT, possibly reflecting congestive pressure to the grafted small liver.

DOI： 10.1186/s12876-018-0793-z

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BACKGROUND: Invasive fungal infection (IFI) is associated with high mortality after living donor liver transplant (LDLT). The aim of this study was to identify the risk factors for post-LDLT IFI for early diagnosis and improvement of antifungal treatment outcome. METHODS: Risk analysis data were available for all 153 patients who underwent LDLT between January 2005 and April 2012. RESULTS: During the follow-up period (1,553 ± 73 days, range 20-2,946 days), 15 patients (9.8%) developed IFI classified as "proven" (n = 8) and "probable" (n = 7) with fungal pathogens including Candida spp. (n = 10), Aspergillus spp. (n = 4), and Trichosporon (n = 2). Of these patients, 7 patients with IFI died despite treatment. The 1-, 3-, and 5-year survival rates were lower in patients with IFI than those without IFI (66.7/59.3/44.4 vs. 90.4/85.7/81.8%, respectively; p = 0.0026). Multivariate analysis identified model for end-stage liver disease score of ≥26 (OR 16.0, p = 0.0012) and post-transplant acute kidney injury (RIFLE criteria I- or F-class; OR 4.87, p = 0.047) as independent risk factors for IFI. CONCLUSION: Preoperative recipients' status and postoperative kidney dysfunction can affect an occurrence of post-transplant IFI. These risk factors would be taken into consideration for designation of proper antifungal therapy.

DOI： 10.1159/000486548

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BACKGROUND AND AIM: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing all over the world. NAFLD develops in patients with liver disease, including patients with autoimmune hepatitis (AIH). NAFLD and AIH have some similar laboratory and histological findings. The aim of this study was to elucidate the characteristics of AIH patients with NAFLD. METHODS: We re-evaluated the nationwide survey performed in Japan in 2015 of AIH patients diagnosed between 2009 and 2013. RESULTS: A total of 1151 subjects (144 men and 1007 women) were enrolled in the present study. The overall prevalence of NAFLD was 17.0%. Compared to AIH without NAFLD, AIH patients with NAFLD had the following characteristics: (i) low female-to-male ratio, (ii) older age, (iii) mild elevation in hepatobiliary enzymes, (iv) histologically progressive fibrosis and mild plasma cell infiltration or mild lobular hepatitis, (v) lower prevalence of prednisolone administration and higher prevalence of ursodeoxycholic acid administration, (vi) higher levels of hepatic enzymes and immunoglobulin G after treatment, and (vii) similar prevalence of autoimmune and malignant complications. CONCLUSION: AIH patients with NAFLD have many features that are different from AIH patients without NAFLD. Understanding these differences is essential for the proper diagnosis and treatment of AIH patients with NAFLD.

DOI： 10.1002/jgh3.12046

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Transcatheter arterial chemoembolization (TACE) is often performed before radiofrequency ablation (RFA) for the treatment of early-stage hepatocellular carcinoma (HCC). TACE prior to RFA can expand the ablated area and reduce the tumor size, facilitating complete ablation. However, the factors correlated with size reduction remain uncertain. The aim of this study was to identify the factors associated with size reduction by TACE and develop a formula to predict the reduction rate. A total of 100 HCC patients treated with TACE followed by RFA at least 20 days later were enrolled. The tumor size was measured at the time of TACE and RFA, and correlations between the reduction rate and 13 clinical factors were examined. A formula to predict the reduction rate was built using the factors obtained by the analysis. Reduction in the tumor size was observed in 69 nodules, and the median reduction rate was 16.2%. A multivariate regression analysis revealed that a large tumor size (p< 0.01) and a long interval between the therapies (p= 0.01) were factors for a high tumor reduction rate, with tumor size more strongly related to the degree of reduction. A size reduction of more than 10% can be expected by waiting 20 days after TACE when the size of the tumor at TACE is over 25 mm in diameter. The tumor size.

DOI： 10.18926/AMO/55662

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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AIM: Health-related quality of life is impaired in patients with autoimmune hepatitis, but the association between health-related quality of life and patients' backgrounds remains unknown. We assessed health-related quality of life in patients with autoimmune hepatitis and identified factors associated with its impairment. METHODS: We assessed health-related quality of life in patients with autoimmune hepatitis, patients with chronic hepatitis C, and healthy subjects using the Japanese version of the Chronic Liver Disease Questionnaire and the 36-Item Short Form Survey. We compared health-related quality of life in patients with autoimmune hepatitis with that of patients with chronic hepatitis C and healthy subjects. RESULTS: A total of 265 patients with autoimmune hepatitis, 88 patients with chronic hepatitis C, and 97 healthy subjects were enrolled; most patients were women. The median ages of patients were 65, 66, and 57 years, respectively. Of these patients with autoimmune hepatitis, 10.6% and 57.0% had cirrhosis and comorbid diseases, respectively. The overall Chronic Liver Disease Questionnaire scores (5.5 vs. 6.2, P < 0.001) and physical (48.1 vs. 54.2, P < 0.001) and mental (51.8 vs. 55.0, P = 0.004) component summaries of 36-Item Short Form Survey were significantly lower in patients with autoimmune hepatitis than in healthy subjects, and similar to scores in patients with chronic hepatitis C. Having cirrhosis, comorbid diseases, and treatment for autoimmune hepatitis were associated with impaired health-related quality of life among patients with autoimmune hepatitis. In particular, prednisolone use was associated with lower scores on the worry domain of the Chronic Liver Disease Questionnaire. CONCLUSIONS: Patients with autoimmune hepatitis showed impairment in health-related quality of life, which was associated with not only disease progression, but also comorbid diseases and treatment. Ways to improve health-related quality of life should be considered in patients with AIH when disease outcome is not favorable and when using prednisolone.

DOI： 10.1371/journal.pone.0204772

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

DOI： 10.2957/kanzo.59.625

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00263&link_issn=&doc_id=20171128110001&doc_link_id=10.2957%2Fkanzo.58.599&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.58.599&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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Determining the indications for and timing of liver transplantation (LT) for acute liver failure (ALF) is essential. The King's College Hospital (KCH) guidelines and Japanese guidelines are used to predict the need for LT and the outcomes in ALF. These guidelines' accuracy when applied to ALF in different regional and etiological backgrounds may differ. Here we compared the accuracy of new (2010) Japanese guidelines that use a simple scoring system with the 1996 Japanese guidelines and the KCH criteria for living donor liver transplantation (LDLT). We retrospectively analyzed 24 adult ALF patients (18 acute type, 6 sub-acute type) who underwent LDLT in 1998-2009 at our institution. We assessed the accuracies of the 3 guidelines' criteria for ALF. The overall 1-year survival rate was 87.5%. The new and previous Japanese guidelines were superior to the KCH criteria for accurately predicting LT for acute-type ALF (72% vs. 17%). The new Japanese guidelines could identify 13 acute-type ALF patients for LT, based on the timing of encephalopathy onset. Using the previous Japanese guidelines, although the same 13 acute-type ALF patients (72%) had indications for LT, only 4 patients were indicated at the 1st step, and it took an additional 5 days to decide the indication at the 2nd step in the other 9 cases. Our findings showed that the new Japanese guidelines can predict the indications for LT and provide a reliable alternative to the previous Japanese and KCH guidelines.

DOI： 10.18926/AMO/55435

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Several studies have indicated that periodontitis is a risk factor for cancer. However, the association between periodontitis and the prognosis of pancreatobiliary tract cancer remains unclear. The aim of this pilot study was to investigate the association between periodontitis and prognosis of pancreatobiliary tract cancer. A total of 22 patients diagnosed with pancreatobiliary tract cancer were analyzed. Oral health status, including severity of periodontitis, general health status and biochemical serum markers were evaluated. The Kaplan-Meier method and Cox proportional hazards model were used to assess factors affecting the prognosis of pancreatobiliary tract cancer. The Kaplan-Meier analysis demonstrated that low body mass index, high concentration of serum C-reactive protein (CRP) and severe periodontitis were significant prognostic factors for survival rate. The Cox proportional hazards model revealed that serum carbohydrate antigen 19-9 concentration [hazard ratio (HR)=1.002; 95% confidence interval (CI): 1.000-1.004] and serum CRP concentration (HR=2.57; 95% CI: 1.15-5.74) were significantly associated with the prognosis of pancreatobiliary tract cancer. In addition, cancer patients with severe periodontitis had higher serum CRP concentrations compared with those without severe periodontitis. Therefore, severe periodontitis indirectly affected the prognosis of pancreatobiliary tract cancer through promoting systemic inflammation.

DOI： 10.3892/mco.2017.1220

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier  

DOI： 10.1016/B978-0-12-804274-8.00012-6

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Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

DOI： 10.2169/internalmedicine.56.7002

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Language：English   Publishing type：Part of collection (book)   Publisher：CRC Press  

DOI： 10.1201/b20228

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NLM (Medline)  

DOI： 10.1155/2017/6418529

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DOI： 10.1155/2017/8193821

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Language：Japanese   Publisher：日本臨床免疫学会  

<p>【背景】生薬であるベルベリン（BBR）は下痢止めとして臨床応用されているが，抗炎症など多彩な作用も有することが明らかになっている．BBRは細胞のエネルギーの調節因子であるAMPKを活性化させることが知られており，近年，このAMPKがT細胞を含む免疫細胞の応答に関わっていることが報告されている．【目的，方法】慢性腸炎マウスモデルを用いて，大腸炎粘膜のCD4⁺T細胞（LP CD4⁺T細胞）におけるBBRの抗炎症作用とその機序についての検証をin vitroおよびIn vivoで行う．1）CD4⁺CD45RB^highT細胞移入腸炎マウスのLPCD4⁺T細胞をPMA/Ionomysinで刺激し，IFN-γ産生細胞を誘導，BBRの効果について，AMPKの関与も含めて検討．2）上記腸炎マウスにBBRを含んだ餌を投与し，腸炎の抑制効果について検討．【結果】1）LP CD4⁺T細胞はBBRと共培養すると，IFN-γ産生細胞が優位に低下し，ウェスタンブロッティングでは，AMPKの活性化を認めた．次に，AMPKのagonistとantagonistを用いた培養系でIFN-γの産生を調べたところ，agonistで抑制，antagonistで増加を認めた．以上から，BBRにより活性化されたAMPKがIFN-γを制御していることが示唆された．2）上記腸炎マウスにBBRを経口投与した結果，腸炎は優位に抑制された．【結論】BBRは，慢性腸炎マウスモデルの腸炎を抑制し，その作用機序の一つとしてAMPKを介した機序が示唆された．</p>

DOI： 10.2177/jsci.40.311b

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Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH. Methods We recruited patients with decompensated cirrhosis (n=69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolar-arterial oxygen gradient (AaDO2) 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study. Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p=0.037) and higher oxidative index values (p=0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p=0.049). The potential POPH patients exhibited elevated AaDO2, suggesting the presence of pulmonary shunting. Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

DOI： 10.2169/internalmedicine.54.4889

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Microenvironment plays an important role in epithelial-mesenchymal transition (EMT) and stemness of cells in hepatocellular carcinoma (HCC). Epithelial cell adhesion molecule (EpCAM) is known as a tumor stemness marker of HCC. To investigate the relationship between microenvironment and stemness, we performed an in vitro co-culture assay. Four HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) were co-cultured with the TWNT-1 immortalized hepatic stellate cells (HSCs), which create a microenvironment with HCC. Cell proliferation ability was analyzed by flow cytometry (FCM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while migration ability was assessed by a wound healing assay. Expression of EpCAM was analyzed by immunoblotting and FCM. HCC cell lines were co-cultured with TWNT-1 treated with small interfering RNA (siRNA) for TGF-β and HB-EGF; we then analyzed proliferation, migration ability and protein expression using the methods described above. Proliferation ability was unchanged in HCC cell lines co-cultured with TWNT-1. Migration ability was increased in HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) directly (216.2±67.0, 61.0±22.0, 124.0±66.2 and 51.5±40.3%) and indirectly (102.5±22.0, 84.6±30.9, 86.1±25.7 and 73.9±29.7%) co-cultured with TWNT-1 compared with the HCC uni-culture. Immunoblot analysis revealed increased EpCAM expression in the HCC cell lines co-cultured with TWNT-1. Flow cytometry revealed that the population of E-cadherin-/N-cadherin+ and EpCAM-positive cells increased and accordingly, EMT and stemness in the HCC cell line were activated. These results were similar in the directly and indirectly co-cultured samples, indicating that humoral factors were at play. Conversely, HCC cell lines co-cultured with siRNA‑treated TWNT-1 showed decreased migration ability, a decreased population of EpCAM-positive and E-cadherin-/N-cadherin+ cells. Taken together, humoral factors secreted from TWNT-1 promote upregulation of EpCAM and EMT in hepatic cancer cells.

DOI： 10.3892/or.2015.4126

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DOI： 10.1016/j.pan.2015.05.470

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DOI： 10.1097/MPA.0000000000000321

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DOI： 10.1002/jmv.24097

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BACKGROUND AND AIMS: Serum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). METHODS: We collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined. RESULTS: Among the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis. CONCLUSION: We clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

DOI： 10.1111/jgh.12726

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DOI： 10.4254/wjh.v7.i19.2220

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Language：English   Publisher：Okayama University Medical School  

DOI： 10.18926/AMO/53558

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Other Link： http://search.jamas.or.jp/link/ui/2016215092

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Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that leads to hyperviscosity and the risk of thrombosis. We encountered the case of a young male Filipino patient diagnosed with PV after the rupture of esophageal varices. The complete blood cell count showed a slight increase in white blood cells. An abdominal computed tomography scan disclosed splenomegaly and occlusion of the portal vein and collateral vessels. A blood examination demonstrated an increase in all three blood cell lines within three months. Based on the presence of severe hypercellularity of the bone marrow and positivity for the JAK2V617F mutation, we finally diagnosed the patient with PV.

DOI： 10.2169/internalmedicine.54.4687

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DOI： 10.1016/j.clinre.2013.11.005

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DOI： 10.1371/journal.pone.0100627

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DOI： 10.18926/AMO/52139

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DOI： 10.1097/MCG.0b013e3182a39116

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DOI： 10.1111/jgh.12340

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The impact of single-nucleotide polymorphisms (SNP) of patatin-like phospholipase domain-containing protein 3 (PNPLA3) on development of hepatocellular carcinoma (HCC) is not clarified for Japanese patients with chronic hepatitis C. The present study investigated the associations of rs738409 PNPLA3 with HCC development after the antiviral therapy with peg-interferon and ribavirin for Japanese patients with hepatitis C virus serotype 1 and high viral load. Of the 271 patients enrolled in the study, 20 patients developed HCC, during a median follow-up period of 4.6 years. Multivariate analysis in the proportional hazards models revealed that sex, body mass index, platelet counts, and alpha feroprotein (AFP) had significant associations with HCC development (p = 0.011, 0.029, 0.0002, and 0.046, respectively). Multivariate regression analysis revealed that PNPLA3 148 M was significantly associated with serum AFP level (p = 0.032), other than body mass index, platelet count, and alanine aminotransferase (p = 0.0006, 0.0002, and 0.037, respectively), and that serum AFP level was significantly associated with PNPLA3 148 M (p = 0.017). Serum AFP level is an important factor in predicting HCC development after the antiviral therapy for Japanese patients with chronic hepatitis C, the mechanism of which might involve its significant associations with the SNP genotype of PNPLA3.

DOI： 10.1186/2193-1801-2-251

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DOI： 10.1007/s00535-011-0508-5

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DOI： 10.1007/s12072-011-9265-z

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DOI： 10.1111/j.1600-051X.2011.01777.x

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DOI： 10.1186/1471-2407-11-458

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HCC patients with periodontitis had higher JIS score and circulating ROS level than HCC patients without periodontitis.

DOI： 10.1111/j.1600-051X.2011.01777.x

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DOI： 10.1111/j.1440-1746.2011.06737.x

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DOI： 10.1111/j.1872-034X.2010.00761.x

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DOI： 10.1111/j.1872-034X.2010.00757.x

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The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n=336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n=227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.

DOI： 10.18926/AMO/43825

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DOI： 10.1111/j.1440-1746.2010.06441.x

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DOI： 10.1182/blood-2010-06-289231

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DOI： 10.2169/internalmedicine.49.4221

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DOI： 10.1007/s12072-009-9155-9

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DOI： 10.1016/j.molonc.2008.06.004

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To examine the relationship between the length of the predialysis period and the pathogenesis of diabetic end-stage renal failure, we retrospectively studied 58 hemodialyzed patients (36 males, 22 females; 62.8±10.6 (SD) years). They were subgrouped into group A (n=34) or B (n=29), respectively, depending on whether hemodialysis was started less or more than 2 years after their serum creatinine concentration had reached 2mg/dL.<br>Group A patients were ten years younger than those of group B, and showed significantly higher urinary protein excretion, lower plasma albumin concentration, and larger renal size. The incidence of cerebral infarction was higher in group B. Multiple regression analysis demonstrated that the length of predialysis period was well correlated with both patients' age and renal size. These findings suggest that the major pathogenesis of renal failure is microangiopathic glomerulosclerosis in group A, and macroangiopathic nephrosclerosis in group B. The length of the predialysis period in each case must reflect the different involvements of these two mechanisums. Especially, in older hemodialyzed diabetic patients, the number of which has been increasing in recent years, nephrosclerosis may play a larger role in diabetic nephropathy.

DOI： 10.4009/jsdt.38.1385

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A 52-year-old man was admitted to our hospital because of nephrotic syndrome. He had been monitored at our outpatient clinic for chronic hepatitis B, and had experienced histologically proven minimal change nephrotic syndrome at the ages of 40 and 51 years. Because of HBsAg positivity in his serum, steroid therapy was withheld in his earlier episodes and he recovered from nephrotic syndrome spontaneously. However, in the most recent episode the nephrotic syndrome was found difficult to control and the findings of renal biopsy showed FSGS, which is not expected in HBV-associated nephropathy. Finally, prednisolone was administered at the dose of 40 mg/day for four weeks, after which the dose was tapered. LDL apheresis was also administered three times because of the patient's incomplete response to prednisolone. His proteinuria was reduced from>10 g/day to<1 g/day, but the ALT levels and HBsAg titer increased. With stronger neominophagen C induction and very careful tapering of glucocorticoid, ALT levels and the HBsAg titer decreased. During the two-year period since the induction of glucocor ticoid therapy, urinary protein excretion has been maintained at less than 1 g/gcr, and ALT levels and HBsAg titer have not increased. We conclude that attention must be paid to dose modification of steroid therapy and strategies without immunosuppressive agents such as LDL apheresis should be considered in the case of treatment of nephrotic syndrome with HB virus.

DOI： 10.14842/jpnjnephrol1959.44.806

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：BMJ Publishing Group  

DOI： 10.1136/bmjgast-2018-000260

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DOI： 10.1007/s00535-017-1396-0

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DOI： 10.1136/jclinpath-2016-204271

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DOI： 10.1111/jgh.13757

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