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Abstract Baveno VII criteria (B7C) and Baveno VI criteria (B6C) have been widely used to estimate the risk of hepatic decompensation. However, the impact of age on these criteria warrants further investigation. The international, multicenter cohort study included 1138 patients with compensated cirrhosis (median follow‐up of 40.6 months), aiming to evaluate the value of age in predicting hepatic decompensation. We identified age as an independent predictor of hepatic decompensation, with 60 years determined as the optimal cut‐off value. The occurrence of decompensation was 18.7% and 6.7% in the older (age ≥60 years) and younger (age 0.05). In conclusion, our study demonstrated that integrating age into the Baveno criteria could enhance the assessment of hepatic decompensation. Age should be considered before discharging patients with compensated cirrhosis from the surveillance of hepatic decompensation.

Abstract Aim This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma. Methods We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity‐score‐matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed‐effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow‐up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups. Results Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were −2.41 ± 0.40 and −2.44 ± 0.42 at baseline, and −2.17 ± 0.56 and −2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p

Abstract Aims The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment. Methods A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression‐free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c‐index) and Akaike information criterion (AIC) results. Results Cox‐hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI‐De) scoring system. For IMABALI‐De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p

Introduction The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post-hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab is equally effective in viral and non-viral patients. Methods We retrospectively analyzed 885 HCC patients treated with first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% non-viral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multi-variate models to explore potential differences on overall survival (OS), time to progression (TTP), disease control rates based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to second-line treatments and outcomes were also reported and compared between etiologies. Results Overall, no statistically significant differences were found in OS (mOS: viral 15.9 months; non-viral 16.3 months), TTP (mTTP: viral 8.3 months; non-viral 7.2 months), and disease control rates (DCR: viral 78.1%; non-viral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and non-viral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e. NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post-hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and non-viral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

Abstract Aim Multiple studies have revealed the correlation between gut microbiome and the response to checkpoint inhibitors (CPIs) in patients with cancer, and oral administration of butyrate‐producing enterobacteria has been reported to enhance the efficacy of CPIs. However, the effects of enterobacteria on patients with hepatocellular carcinoma (HCC) are not well understood. Methods In this retrospective multicenter study, we enrolled 747 patients with advanced HCC, treated with atezolizumab and bevacizumab combination therapy. Tumor response, survival, and adverse effects were compared between 99 patients who ingested drugs containing butyric acid‐producing enterobacteria (butyric acid group) and the remaining patients (control group). Results Objective response and disease control rates in butyric acid group (29.7% and 77.8%, respectively) were higher than those in the control group (26.4% and 72.7%, respectively). However, the differences were not statistically significant (p = 0.543 and p = 0.222, respectively). No difference in median survival time was observed between the two groups (20.0 months and 21.4 months, respectively; p = 0.789), even after matching the backgrounds of the patients with propensity scores (p = 0.714). No adverse effects occurred upon the administration of butyrate‐producing bacteria. However, proteinuria (41.4% vs. 30.9%; p = 0.041), fever (17.2% vs. 10.2%, p = 0.036), and diarrhea (15.2% vs. 6.2%; p = 0.001) occurred more frequently in the butyric acid group. Conclusion Butyrate‐producing bacteria does not enhance the efficacy of atezolizumab–bevacizumab combination therapy in patients with HCC.

Abstract Aim To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). Methods A total of 286 patients with unresectable HCC treated with Atez/Bev as first‐line systematic therapy were included. Results Regarding treatment‐related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune‐related liver injury, immune‐related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child–Pugh score, and α‐fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.326–0.854; p = 0.009) and α‐fetoprotein ≥100 ng/ml (HR, 1.642; 95% CI, 1.111–2.427; p = 0.013) were independently associated with progression‐free survival. Multivariate analysis adjusted for the same AEs showed that fatigue (HR, 2.354; 95% CI, 1.299–4.510; p = 0.010) was independently associated with overall survival. Median progression‐free survival was 6.5 months (95% CI, 5.2–8.1) in patients without hypertension of any grade and 12.6 months (95% CI, 6.7–not available) in patients with hypertension of any grade (p = 0.035). The overall survival was significantly shorter in patients in whom treatment‐related fatigue of any grade was observed (p

Abstract Aim Recently, the neo‐Glasgow prognostic score (GPS), a composite biomarker determined by the C‐reactive protein level and albumin–bilirubin grade, was developed to predict outcomes in hepatocellular carcinoma (HCC) patients who undergo hepatic resection. The present research investigated whether the neo‐GPS could predict prognosis in HCC patients treated with atezolizumab plus bevacizumab (Atez/Bev). Methods A total of 421 patients with HCC who were treated with Atez/Bev were investigated. Results Multivariate Cox hazards analysis showed that a GPS of 1 (hazard ratio (HR), 1.711; 95% confidence interval (CI), 1.106–2.646) and a GPS of 2 (HR, 4.643; 95% CI, 2.778–7.762) were independently associated with overall survival. Conversely, multivariate Cox hazards analysis showed that a neo‐GPS of 1 (HR, 3.038; 95% CI, 1.715–5.383) and a neo‐GPS of 2 (HR, 5.312; 95% CI, 2.853–9.890) were also independently associated with overall survival in this cohort. Additionally, cumulative overall survival rates differed significantly by GPS and neo‐GPS (p

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

Abstract Aim This study investigated whether or not the hepatocellular carcinoma modified Gustave Roussy Immune Score (HCC‐GRIm‐Score) serves as a prognostic indicator for HCC patients treated with atezolizumab and bevacizumab (Atez/Bev). Methods A total of 405 HCC patients who received Atez/Bev from September 2020 to January 2022 at 22 different institutions were included in this retrospective study. The HCC‐GRIm score was based on the combination of the albumin level (

Abstract Background/Aim A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first‐line therapy for unresectable hepatocellular carcinoma (u‐HCC) in regard to progression‐free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u‐HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. Materials/Methods From 2020 to January 2022, 251 u‐HCC (Child–Pugh A, ECOG PS 0/1, BCLC‐B/C) treated were enrolled (Atez/Bev‐group, n = 194; lenvatinib‐group, n = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). Results There was a greater number of patients with macro‐vascular invasion in Atez/Bev‐group (22.7% vs. 8.8%, p = 0.022). In lenvatinib‐group, the frequencies of appetite loss (38.6% vs. 19.6%, p = 0.002), hypothyroidism (21.1% vs. 6.7%, p = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p

Abstract In Japan, viral hepatitis is the main cause of chronic liver diseases, including liver cirrhosis. Due to the availability of highly effective antiviral drugs in combination with antihepatitis measures, Japan has become one of the most successful countries in the world with regard to hepatitis virus elimination. In Japan, there are many elderly patients who have been infected with hepatitis C virus for a long time, and antihepatitis measures have been in place since the 2000s. Thus, the medical situation in Japan is expected to reflect the future situation in other countries where hepatitis countermeasures have been recently initiated and the infected population is aging. Our nationwide survey clarified the changes in the etiologies of liver cirrhosis in Japan. Although viral hepatitis remains a major cause of liver cirrhosis in Japan, nonviral cirrhosis is suggested to increasingly contribute to the etiologies of liver cirrhosis, as opposed to viral hepatitis‐related liver cirrhosis. The changing etiology of liver cirrhosis in Japan may help to predict future global trends in chronic liver diseases.

Abstract Aim The safety and efficacy of atezolizumab plus bevacizumab (Atez/Bev) in elderly patients with unresectable hepatocellular carcinoma (HCC) have not been sufficiently investigated. Methods A total of 317 patients with HCC treated with Atez/Bev were studied. We compared the survival and frequency of adverse events in elderly versus non‐elderly patients with HCC who were treated with Atez/Bev using an analysis of inverse probability weighting (IPW). Results Univariate analysis adjusted with IPW showed that being elderly is not associated with worse overall or progression‐free survival (hazard ratio [HR], 1.239; 95% confidence interval [CI], 0.640–2.399; p = 0.526 and HR, 1.256; 95% CI, 0.871–1.811; p = 0.223, respectively). Regarding treatment‐related adverse events, any grade of fatigue, proteinuria, decreased appetite, hypertension, and liver injury occurred in ≥10% of patients. There were no significant differences in treatment‐related adverse events between the elderly and non‐elderly groups. In a subgroup analysis of elderly patients aged 75–79, 80–84, or ≥ 85 years, there were no significant differences in cumulative overall or progression‐free survival among these age groups (p = 0.960 and 0.566, respectively). In addition, there were no significant differences in treatment‐related adverse events among these three age groups, except for proteinuria of any grade. In a subgroup analysis of patients treated with Atez/Bev as first‐line systemic therapy, there were no significant differences in cumulative overall or progression‐free survival between the elderly and non‐elderly groups (p = 0.728 and 0.805, respectively). Conclusions Atez/Bev can be used efficaciously and safely in spite of age in patients with unresectable HCC.

Abstract Background and Aim The relationship between the characteristics of hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) with direct‐acting antiviral (DAA) therapy and surveillance status has not been sufficiently investigated. This study investigated the clinical risk factors for HCC development and HCC characteristics according to which type of physician performed follow‐up after SVR. Methods A total of 1070 patients in whom hepatitis C virus (HCV) was eradicated with DAA therapy were evaluated. Results There were 458 patients followed by hepatologists (specialist group) and 612 followed by non‐hepatologists (non‐specialist group) after SVR. During the follow‐up period, 54 patients developed HCC. The 1‐, 2‐, 3‐, 4‐, and 5‐year cumulative incidence rates of HCC were 1.8, 4.1, 6.9, 10.5, and 17.2%, respectively. Multivariate Cox proportional hazards analysis showed that male sex (hazard ratio [HR], 3.139; 95% confidence interval [CI], 1.732–5.690), α‐fetoprotein level (HR, 1.056; 95% CI, 1.035–1.077), and fibrosis‐4 (FIB‐4) index (HR, 1.051; 95% CI, 1.017–1.085) were significantly associated with HCC development, while the follow‐up physician type after SVR was not. There were 25 patients with stage I HCC, 17 with stage II, 9 with stage III, and 3 with stage IV. Multivariate ordinal logistic regression showed that follow‐up physician type (non‐specialist) (HR, 39.100; 95% CI, 9.350–224.00) was independently associated with HCC stage, while α‐fetoprotein level and FIB‐4 index were not. Conclusion When patients have more risk factors for HCC development after SVR (i.e., male sex, elevated α‐fetoprotein, or elevated FIB‐4 index), they should be followed by a hepatologist for HCC surveillance.

Cancer associated abdominal pain, as typified by pancreatic cancer, has conventionally been treated with narcotic drugs, but often the severe abdominal pain is difficult to control. Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) is commonly performed for abdominal pain that is difficult to control. EUS-CPN can be performed more safely and reliably than other conventional procedures on the celiac plexus, and good outcomes of pain relief have been reported. Although a variety of endoscopic techniques are available for EUS-CPN, the choice varies among institutions, and evidence on the efficacy and safety of each procedure is limited. In this review, we summarize the indications for treatment, specific endoscopic techniques, therapeutic efficacy for pain relief, and complications from previous reports on EUS-CPN.

Background and Objectives: The geriatric nutritional risk index (GNRI) is an easily calculable index that can be determined using three common clinical variables. The GNRI is suggested to be related to sarcopenia in cirrhotic patients. However, the relationship between the GNRI and the prognosis in patients with liver cirrhosis (LC) has not been reported. The aim of the present research is to study the association of the GNRI with the nutritional status, hepatic function reserve, and prognosis in patients with liver cirrhosis (LC). Materials and Methods: A total of 370 cirrhotic patients whose nutritional statuses were evaluated using anthropometric measurements and bioimpedance analysis were studied. The associations between the GNRI and nutritional status and the GNRI and hepatic function reserve were analyzed. We also investigated the GNRI and prognosis of patients with LC. Results: The median age of the enrolled patients was 66 years old, and 266 (71.9%) patients had viral hepatitis-related LC. The GNRI was shown to decrease with the progression of chronic liver disease, represented by an increased FIB-4 index and severe Child–Pugh and mALBI grades. In addition, a low GNRI (2 for men or 2 for women), as determined by using bioimpedance analysis. In addition, patients with a low GNRI (p = 0.0161, and generalized Wilcoxon test, p = 0.01261). Conclusions: Our results suggest that a low GNRI is related to severe chronic liver disease, low muscle volume, and a poor prognosis of patients with cirrhosis.

Background/Aim: There is no known report regarding the relationship of atezolizumab plus bevacizumab (Atez/Bev) treatment with muscle volume loss (MVL) in unresectable hepatocellular carcinoma (u-HCC) patients. This study aimed to elucidate the clinical relationship between MVL and Atez/Bev. Materials/Methods: From September 2020 to December 2021, 229 u-HCC patients treated with Atez/Bev and with muscle volume data obtained by computed tomography at the baseline available were analyzed (median age, 74 years; males, 186 (81.2%); ECOG PS 0/1, 221 (96.5%); HCV:HBV:alcohol:others=81:33:40:75; Child-Pugh A, 212 (92.6%); mALBI grade 1:2a:2b=79:60:90; BCLC 0:A:B:C =1:24:87:117; median observation period, 6.8 months). Japan Society of Hepatology criteria were used for definition of MVL and prognostic factors were retrospectively evaluated. Results: Multivariate Cox-hazard analysis of prognostic factors for progression-free survival (PFS) showed elevated alpha-fetoprotein (AFP) (≥100 ng/mL) (HR 1.848, 95%CI 1.264-2.702, P=0.002), modified albumin-bilirubin (mALBI) grade (≥2a) (HR 1.563, 95%CI 1.035-2.359, P=0.034), and MVL (HR 1.479, 95%CI 1.020-2.144, P=0.039) as significant factors. For overall survival (OS), significant factors included elevated AFP (≥100 ng/mL) (HR 3.564, 95%CI 1.856-6.844, P

Afferent loop syndrome (ALS) is a mechanical obstruction of the afferent limbs after gastrectomy with gastrojejunostomy reconstruction. Patients with cancer recurrence require immediate and less invasive treatment because of their poor condition. Percutaneous transhepatic/transluminal drainage (PTD) and endoscopic enteral stenting offer reasonable palliative treatment for malignant ALS but are not fully satisfactory in terms of patient quality of life (QoL) and stent patency. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) using a lumen-apposing metal stent may address these shortcomings. Clinical data from 11 reports showed that all patients who had undergone EUS-GE had positive technical and clinical outcomes. The adverse event rate was 11.4%, including only mild or moderate abdominal pain, with no severe adverse events. Indirect comparative studies indicated that patients who had undergone EUS-GE had a significantly superior QoL, a higher clinical success rate, and a lower reintervention rate than those who had undergone PTD or endoscopic enteral stenting. Although the evidence is limited, EUS-GE may be considered as a first-line treatment for malignant ALS because it has better clinical outcomes than other less invasive treatments, such as PTD or endoscopic enteral stenting. Further prospective randomized control trials are necessary to establish EUS-GE as a standard treatment for ALS.

The first edition of the guidelines for the use of ultrasound contrast agents was published in 2004, dealing with liver applications. The second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some nonliver applications. The third edition of the contrast-enhanced ultrasound (CEUS) guidelines was the joint World Federation for Ultrasound in Medicine and Biology-European Federation of Societies for Ultrasound in Medicine and Biology (WFUMB-EFSUMB) venture in conjunction with other regional US societies such as Asian Federation of Societies for Ultrasound in Medicine and Biology, resulting in a simultaneous duplicate on liver CEUS in the official journals of both WFUMB and EFSUMB in 2013. However, no guidelines were described mainly for Sonazoid due to limited clinical experience only in Japan and Korea. The new proposed consensus statements and recommendations provide general advice on the use of Sonazoid and are intended to create standard protocols for the use and administration of Sonazoid in hepatic and pancreatobiliary applications in Asian patients and to improve patient management.

Abstract Background Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u‐HCC), changes in hepatic function during therapy have yet to be reported. Aim This retrospective clinical study aimed to elucidate early responses to Atez/Bev. Methods From September 2020 to April 2021, 171 u‐HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin‐bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively. Results In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR‐6W/DCR‐6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR‐6W/DCR‐6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post‐progression treatment following lenvatinib (ORR‐6W/DCR‐6W = 7.7%/79.5%), for which no known effective post‐progression treatment has been established. In 111 patients who underwent a 6‐week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (−2.525 ± 0.419 vs −2.323 ± 0.445, p

Metastasis of hepatocellular carcinoma (HCC) in the pouch of Douglas is relatively rare. A 65-year-old man with liver cirrhosis was admitted for detailed examination of a pelvic tumor. He had a previous history of ruptured HCC, and received emergent hemostasis with transcatheter arterial embolization followed by curative ablation. His blood tests showed an increase in des-gamma-carboxy prothrombin (DCP). Contrast-enhanced computed tomography (CE-CT) revealed a heterogeneously enhanced large pelvic tumor, but no additional tumorous lesions were detected in other organs, including the lungs, liver and abdominal lymph nodes. The colonoscopy showed compression by an extra-luminal/submucosal tumor, and computed tomography-guided percutaneous needle biopsy revealed that the pelvic tumor was metastasis of HCC. Because of the poor liver function, the solitary pelvic tumor was treated with three-dimensional conformal radiation therapy (3D-CRT). The tumor size and the DCP value were markedly decreased after radiation therapy. Nine months later, occasional mild bloody stool due to radiation proctitis was observed; however, no serious side effects occurred. Our case suggests that radiation therapy may be a therapeutic option for a solitary metastatic lesion of HCC in the pouch of Douglas.

Abstract Background Noninvasive biomarkers are urgently needed for optimal management of nonalcoholic fatty liver disease (NAFLD) for the prevention of disease progression into nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In order to identify the biomarkers, we generated the swine hepatocellular carcinoma (HCC) model associated with NAFLD and performed serum proteomics on the model. Methods Microminipigs were fed a high-fat diet to induce NAFLD and a normal diet as the control. To induce HCC, diethylnitrosamine was intraperitoneally administered. Biopsied liver samples were histopathologically analyzed every 12 weeks. Serum proteins were separated by blue native two-dimensional gel electrophoresis and proteins of interest were subsequently identified by MALDI-TOF MS/MS. Human serum samples were analyzed to validate the candidate protein using antibody-mediated characterization. Results In the NAFLD pigs, hepatic histology of nonalcoholic steatohepatitis (NASH) was observed at 36 weeks, and HCC developed at 60 weeks. Among serum proteins identified with MALDI-TOF MS/MS, serum inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), an acute response protein which is secreted primarily by liver, was identified as the most characteristic protein corresponding with NAFLD progression and HCC development in the NAFLD pigs. With immunoassay, serum ITIH4 levels in the NAFLD pigs were chronologically increased in comparison with those in control animal. Furthermore, immunohistochemistry showed ITIH4 expression in hepatocytes also increased in both the cancer lesions and parenchyma as NAFLD progressed. Human study is also consistent with this observation because serum ITIH4 levels were significantly higher in HCC-NAFLD patients than in the simple steatosis, NASH, and virus-related HCC patients. Of note, HCC-NAFLD patients who had higher serum ITIH4 levels exhibited poorer prognosis after hepatectomy. Conclusions We established an HCC pig model associated with NAFLD. Serum proteomics on the swine HCC with NAFLD model implicated ITIH4 as a non-invasive biomarker reflecting NAFLD progression as well as subsequent HCC development. Most importantly, the results in the swine study have been validated in human cohort studies. Dissecting speciation of serum ITIH4 promises to have clinical utility in monitoring the disease.

Inflammatory pseudotumor (IPT) of the liver is a rare benign disease. IPTs generally develop as solitary nodules, and cases with multiple lesions are uncommon. We herein report a case of multiple IPTs of the liver that spontaneously regressed. A 70-year-old woman with a 10-year history of primary biliary cholangitis and rheumatoid arthritis visited our hospital to receive a periodic medical examination. Abdominal ultrasonography revealed multiple hypoechoic lesions, with a maximum size of 33 mm, in the liver. Contrast-enhanced computed tomography revealed low-attenuation areas in the liver with mild peripheral enhancement at the arterial and portal phases. We first suspected metastatic liver tumors, but fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and contrast-enhanced ultrasonography suggested the tumors to be inconsistent with malignant nodules. A percutaneous biopsy showed shedding of liver cells and abundant fibrosis with infiltration of inflammatory cells. Given these findings, we diagnosed the multiple tumors as IPTs. After careful observation for two months, the tumors almost vanished spontaneously. Physicians should avoid a hasty diagnosis of multiple tumors based solely on a few clinical findings, and a careful assessment with various imaging modalities should be conducted.

We aimed to examine the association between sarcopenia-related factors and metabolic syndrome (Met-S) in patients with chronic liver diseases (CLDs, n = 582, average age = 59.5 years, 290 males, 168 liver cirrhosis cases). Met-S was determined based on the Japanese criteria. Sarcopenia was determined based on grip strength (GS) and skeletal muscle index (SMI) by bioelectrical impedance analysis. Our cohort was divided into the four groups: (A) sarcopenia (n = 44), (B) dynapenia (n = 45), (C) presarcopenia (n = 112), and (D) the control (n = 381). Impacts of GS and SMI on Met-S were investigated. In males, waist circumference (WC) ≥ 85 cm was observed in 199 patients (68.6%), while in females, WC ≥ 90 cm was observed in 94 patients (32.2%). Met-S was identified in 109 patients (18.7%). The proportion of Met-S in the group A, B, C and D were 18.2%, 48.9%, 8.0%, and 18.4% (A vs. B, p = 0.0033; B vs. C, p < 0.0001; C vs. D, p = 0.0081; A vs. C, p = 0.0867; A vs. D, p = 1.000, B vs. D, p < 0.0001; overall p value < 0.0001). Multivariate analysis revealed that age, gender, and group B (dynapenia) were significant factors linked to the presence of Met-S. In conclusion, dynapenia rather than sarcopenia is associated with Met-S in CLD patients.

We aimed to investigate the association in frailty and sleep disorder as assessed by the Japanese version of Pittsburgh Sleep Quality Index (PSQI-J) in patients with chronic liver diseases (CLDs, n = 317, 141 males). Frailty was determined using the following five phenotypes: unintentional body weight loss, self-reported exhaustion, muscle weakness, slow walking speed, and low physical activity. Sleep disorder was defined as patients with PSQI-J score 6 or greater. Robust (phenotype, 0), prefrail (1 or 2 phenotypes) and frailty (3 phenotypes or greater) were observed in 101 (31.9%), 174 (54.9%) and 42 (13.2%), respectively. The median (interquartile range (IQR)) PSQI-J score was 4 (3, 7). Sleep disorder was found in 115 patients (36.3%). The median (IQR) PSQI-J scores in patients of the robust, prefrail, and frail groups were 3 (2, 5), 5 (3, 7), and 8 (4.75, 10.25), respectively (p < 0.0001 between any two groups and overall p < 0.0001). The ratios of sleep disorder in patients with robust, prefrail and frailty were 15.8% (16/101), 39.1% (68/174), and 73.8% (31/42), respectively (overall p < 0.0001). In conclusion, CLD patients with frailty can involve poorer sleep quality. As sleep disorder in CLDs is potentially remediable, future frailty-preventive strategies must take sleep complaints into account.

Background and objectives: Few data with regard to the relevance between depression and frailty in chronic liver disease (CLD) patients are currently available. We aimed to elucidate the relationship between frailty and depression as evaluated by the Beck Depression Inventory—2nd edition (BDI-II) in CLD patients (n = 340, median age = 65.0 years). Methods: Frailty was defined as a clinical syndrome in which three or more of the following criteria were met: body weight loss, exhaustion, muscle weakness, slow walking speed and low physical activity. Depressive state was defined as BDI-II score 11 or greater. Results: Robust (frailty score = zero), prefrail (frailty score = one or two) and frailty were identified in 114 (33.5%), 182 (53.5%) and 44 (12.9%). The median BDI-II score was five. Depressive state was identified in 84 patients (24.7%). The median BDI-II scores in patients with robust, prefrail and frail traits were 2, 7 and 12.5 (robust vs. prefrail, p < 0.0001; prefrail vs. robust, p = 0.0003; robust vs. frail, p < 0.0001; overall p < 0.0001). The proportions of depressive state in patients with robust, prefrail and frail traits were 3.51%, 30.77% and 54.55% (robust vs. prefrail, p < 0.0001; prefrail vs. robust, p = 0.0046; robust vs. frail, p < 0.0001; overall p < 0.0001). BDI-II score significantly correlated with frailty score (rs = 0.5855, p < 0.0001). Conclusions: The close correlation between frailty and depression can be found in CLD. Preventing frailty in CLD should be approached both physiologically and psychologically.

There have been scarce data regarding the relationship between frailty and anthropometry measurements (AMs) in patients with chronic liver diseases (CLDs). We aimed to elucidate the influence of AMs on frailty in CLDs (median age = 66 years, 183 men and 192 women). AMs included arm circumference, triceps skinfold thickness, calf circumference (CC), waist circumference, and body mass index. Frailty assessment was done by using five phenotypes (body weight loss, exhaustion, decreased muscle strength, slow walking speed, and low physical activity). Robust (frailty point 0), prefrail (frailty point 1 or 2), and frailty (frailty point 3 or more) were observed in 63 (34.4%), 98 (53.6%), and 22 (12.0%) of males, respectively, and 63 (32.8%), 101 (52.6%), and 28 (14.6%) of females, respectively. In receiver operating characteristics (ROC) curve analyses for the presence of frailty, CC had the highest area under the ROC (AUC) both in male (AUC = 0.693, cutoff point = 33.7 cm) and female (AUC = 0.734, cutoff point = 33.4 cm) participants. In the multivariate analysis associated with frailty, for the male participants, only the presence of liver cirrhosis (p = 0.0433) was identified to be significant, while among the female participants, serum albumin (p = 0.0444) and CC (p = 0.0010) were identified to be significant. In conclusion, CC can be helpful for predicting frailty, especially in female CLD patients.

We sought to examine the relationship between frailty and health-related quality of life as evaluated using the 36-item Short-Form Health Survey (SF-36) questionnaire in Japanese chronic liver disease (CLD) patients (n = 341, 122 liver cirrhosis cases, median age = 66 years). Frailty was defined as a clinical syndrome in which three or more of the following criteria were met (frailty score 3, 4, or 5): unintentional body weight loss, self-reported exhaustion, muscle weakness (grip strength: p < 0.0001). In the multivariate analysis, age (p = 0.0126), physical functioning (p = 0.0005), and vitality (p = 0.0246) were independent predictors linked to the presence of frailty. In conclusion, Japanese CLD patients with frailty displayed poorer conditions, both physically and mentally.

Here we sought to clarify the prognostic impact of sarcopenia-related markers (grip strength (GS), muscle mass using bioimpedance analysis and patient quality of life as assessed by the 36-Item Short-Form Health Survey (SF36)) in patients with chronic liver diseases (CLDs, n = 411; 160 liver cirrhosis patients; median age, 64 years) on the incidence of composite hepatic events (CHEs). A GS decrease was defined as 2 in men and 2 in women based on the current guidelines. The physical and metal component summary scores on the SF36 were also included into the analysis. Sixty-two patients (15.1%) had the first incidence of CHEs. The three-year cumulative incidence rates of CHEs in patients with GS decrease or non-decrease were 24.51% and 12.44% (p = 0.0057). The three-year cumulative incidence rates of CHEs in patients with an SMI decrease or non-decrease were 19.65% and 12.99% (p = 0.0982). Multivariate analysis revealed that GS decrease (p = 0.0350) and prothrombin time (p = 0.0293) were significantly associated with the incidence of CHEs. In conclusion, GS can be an independent predictor for CHE development in patients with CLDs.

Succinate and lactate are commodity chemicals used for producing bioplastics. Recently, it was found that such organic acids are excreted from cells of the unicellular cyanobacterium Synechocystis sp. PCC 6803 under dark, anaerobic conditions. To conduct the dark, anaerobic incubation, cells were concentrated within a vial that was then sealed with a butyl rubber cap, following which N2 gas was introduced into the vial. The organic acids produced were quantified by high-performance liquid chromatography via post-labeling with bromothymol blue as a pH indicator. After separation by ion-exclusion chromatography, the organic acids were identified by comparing their retention time with that of standard solutions. These procedures allow researchers to quantify the organic acids produced by microorganisms, contributing to knowledge about the biology and biotechnology of cyanobacteria.

Background. The relationships between the metabolic parameters and the endoscopic findings of esophageal varices have been poorly investigated. We investigated the association of the branched-chain amino acids to tyrosine ratio (BTR) with the severity of liver fibrosis and esophageal varices.Material and Methods. We studied hepatitis C virus (HCV)-positive chronic liver disease patients who had undergone liver biopsy (n = 149). The relationship between the BTR values and the liver fibrotic stage was investigated. We also studied whether the BTR value was associated with the presence and bleeding risk of varices in patients with HCV-related compensated cirrhosis.Results. The mean values of the BTR decreased with the progression of the fibrosis (METAVIR score: F0-1: 6.40 ± 1.19; F2: 5.85 ± 1.33; F3: 5.24 ± 0.97, F4: 4.78 ± 1.14). In the 58 patients with HCV-related compensated cirrhosis, the mean values of the BTR decreased with the severity of varices (patients without varices: 5.01 ± 1.15, patients with a low-risk varices: 4.42 ± 1.06, patients with a high-risk varices: 3.86 ± 1.02). The BTR value was significantly lower in the patients with varices than in those without varices (4.17 ± 1.07 vs. 5.01 ± 1.15, P < 0.01). The BTR value was also significantly lower in the patients with a high risk of hemorrhage than in those with a low risk (3.86 ± 1.02 vs. 4.78 ± 1.14, P < 0.01). Furthermore, the BTR value was the most significantly different parameter, with the smallest P-value among all the factors examined, including the platelet count and albumin level.Conclusion. A decreased BTR value was found to be associated with the progression of liver fibrosis and severity of varices.

Primary squamous cell carcinoma (SCC) of the liver is rare tumor with an unfavorable prognosis. We report a case of advanced primary SCC of the liver arising adjacent to a nonparasitic liver cyst, invading into the right diaphragm and the right lung tissue. Contrast-enhanced ultrasonography (CE-US) demonstrated unique enhancement in the late vascular phase, which was incompatible with those observed in hepatocellular carcinoma, cholangiocellular carcinoma, or metastatic adenocarcinoma. The patient underwent surgical resection of the tumor followed by systemic chemotherapy with 5-fluorouracil (5-FU) and cisplatin (CDDP), while radiation chemotherapy was not applied because of relatively poor performance status. Although postoperative image analysis revealed no recurrence 4 months later, the patient died 13 months after the operation from recurrence. Immunohistological analysis of the resected specimen revealed that this SCC contained many capillary endothelial vessels expressing CD31 or CD34, possibly reflecting the unique imaging pattern in the late vascular phase of CE-US, which has been reported in choangiolocellular carcinoma. In addition, we reviewed which kind of treatment would be suitable for advanced hepatic primary SCC in the literature. From the review, it could be proposed that a combination of radiation therapy, systemic chemotherapy (5-FU and CDDP) and surgical resection, if possible, is appropriate for advanced primary SCC of the liver.

Background. Only a few biomarkers based on metabolic parameters for evaluating liver fibrosis have been reported. The aim of this study was to investigate the relevance of an index obtained from three metabolic variables (glycated albumin: GA, glycated hemoglobin: HbA1c, and branched-chain amino acids to tyrosine ratio: BTR) to the degree of liver fibrosis in hepatitis C virus virus- (HCV-) positive patients. Methods. A total of 394 HCV-positive patients were assessed based on the values of a new index (GA/HbA1c/BTR). The index findings were used to investigate the relationship with the degree of liver fibrosis. Results. The new index showed an association with the stage of fibrosis (METAVIR scores: F0-1: 0.42 ± 0.10, F2: 0.48 ± 0.15, F3: 0.56 ± 0.22, and F4: 0.71 ± 0.30). The index was negatively correlated with three variables of liver function: the prothrombin time percentage (P

Background. In hepatitis B virus- (HBV-) positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated. Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c) were calculated in order to investigate the relationship with the degree of liver fibrosis. Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63). The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT) percentage (P

The tricarboxylic acid (TCA) cycle and pyruvate metabolism of cyanobacteria are unique and important from the perspectives of biology and biotechnology research. Rre37, a response regulator induced by nitrogen depletion, activates gene expression related to sugar catabolism. Our previous microarray analysis has suggested that Rre37 controls the transcription of genes involved in sugar catabolism, pyruvate metabolism, and the TCA cycle. In this study, quantitative real-time PCR was used to measure the transcript levels of 12 TCA cycle genes and 13 pyruvate metabolism genes. The transcripts of 6 genes (acnB, icd, ppc, pyk1, me, and pta) increased after 4 h of nitrogen depletion in the wild-type GT strain but the induction was abolished by rre37 overexpression. The repression of gene expression of fumC, ddh, and ackA caused by nitrogen depletion was abolished by rre37 overexpression. The expression of me was differently affected by rre37 overexpression, compared to the other 24 genes. These results indicate that Rre37 differently controls the genes of the TCA cycle and pyruvate metabolism, implying the key reaction of the primary in this unicellular cyanobacterium.

Background/Aim: We identified a new growth factor, hepatoma-derived growth factor (HDGF), which is a presumed growth-stimulating factor of hepatocellular carcinoma (HCC). Recently, we identified two microRNAs (miR-6072 and miR-3137) induced by HDGF, which were also found to be associated with the prognosis of HCC patients. This study aimed to identify the target genes of these HDGF-related microRNAs. Materials and Methods: A public database was searched for candidate target genes of HDGF-related microRNAs. Using the microarray system, the genes whose expression changed in response to HDGF administration were determined. Finally, a public cancer genomics database was searched for genes that were induced by HDGF and associated with the prognosis of HCC. Results: A total of 1,132 genes were identified as common target genes of the 2 HDGF-related microRNAs. Among these genes, a microarray system showed that the expression of 6 genes was increased (≥1.5-fold) or decreased (≤0.67- fold) after HDGF administration. Using a cancer genomics database, two of the six genes were found to be related to the prognosis of HCC. A high expression of alkylglycerone phosphate synthase (AGPS) was significantly associated with a poor survival (p=0.0025, 0.0063 and 0.0081 for the 1-, 3- and 5-year survival, respectively). A high expression of the shroom family member 4 (SHROOM4) gene was found to be significantly associated with a better survival (p=0.003, 0.0006 and 0.0006 for the 1-, 3- and 5-year survival, respectively). Conclusion: This study identified potential target genes of HDGF-related microRNAs that were associated with the prognosis of HCC. [ABSTRACT FROM AUTHOR]