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Background/Aim The aim of this study was to compare the therapeutic efficacy of ablation and surgery in solitary hepatocellular carcinoma (HCC) measuring ≤5 cm with a large HCC cohort database. Methods The study included consecutive 2,067 patients with solitary HCC who were treated with either ablation (n=1,248) or surgery (n=819). Th e patients were divided into three groups based on the tumor size and compared the outcomes of the two therapies using propensity score matching. Results No significant difference in recurrence-free survival (RFS) or overall survival (OS) was found between surgery and ablation groups for tumors measuring ≤2 cm or >2 cm but ≤3 cm. For tumors measuring >3 cm but ≤5 cm, RFS was significantly better with surgery than with ablation (3.6 and 2.0 years, respectively, P=0.0297). However, no significant difference in OS was found between surgery and ablation in this group (6.7 and 6.0 years, respectively, P=0.668). Conclusion The study suggests that surgery and ablation can be equally used as a treatment for solitary HCC no more than 3 cm in diameter. For HCCs measuring 3-5 cm, the OS was not different between therapies; thus, ablation and less invasive therapy can be considered a treatment option; however, special caution should be taken to prevent recurrence.

Background: While the current guidelines recommend laparoscopic deroofing for symptomatic simple liver cysts, percutaneous drainage may serve as a less invasive alternative method. In this study, the treatment effects of percutaneous drainage with or without sclerotherapy for symptomatic simple liver cysts were evaluated. Methods: Between April 2016 and March 2021, 79 patients who initially required hospitalization due to symptomatic simple liver cysts were enrolled in this multicenter retrospective study. They were treated percutaneously with or without sclerotherapy. The factors associated with symptom recurrence, clinical course and prognosis were investigated. Results: Of the 79 patients treated percutaneously, 11 (13.9%) had symptom recurrence due to liver cysts during the observation period. The maximum diameter of liver cysts at baseline was the only significant factor for the recurrence of these symptoms (p = 0.004). In a receiver operating characteristics analysis, the cut-off of the diameter for symptom recurrence was 16.5 cm. No additional effect of sclerotherapy on drainage was demonstrated in patients with a cyst diameter of

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.

Key Clinical Message SARS‐CoV‐2 infection has been associated with a prolonged course and a poor prognosis in patients who receive anti‐CD20 antibodies. However, there are no established treatments for such patients. Serial changes in the SARS‐CoV‐2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed. Abstract We report a case of prolonged SARS‐CoV‐2 infection during obinutuzumab and bendamustine treatment for follicular lymphoma. Four years previously, the patient had been diagnosed with follicular lymphoma (Stage IIIA, Grade 2). She received several chemotherapy regimens, including rituximab and radiation therapy. Although these therapies achieved complete response temporally, they did not continue and recurred at 8 months before. Obinutuzumab and bendamustine therapy was selected, and she received five courses of obinutuzumab and bendamustine. She also received a SARS‐CoV‐2 mRNA vaccine two times. Although she did not have any symptoms, a routine check‐up just before the 6th course of obinutuzumab and bendamustine revealed SARS‐CoV‐2 infection. Because she was immunosuppressed and was considered to be at high risk for the exacerbation of her disease, molnupiravir was immediately administered, and her SARS‐CoV‐2 antigen decreased. However, it was not completely cleared and flared‐up at 6 weeks, with symptoms of COVID‐19 appearing. Despite intensive treatment for SARS‐CoV‐2 infection, including remdesivir, baricitinib, tocilizumab and intravenous immunoglobulin, her SARS‐CoV‐2 antigen titer never became negative, and she finally died of respiratory failure caused by prolonged SARS‐CoV‐2 infection. Serial changes in the SARS‐CoV‐2 antigen titer during the clinical course and treatment strategies for immunosuppressed patients are discussed.

Summary: Background: Atezolizumab-bevacizumab (atezo-bev) is recommended as first-line therapy for patients with unresectable hepatocellular carcinoma (uHCC). However, its effectiveness and safety in other populations, including those with Child-Turcotte-Pugh (CTP) class B cirrhosis, is unclear. Methods: For this systematic review and meta-analysis, electronic databases, including PubMed, Embase, and Scopus, were searched from 1st May, 2020 till 5th October, 2022; the last date of access was January 31, 2023. Pooled progression-free survival (PFS), overall survival (OS), and radiological response rate among patients receiving atezo-bev were compared between patients with CTP-A and CTP-B cirrhosis, with tyrosine kinase inhibitors (TKIs) and among those receiving the drug as first-line and later line therapy. The protocol was registered in Prospero (CRD42022364430). Findings: Among 47 studies (n = 5400 patients), pooled PFS and OS were 6.86 (95% CI, 6.31–7.41) and 13.8 months (95% CI, 11.81–15.8), respectively. Objective response rate (ORR) and disease control rate were 26.7% (24.6–29.1) and 75.3% (73.1–77.4) using RECIST criteria, and 34% (30.3–37.8) and 73.6% (68.8–78) using mRECIST criteria, respectively. Among those receiving atezo-bev, patients with CTP-B cirrhosis had similar ORRs by RECIST (odds ratio [OR], 1.42 [0.77–2.6]; P = 0.25) and mRECIST criteria (OR, 1.33 [0.52–3.39]; P = 0.53) but shorter PFS (mean difference [MD]:3.83 months [1.81–5.84]) than those with CTP-A cirrhosis. Compared to patients receiving TKIs, those receiving atezo-bev had longer PFS (MD: 2.27 months [0.94–3.5]) and higher ORR (RECIST: OR, 1.44 [1.01–2.04] and mRECIST: OR, 1.33 [1.01–1.75]). Compared to first-line therapy, later-line therapy had lower ORR (RECIST: OR, 1.82 [1.3–2.53]; P

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 Aims This retrospective study compared the survival between elderly and non‐elderly patients. Methods A total of 5545 treatment‐naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively. Results There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p

Abstract Background Factor V (FV) deficiency is an extremely rare disease, with an incidence of 1 in 1 million. The bleeding symptoms are mild, and the prognosis is good; however, the safety of surgical treatment is unclear, because there are few available reports. Herein, we report a case of hepatocellular carcinoma with congenital FV deficiency in a patient who safely underwent laparoscopic hepatectomy. Case presentation A 79-year-old man, diagnosed with hepatocellular carcinoma of liver segment 5, with type C cirrhosis and sustained virological response visited our hospital. He had congenital FV deficiency, and blood tests showed coagulation deficiencies with an FV activity of

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 We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2–22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495–2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use maybe limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy (UGE) available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence and risk factors for the presence of EGV and high risk EGV at baseline, impact of EGV bleeding on patients’ survival. Results: 535 patients were enrolled in the study [median age 72 years, 78% male, 63% viral aetiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis (nPVT), 56% BCLC-C]: 234 had EGV (44%): 70 (30%) at high-risk and 59 on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high risk EGV (HR 6.94, 95% CI 2.23-21.57, p=0.001). In these patients the 12-month risk was 17%. High risk varices were independently associated with Child-Pugh B score (OR 2.12; 95%CI 1.08-4.17, p=0.03), nPVT (OR 2.54; 95%CI 1.40-4.61, p=0.002) and platelets

Introduction: Prospective evidence supporting the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) remains lacking. This prospective study aimed to evaluate the safety and efficacy of hypofractionated C-ion RT in patients with HCC. Methods: The inclusion criteria were as follows: (1) pathologically or clinically diagnosed HCC; (2) measurable tumor and tumor size ≤10 cm; (3) absence of major vascular invasion; (4) no extrahepatic metastasis; (5) the alimentary tract was not adjacent to the target lesion (>1 cm); (6) not suitable for or refusal to undergo surgery or local ablative therapies; (7) an interval ≥4 weeks from previous therapy; (8) no other intrahepatic lesion or at least 2 years after the previous curative therapy; (9) performance status score, 0–2; and (10) Child-Pugh score, 5–9. The prescribed C-ion RT dose was 52.8 Gy (relative biological effectiveness [RBE]) or 60.0 Gy (RBE) in 4 fractions. Results: In total, 35 patients with HCC were enrolled between October 2010 and May 2016. The median follow-up durations in the survivor group (n = 23) and in the whole cohort were 55.1 and 49.0 months, respectively. The 2-, 3-, and 4-year overall survival rates were 82.8%, 76.7%, and 69.4%, respectively. The 2-, 3-, and 4-year local control (LC) rates were 92.6%, 76.5%, and 76.5%, respectively. The median time-to-progression was 25.6 months (95% confidence interval, 13.7–37.5 months). Grade 4 or 5 toxicities were not observed. Grade 3 acute and late toxicities were observed in 2 patients. There was no significant deterioration in serum albumin, bilirubin, prothrombin time-international normalized ratio, platelet count, or Child-Pugh score after C-ion RT. Conclusion: Four fractions of C-ion RT for HCC did not yield serious adverse events and showed promising LC, thus making it a safe and effective modality for this type of malignancy.

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

Abstract Background and Aim This retrospective study investigated the effect of 48‐week pemafibrate therapy in non‐alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia, as evaluated by the FibroScan‐aspartate aminotransferase (FAST) score. Methods A total of 31 NAFLD patients who were treated with pemafibrate in Gunma Saiseikai Maebashi Hospital and Kusunoki Hospital from September 2018 to April 2020 were included in the current study. We used the FAST score, which is a novel index of steatohepatitis that can be calculated based on the AST value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM), to evaluate the effect of pemafibrate treatment. Results The median age was 64.0 (interquartile range [IQR] 55.0–75.0) years and 14 patients (45.2%) were male. Median body mass index was 26.8 (IQR 23.8–28.8). Hypertension and diabetes mellitus were detected in 14 (45.2%) and five (16.1%) patients, respectively. Fasting triglyceride and high‐density lipoprotein cholesterol were significantly improved (P

Abstract We herein report a case of Guillain‐Barré syndrome (GBS) after SARS‐CoV‐2 infection. The patient was a close contact with a SARS‐CoV‐2 patient. Initially, she did not have any symptoms and quarantined at a hotel. Dysgeusia and olfactory abnormality appeared at day 6 after testing positive for infection and disappeared by day 9. Subsequently, the patient developed numbness of the arms and legs, difficulty walking, and dyspnea and was referred to our hospital. Her clinical examination showed generalized weakness and hyporeflexia. A cerebrospinal fluid analysis showed albuminocytological dissociation. Her nerve conduction studies were consistent with demyelinating polyneuropathy. Intravenous immunoglobulin was administered based on a diagnosis of GBS.

Abstract An 81‐year‐old man initially underwent right hepatic lobectomy for liver cancer and was pathologically diagnosed with combined hepatocellular and cholangiocarcinoma (CHC). At 13 months after resection, multiple lymph node metastases were observed. We started atezolizumab plus bevacizumab (Atez/Bev), achieving a 7.5‐month progression‐free survival. Atez/Bev might exhibit efficacy for CHC patients.

Background/Aim: Because of recent developments in treatments for hepatocellular carcinoma (HCC), methods for determining suitable therapy for initial or recurrent HCC have become important. This study used artificial intelligence (AI) findings to establish a system for predicting prognosis of HCC patients at time of reoccurrence based on clinical data as a reference for selection of treatment modalities. Material/Methods: As a training cohort, 5701 observations obtained at the initial and each subsequent treatment for recurrence from 1985 HCC patients at a single center from 2000 to 2021 were used. The validation cohort was 5692 observations from patients at multiple centers obtained at the time of the initial treatment. An AI calculating system (PRAID) was constructed based on 25 clinical factors noted at each treatment from the training cohort, then predictive prognostic values for one- and three-year survival in both cohorts were evaluated. Results: After exclusion of patients lacking clinical data regarding albumin-bilirubin grade (ALBI) and/or tumor-node-metastasis stage (TNM), ALBI-TNM (ALBI-T) and modified ALBI-T scores confirmed that prognosis for patients in both cohorts was similar. The area under the curve (AUC) for prediction of both one- and three-year survival in the validation cohort were 0.841 [sensitivity 0.933 (95%CI 0.925-0.940), specificity 0.517 (95%CI 0.484-0.549)] and 0.796 [sensitivity 0.806 (95%CI 0.790-0.821), specificity 0.646 (95%CI 0.624-0.668)], respectively. Conclusion: The present PRAID system might provide useful prognostic information related to short and medium survival for decision making regarding best therapeutic modality for both initial and recurrent HCC cases.

Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. Twenty million HEV infections worldwide are estimated each year. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7—usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. CHE can be easily misdiagnosed by usual diagnostic methods of antibody response, such as anti-HEV IgM or IgA, because of the low antibody response in the immunosuppressive condition. HEV RNA should be evaluated in these patients, and appropriate treatments—such as ribavirin—should be given to prevent progression to liver cirrhosis or liver failure. While still rare, cases of CHE in immunocompetent patients have been reported, and care must be taken not to overlook these instances. Herein, we conduct an overview of hepatitis E, including recent research developments and management of CHE, in order to improve our understanding of such cases. The early diagnosis and treatment of CHE should be performed to decrease instances of hepatitis-virus-related deaths around the world.

Abstract Background and Aim We investigated the prognosis of late elderly patients (≥75 years old) after the achievement of a sustained viral response (SVR) by direct‐acting antivirals (DAAs). Methods One hundred and four late elderly patients and 251 young patients (≤74 years old) who had achieved an SVR were included. We compared the cumulative hepatocellular carcinoma (HCC) incidence rates and survival rates after DAA administration. Furthermore, the factors associated with HCC incidence and the causes of death after DAA administration were also investigated. Results The cumulative HCC incidence rates for 1 and 3 years were 2.9% and 11.7% in the late elderly patients and 2.4% and 5.4% in the young patients, respectively. The cumulative survival rates for 1 and 3 years were 100% and 95.6% in the late elderly patients and 100% and 96.4% in the young patients, respectively, with no significant differences in those rates noted (P = 0.133, P = 0.322, respectively). In the late elderly patients, only a history of HCC was a significant factor associated with HCC incidence after DAA administration. Five late elderly patients died after achieving an SVR, and malignant liver tumor was the cause of death in three of those patients. Conclusions The prognosis did not differ markedly between late elderly patients and young patients. The factor most strongly influencing the prognosis of late elderly patients was likely liver disease, including HCC. DAAs should be introduced even in late elderly patients who can be expected to have a relative long‐term survival.

Abstract Three Japanese adolescents with chronic hepatitis C were treated by direct‐acting antivirals (DAAs). No adverse events or laboratory abnormalities were observed during and after DAA therapy, and a sustained virological response was achieved in all cases. The emotional functioning of the patients and their mothers were improved after DAA therapy.

Abstract Objectives The changes in portal hypertension after achieving a sustained viral response (SVR) by direct‐acting antivirals (DAAs) have not been fully elucidated. Consequently, noninvasive and inexpensive predictors need to be investigated. We therefore explored factors associated with the progression of EVs after the achievement of an SVR with DAAs in patients with chronic hepatitis C. Methods Eighty‐nine patients, who had achieved an SVR with DAAs and could have their esophagogastroduodenoscopy (EGD) findings compared between before DAAs administration and after achieving an SVR achievement were enrolled in this study. We compared the patients with and without EVs progression. Furthermore, the cumulative progression rates of EVs were also analyzed. Results The fibrosis‐4 index (FIB‐4) before DAAs administration was the only significant factor for the progression of EVs after an SVR (odds ratios: 1.2, 95% confidence intervals: 1.05–1.38, p = 0.01). In a receiver operating characteristics analysis, the cut‐off of FIB‐4 for the progression of EVs was 8.41 (sensitivity: 0.63, specificity: 0.86, positive predictive value: 0.31, negative predictive value: 0.96), namely EVs of those with more than 8.41 of FIB‐4 progressed and those with less than 8.41 of FIB‐4 did not. Conclusions As patients with FIB‐4 ≥ 8.41 may have progressions of EVs, periodic surveillance by EGD should be continued in such cases, even after an SVR is achieved.

Abstract Background The Gut and Obesity in Asia (GOASIA) Workgroup was formed to study obesity and gastrointestinal diseases in the Asia Pacific region. We aimed to 1) compare the characteristics of elderly (i.e. age ≥ 60) vs. non-elderly patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD); 2) identify predictors of advanced fibrosis in elderly patients with NAFLD; and 3) assess the performance of non-invasive fibrosis scores in the prediction of advance fibrosis in the elderly population. Methods We abstracted the data of 1008 patients with NAFLD from nine centers across eight countries. Characteristics of elderly and non-elderly patients with NAFLD were compared using 1:3 sex-matched analysis. Results Of the 1008 patients, 175 were elderly [age 64 (62–67) years], who were matched with 525 non-elderly patients [46 (36–54) years]. Elderly patients were more likely to have advanced fibrosis (35.4% vs. 13.3%; p

Abstract Noonan syndrome is a genetic multisystem disorder and is associated with mutation of genes encoding the proteins in the RAS‐MAPK pathway. We reported the first case of Noonan syndrome complicated with hepatocellular carcinoma.

Abstract Background We compared clinical outcomes of carbon ion radiotherapy and transarterial chemoembolization in the treatment of hepatocellular carcinoma. Methods Data of 477 patients with hepatocellular carcinoma who had undergone carbon ion radiotherapy or transarterial chemoembolization between April 2007 and September 2016 were retrospectively reviewed. Treatment naïve patients with single HCC, who underwent carbon ion radiotherapy or transarterial chemoembolization as a primary treatment were included. Clinical outcomes of the treatments were compared after utilizing propensity score matching. Results Of 124 patients who received carbon ion radiotherapy and 353 patients who received transarterial chemoembolization, 31 and 23 patients met our inclusion criteria, respectively. After utilizing propensity score matching, 17 matched pairs of patients from each treatment group were analyzed. The median follow-up durations after carbon ion radiotherapy and transarterial chemoembolization were 43 and 32 months, respectively. The 3-year overall survival, local control, and progression-free survival rates in the carbon ion radiotherapy versus transarterial chemoembolization groups were 88% versus 58% (p

The patient was an 86-year-old man who was admitted with obstructive jaundice. Computed tomography revealed a tumor in the hilar choledochus with peripheral hepatic duct dilatation. Endoscopic cholangiography (ERC) demonstrated the defect in the choledochus. Brushing cytology during ERC showed Orange-G-philic keratinized atypical cells, which led to a diagnosis of squamous cell carcinoma. Chemotherapy with tegafur-gimeracil-oteracil potassium was ineffective and was discontinued due to adverse effects. The patient died 5 months after the diagnosis and autopsy revealed tubular adenocarcinoma of the hilar bile duct with squamous cell carcinoma component. Progression of the disease might influence the distribution of adenosquamous carcinoma. The clinicopathological sequence of adenosquamous carcinoma of the choledochus was documented.

Background & Aims: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. Methods: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. Results: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p

The clinical significance of mac-2 binding protein glycosylation isomer (M2BPGi) levels based on virological responses due to antiviral therapy has not been fully evaluated. We compared the change before and 24 weeks after the therapy with daclatasvir and asunaprevir (DCV+ASV) of M2BPGi levels with those of other fibrosis markers in 73 chronic hepatitis C cases. Moreover, we examined the association between M2BPGi levels and hepatocarcinogenesis in sustained virological response (SVR) and non-SVR cases. M2BPGi levels were significantly improved at post-treatment week 24 (PTW24) in SVR but not non-SVR cases, whereas the changes of other fibrosis markers showed the same tendency in both SVR and non-SVR cases. M2BPGi levels were well correlated with other fibrosis markers at baseline but not PTW24. The incidence of hepatocellular carcinoma (HCC) was significantly associated with M2BPGi levels at PTW24. The achievement of SVR significantly affected the improvement of M2BPGi levels that best reflected the effect of direct-acting antivirals among the fibrosis markers. Furthermore, M2BPGi levels at PTW24 were also associated with the incidence of HCC in only SVR cases. However, the rapid decrease of M2BPGi levels might reflect the amelioration of liver inflammation rather than the improvement of liver fibrosis, which should be further elucidated.

Abstract Background To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) for 80 years or older patients with hepatocellular carcinoma (HCC). Methods Eligibility criteria of this retrospective study were: 1) HCC confirmed by histology or typical hallmarks of HCC by imaging techniques of four-phase multidetector-row computed tomography or dynamic contrast-enhanced magnetic resonance imaging; 2) no intrahepatic metastasis or distant metastasis; 3) no findings suggesting direct infiltration of the gastrointestinal tract; 4) performance status ≤2 by Eastern Cooperative Oncology Group classification; and 5) Child-Pugh classification A or B. Patients received C-ion RT with 52.8 Gy (RBE) or 60.0 Gy (RBE) in four fractions for usual cases and 60.0 Gy (RBE) in 12 fractions for close-to-gastrointestinal tract cases. Toxicities were classified using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (Version 4.0). Results Between March 2011 and November 2015, 31 patients were treated. The median follow-up period of all patients was 23.2 months (range: 8.4–55.3 months). Median age at the time of registration of C-ion RT was 83 years (range: 80–95 years). Child-Pugh grade A and B were 27 patients and 4 patients, respectively. The 2-year estimated overall survival, local control, and progression-free survival rates were 82.3%, 89.2%, and 51.3%, respectively. No patients had Grade 2 or higher acute toxicities (within 3 months after C-ion RT). One patient experienced progression in Child-Pugh classification from A to B within 3 months after C-ion RT. In late toxicities, Grade 3 encephalopathy was observed in 3 patients, and 2 improved with medication. Conclusions C-ion RT was effective with minimal toxicities for 80 years or older patients with hepatocellular carcinoma. Trial registration UMIN000020571 : date of registration, 14 January 2016, retrospectively registered.

Lenvatinib, which is an oral multikinase inhibitor, showed non-inferiority to the sorafenib in terms of overall survival (OS) and a higher objective response rate (ORR) and better progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC). A good liver function and Barcelona Clinic Liver Cancer (BCLC) intermediate stage were the key factors in achieving therapeutic efficacy. The management of adverse events plays an important role in continuing lenvatinib treatment. While sequential therapies contributed to prolonging overall survival, effective molecular targeted agents for the administration after lenvatinib have not been established. Repeated transcatheter arterial chemoembolization (TACE) was associated with a decline in the liver function and poor therapeutic response in BCLC intermediate patients. Recently, the Asia-Pacific Primary Liver Cancer Expert (APPLE) Consensus Statement proposed the criteria for TACE unsuitability. Upfront systemic therapy may be better for the BCLC intermediate stage HCC patients with a high tumor burden, while selective TACE will be recommended for obtaining a curative response in patients with a low tumor burden. This article reviews the therapeutic response, management of adverse events, post-progression treatment after Lenvatinib, and treatment strategy for BCLC intermediate stage HCC.

Background: Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, small numbers of adults with citrin deficiency develop hyperammonemic encephalopathy, adult-onset type II citrullinemia (CTLN2), which leads to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. We previously reported that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. Citrin deficiency may impair the glycolysis in hepatocytes because of an increase in the cytosolic NADH/NAD+ ratio, leading to an energy shortage. MCT administration can provide energy to hepatocytes and was expected to have a good effect on CTLN2. Methods: An MCT supplementation therapy under a low-carbohydrate formula was administered to five patients with CTLN2. Four of the patients had episodes of hyperammonemic encephalopathy, and one patient had postprandial hyperammonemia with no symptoms. Results: One of the patients displaying hyperammonemic encephalopathy completely recovered with all normal laboratory findings. Others notably improved in terms of clinical and or laboratory findings with no hyperammonemic symptoms; however, the patients displayed persistent mild citrullinemia and occasionally had postprandial mild hyperammonemia most likely due to an irreversible change in the liver. Conclusions: An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to a reduction in the cytosolic NADH/NAD+ ratio. MCT supplementation under a low-carbohydrate formula could be a promising therapy for CTLN2 and should also be used to prevent CTLN2 to avoid irreversible liver damage.

An association between reactive oxygen species and liver damage has been postulated in the course of hepatitis C virus (HCV) infection. Metallothionein (MT), induced by HCV core protein and interferon (IFN), plays a role in scavenging free radicals. MT expression in liver biopsies obtained from 21 patients with chronic HCV infection before and after IFN-alpha therapy was investigated. Changes in Knodell histological activity index (HAI) scores, MT protein levels (immunohistochemistry), MT-I and MT-II messenger (m)RNA expression levels (in situ hybridization) and proliferating cell nuclear antigen (PCNA) labelling index were determined and compared in serial liver specimens. MT staining was clustered around the portal tracts with inflammatory cells and fibrosis. The pattern of MT protein before IFN-alpha therapy was similar in all patients, but was higher in IFN-sustained responders than in nonresponders after IFN-alpha therapy. HAI scores and PCNA labelling indexes were significantly reduced after IFN-alpha therapy. MT-II mRNA expression correlated positively with PCNA index before therapy and with HAI scores after therapy ( P

With the advances in computed tomography (CT) imaging, CT can result in precise imaging, even of the gastrointestinal tract. However, the diagnostic quality of endoscopy is superior to CT because of precise mucosal observations or biopsy procedure. In the present case, CT was useful in the diagnosis of a gastric ulcer because endoscopy was deemed too difficult to perform due to tongue cancer occupying the oral space. Three-dimensional reconstruction of the CT images revealed an ulcerous lesion at the upper posterior wall of the stomach. CT may therefore be helpful for the diagnosis of gastric lesions when usual endoscopy is difficult to perform, as observed in the present patient.

The prevalence of hepatitis G virus (HGV) in liver disease of non-A, -B, -C viral hepatitis, hepatitis B and hepatitis C was determined. Two of 44 patients (4.5%) with liver injury without any hepatitis A, B or C marker were positive for HGV. One of five cases of hepatocellular carcinoma was positive for HGV. One of three cases with fulminant hepatitis was positive for HGV. This case was negative at the onset of fulminant hepatitis and became positive after plasmapheresis. No patient with acute (n=8) or chronic (n=5) hepatitis or liver cirrhosis (n=8) was positive for HGV in non-A, -B, -C liver disease. One of 30 patients with various HBV-positive liver diseases and nine (17.3) of 52 patients with type C liver disease were positive for HGV. In patients with hepatitis C, four (28.6%) of 14 HGV-co-infected patients were complicated with diabetes mellitus compared with four (10.5%) of 38 single hepatitis C virus (HCV)-infected patients (not significant). In 12 HGV-positive patients, eight of 10 (80%) had a history of blood transfusion. In HCV-positive patients, co-infection with HGV was not a risk factor in patients with diabetes mellitus as a complication. HGV appeared to cause non-A, -B, -C hepatitis rarely, and its main route of infection was blood transfusion.

Background. The study aims to analyze in detail the incidence, mortality using the standardized incidence ratio (SIR), and standardized mortality ratio (SMR) of hepatocellular carcinoma (HCC) in primary biliary cirrhosis (PBC), because no large case studies have focused on the detailed statistical analysis of them in Asia. Methods. The study cohorts were consecutively diagnosed at Gunma University and its affiliated hospitals. Age- or sex-specific annual cancer incidence and deaths were obtained from Japanese Cancer Registry and Death Registry as a reference for the comparison of SIR or SMR of HCC. Moreover, univariate analyses and multivariate analyses were performed to clarify predictive factors for the incidence of HCC. Results. The overall 179 patients were followed up for a median of 97 months. HCC had developed in 13 cases. SIR for HCC was 11.6 (95% confidence interval (CI), 6.2–19.8) and SMR for HCC was 11.2 (95% CI, 5.4–20.6) in overall patients. The serum albumin levels were a predictive factor for the incidence of HCC in overall patients. Conclusions. The incidence and mortality of HCC in PBC patients were significantly higher than those in Japanese general population. PBC patients with low serum albumin levels were populations at high risk for HCC.