記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The clinical course of esophagogastric varices (EGV) after sustained virological response (SVR) with direct-acting antiviral (DAA) therapy has not been clearly elucidated. The predictors for the worsening/improvement of EGV after SVR with DAA therapy were investigated. METHODS: Of the cirrhosis patients who achieved SVR with DAA therapy, 328 patients who underwent endoscopic examinations both before and after DAA therapy were enrolled. The predictors of EGV worsening or improvement were investigated. RESULTS: Multivariate analysis identified a history of ascites retention, albumin at baseline, and MELD score at baseline as independent factors that contributed to EGV exacerbation. On multivariate analysis, two factors, BMI and platelet count, were related to EGV improvement. An integrated scoring system was created using these risk factors with or without weighting according to each hazard ratio, and the patients were divided into three groups. A scoring system with weighting of each factor appeared to be more useful, with fewer intermediate patients and more cases classified into the low-risk and high-risk groups. CONCLUSION: Esophagogastric varices after SVR have a varied clinical course. Using this scoring system that can accurately predict EGV outcomes in clinical settings, it may be feasible to establish a risk-based EGV surveillance plan following SVR.

DOI： 10.1007/s00535-024-02174-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

RNA-dependent protein kinase (PKR) may have a positive regulatory role in controlling tumor growth and progression in hepatocellular carcinoma (HCC). However, the downstream substrates and the molecular mechanism of PKR in the growth and progression of HCC have not been clarified. In this study, mass spectrometry analysis was performed with immunoprecipitated samples, and 4.1R was identified as a protein that binds to PKR. In transfected COS7 cells, an immunoprecipitation experiment showed that 4.1R binds to wild-type PKR, but not to a kinase-deficient mutant PKR, suggesting that PKR binds to 4.1R in a kinase activity-dependent manner. In HCC cell lines, HuH7 and HepG2, the expression level of 4.1R protein was shown to be regulated by protein expression and activation of PKR. Interestingly, high expression of 4.1R, as well as PKR, is associated with a worse prognosis in HCC. PKR increased HCC cell growth in both anchorage-dependent and anchorage-independent manners, whereas 4.1R was involved in HCC cell growth only in an anchorage-independent manner, not in an anchorage-dependent manner. The rescue experiment indicated that increased anchorage-independent growth of HCC cells by PKR might be caused by 4.1R. In conclusion, PKR associates with 4.1R and promotes anchorage-independent growth of HCC. The PKR-4.1R axis might be a new therapeutic target in HCC.

DOI： 10.1038/s41598-024-75142-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Since the development of tremelimumab plus durvalumab (Dur/Tre) for unresectable hepatocellular carcinoma (uHCC), it has been used as not only an initial but also later line treatment in clinical practice. This study aimed to elucidate clinical prognostic factors for progression-free survival (PFS) in Dur/Tre treatment cases. METHODS: Enrolled were 183 uHCC patients treated with Dur/Tre from 2023 to May 2024 (median age, 74 years; male patients, 152; Child-Pugh class A:B, 150:33; Barcelona Clinic Liver Cancer stage B:C, 59:124; initial line use, 64). Clinical factors with prognostic influence on PFS in these patients were retrospectively evaluated. RESULTS: The median observation period was 7.2 months (interquartile range, 3.2-10.4). History of atezolizumab plus bevacizumab (Atz/Bev) treatment was the only significant prognostic factor for PFS at introduction of Dur/Tre in multivariate analysis (hazard ratio 2.040, p = 0.028) (median PFS: without vs. with = 5.6 vs. 2.7 months, p < 0.001). Although immune-mediated adverse events (imAE) occurrence was only significant in univariate analysis, when objective response and disease control rates were examined according to imAE positivity (any grade) at the time of analysis, those were noted in 14.4% and 39.2%, respectively, of patients without imAE, while in patients with imAE (any grade), they were noted in 18.2% and 56.1%, respectively (p = 0.523 and p = 0.038, respectively). CONCLUSION: History of Atz/Bev treatment may be an independent clinical factor for poor PFS at Dur/Tre introduction.

DOI： 10.1111/hepr.14136

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 <60 years) groups, respectively (p < 0.001). We subsequently integrated age into the existing Baveno criteria. In patients not meeting Baveno criteria (defined as not meeting B6C or B7C), the older group exhibited a significantly elevated risk of decompensation compared to the younger group (p < 0.05). However, no significant difference was observed between the older and younger groups in patients meeting Baveno criteria (p > 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.

DOI： 10.1002/mco2.781

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. METHODS: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. RESULTS: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. CONCLUSION: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

DOI： 10.1016/j.cyto.2024.156743

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Nocturia is a common symptom of lower urinary tract syndrome (LUTS). In previous studies, a close association between LUTS and colorectal inflammation has been reported. However, evidence regarding the association between nighttime urinary frequency and ulcerative colitis (UC) is limited. Herein, we investigated the association between nighttime urinary frequency and clinical outcomes of UC. METHODS: We surveyed 287 Japanese patients with UC. A self-administered questionnaire was used to collect the information on the variables studied. Patients were divided into three groups based on nighttime urinary frequency: (1) no voids, (2) one void, and (3) two or more voids. The assessment of clinical outcomes was based on mucosal healing (MH) and clinical remission (CR). The association between nighttime urinary frequency and prevalence of MH and CR was evaluated using multivariate logistic regression analyses. RESULTS: The prevalence of one nighttime frequency and two or more nighttime frequency in this cohort was 35.5% and 26.8%, respectively. The percentage of MH and CR was 24.7% and 59.2%, respectively. Two or more nighttime frequency (adjusted odds ratio [OR]: 0.31, 95% confidence interval [CI]: 0.13-0.73) was independently and inversely associated with MH. In nonelderly patients (<70 years) and patients in CR, an association between two or more nighttime frequency and MH remained significant (non-elderly: adjusted OR: 0.27, 95% CI: 0.09-0.72 and only CR: adjusted OR: 0.34, 95% CI: 0.12-0.90). CONCLUSION: Nighttime urinary frequency was independently and inversely associated with MH in Japanese patients with UC. Nighttime urinary frequency may serve as a complementary physical sign of MH in patients with UC.

DOI： 10.1002/nau.25570

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Constipation is a very common medical issue among the general population worldwide. However, the association between exercise habits and constipation is still not fully understood. Additionally, no evidence regarding the association between exercise partners and constipation exists. This study aimed to evaluate this issue in a young Japanese population, taking the presence or absence of an exercise partner as an additional variable. METHODS: The study subjects consisted of 12,497 Japanese university students. Information on constipation, exercise frequency, exercise intensity, and exercise partners was obtained through a self-administered questionnaire. Constipation was defined as present if a student answered "Yes" to the question, "Have you been constipated often recently?" RESULTS: The prevalence of self-reported constipation was 6.5%. Frequency and intensity of exercise were independently inversely associated with constipation. After adjustment for age, body mass index, drinking, smoking, anemia, and sports injury, exercise with groups and friends was independently inversely associated with constipation (groups: adjusted odds ratio (OR) - 0.70 (95% confidence interval (CI): 0.53-0.90), friends: adjusted OR - 0.56 (95% CI: 0.42-0.74)). After further adjustment by adding intensity and frequency of exercise to confounding factors, only the association between exercise with friends and constipation was still significant (adjusted OR: 0.61 (95% CI: 0.39-0.96)). CONCLUSIONS: In this young Japanese population, the frequency and the intensity of exercise and the presence of exercise partners might be independently inversely associated with self-reported constipation. Exercising, especially exercising with others, may have a preventive effect on constipation, and opportunities to exercise with others should be provided.

DOI： 10.7759/cureus.74455

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aims to investigate the predictive factors for conversion therapy in patients with unresectable hepatocellular carcinoma (uHCC) and to evaluate the prognosis of conversion cases by comparing them with partial response (PR) and complete response (CR) cases. METHODS: In this retrospective multicentre study, we included a total of 946 uHCC patients treated with atezolizumab and bevacizumab (Atez/Bev) from September 2020 to September 2023. RESULTS: Out of the patients, 43 (4.5%) received conversion therapy following Atez/Bev treatment. The overall response rate was 65.1% and 23.7% in the conversion and non-conversion group, respectively, with a statistical significance (p < 0.001). Multivariate analyses identified that BCLC stage B or an earlier stage (p = 0.045), absence of macrovascular invasion and extrahepatic spread (p = 0.045), and a low value of neutrophil to lymphocyte ratio (p = 0.04) were significantly favourable predictive factors associated with conversion therapy. The conversion group showed significantly better survival compared to the non-conversion group (p < 0.001). In the landmark analysis at 6, 12 and 18 months, the conversion group exhibited better survival compared to PR patients in the non-conversion group (p = 0.04, 0.01 and 0.03, respectively) and there were no significant differences in the overall survival (OS) between the conversion group and patients who achieved a CR (p = 0.7, 1.0 and 0.3, respectively). CONCLUSIONS: Patients with low tumour burden and low value of NLR were more likely to undergo conversion therapy. The OS of patients undergoing conversion therapy showed better survival compared to those achieving PR and was comparable to those with CR patients. Conversion therapy could be considered if feasible.

DOI： 10.1111/apt.18237

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The incidence of and factors involved in gastroesophageal varix-related events in hepatitis C virus-related cirrhosis patients, including decompensated cirrhosis, after direct-acting antiviral therapy are unclear. METHODS: We conducted a multicenter study using prospective data from 478 hepatitis C virus-related cirrhosis patients treated with direct-acting antiviral therapy from February 2019 to December 2021 at 33 Japanese hospitals. Gastroesophageal varices were classified as F1 (small-caliber), F2 (moderately enlarged), or F3 (markedly enlarged) according to the Japanese criteria. Patients without varix or with F1 without red color signs were defined as low-risk varix, and patients with ≥F2 or red color signs or a history of rupture were defined as high-risk varix. Varix-related events were defined as prophylactic treatment or rupture of gastroesophageal varix. RESULTS: The median age was 70 years, 43% of patients had decompensated cirrhosis, and 16% had high-risk varices (13% in compensated and 33% in decompensated, p < 0.001). Sustained virologic response rates were 94.9% for compensated cirrhosis and 91.3% for decompensated cirrhosis (p = 0.120). Across 35.7 months, 25 patients received prophylactic treatment, and four experienced varix rupture. The 3-year incidence rate of varix-related events was 6.2% (3.5% in compensated and 9.9% in decompensated, p = 0.001). In the multivariate analysis, high-risk varix (p < 0.001), high baseline gamma-glutamyl transpeptidase levels (p < 0.001), and virologic failure (p = 0.004) were significantly involved in varix-related events. CONCLUSIONS: The cumulative incidence rate of varix-related events was significantly higher in decompensated cirrhosis than in compensated cirrhosis. Baseline varix status, baseline gamma-glutamyl transpeptidase levels, and virologic response were related to varix-related events after direct-acting antiviral therapy.

DOI： 10.1111/hepr.14131

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: the most frequently used first-line treatment in patients with advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab. Upon progression after this treatment, the standard of care in many countries is sorafenib, due to the lack of reimbursement for other drugs. Several randomized trials are currently underway to clarify the best second-line therapy in patients with HCC. This real-world study aims to compare outcomes reached by lenvatinib and sorafenib second-line therapy in this setting. METHODS: the overall cohort included 891 patients with HCC from 5 countries treated with atezolizumab plus bevacizumab in first-line setting between October 2018 and April 2022. At data cut-off (May 2022), 41.5% of patients were continuing first-line treatment, 5.5% were lost at follow up, and 53.0% of patients had progressive disease after first-line therapy. 51.5% of patients with progressive disease received a second-line treatment, while 48.5% didn't receive any subsequent therapy. Between patients receiving second-line treatment, 11.1% patients underwent transarterial chemoembolization, 21.0% received sorafenib, 35.4% underwent lenvatinib, and 32.5% were treated with other drugs. RESULTS: lenvatinib second-line subgroup achieved a median overall survival (mOS) of 18.9 months, significative longer (p = 0.01; HR: 2.24) compared to sorafenib subgroup that reached a mOS of 14.3 months. The multivariate analysis highlighted Albumin-Bilirubin 1 grade [p &lt; 0.01; hazard ratio (HR): 5.23] and lenvatinib second-line therapy (p = 0.01; HR: 2.18) as positive prognostic factors for OS. The forest plot highlighted a positive trend in terms of OS in favor of patients treated with lenvatinib second-line regardless of baseline characteristics before first-line therapy. CONCLUSION: these results suggest that, in patients with HCC progressed to first-line atezolizumab plus bevacizumab, lenvatinib second-line therapy is associated to an improved survival compared to sorafenib.

DOI： 10.1159/000541018

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記述言語：英語  

DOI： 10.1007/s12328-024-01996-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 (A + B) is equally effective in viral and nonviral patients. METHODS: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies. RESULTS: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral 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 the 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 nonviral 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.

DOI： 10.1159/000537915

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

CONTEXT: Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease (CVD), is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear. OBJECTIVE: We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD. DESIGN: Cross-sectional single-center observational study. METHODS: We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method. RESULTS: Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5-8, ＞66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1-4, <33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women. CONCLUSION: High serum Rem-C levels were associated with high NAS, but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity.

DOI： 10.1210/clinem/dgae597

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.14309/ajg.0000000000002981

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. METHODS: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvedilol-treating cohort. RESULTS: In the meta-analysis with six studies (n = 819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n = 151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n = 1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvedilol-treated cohort, patients with high-risk CSPH treated with carvedilol (n = 81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n = 613 before propensity score matching [PSM], n = 162 after PSM). CONCLUSIONS: Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

DOI： 10.3350/cmh.2024.0198

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: This retrospective study was conducted to investigate the diagnostic accuracy of ultrasound-derived fat fraction (UDFF) for grading hepatic steatosis using liver histology as the reference standard. METHODS: Seventy-three patients with liver disease were assessed using UDFF and liver biopsy. Pearson's test and the Bland-Altman plot were used to assess the correlation between UDFF and histological fat content in liver sections. The UDFF cutoff values for histologically proven steatosis grades were determined using the area under the receiver operating characteristic curve (AUROC). RESULTS: The median age of the patients was 66 (interquartile range 54-74) years, and 33 (45%) were females. The UDFF values showed a stepwise increase with increasing steatosis grade (p < .001) and were strongly correlated with the histological fat content (r = .7736, p < .001). The Bland-Altman plot revealed a mean bias of 2.384% (95% limit of agreement, - 6.582 to 11.351%) between them. Univariate regression analysis revealed no significant predictors of divergence. The AUROCs for distinguishing steatosis grades of ≥ 1, ≥2, and 3 were 0.956 (95% confidence interval [CI], 0.910-1.00), 0.926 (95% CI, 0.860-0.993), and 0.971 (95% CI, 0.929-1.000), respectively. The UDFF cutoff value of > 6% had a sensitivity and specificity of 94.8% and 82.3%, respectively, for diagnosing steatosis grade ≥ 1. There was no association between UDFF and the fibrosis stage. CONCLUSION: UDFF shows strong agreement with the histological fat content and excellent diagnostic accuracy for grading steatosis. UDFF is a promising tool for detecting and quantifying hepatic steatosis in clinical practice.

DOI： 10.1007/s10396-024-01472-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC). AIMS: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real-world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial. METHODS: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non-IMbrave150 group). RESULTS: Median progression-free survival (PFS) in the IMbrave150 and non-IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non-B, non-C HCC aetiology (hazard ratio [HR], 1.173), α-fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin-bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non-Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α-fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a. CONCLUSIONS: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival.

DOI： 10.1111/apt.18037

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background The ABO blood type has been associated with several digestive diseases. Some evidence has shown an association between ABO blood type and clinical outcomes among Asian patients with Crohn's disease. However, there are no reports about the association between ABO blood type and clinical outcomes in ulcerative colitis (UC). In this study, we aimed to evaluate the association between ABO blood type and clinical characteristics among patients with UC. Methodology The study subjects consisted of 277 Japanese patients with UC. Information on clinical characteristics and ABO blood type data was collected using medical records and a self-reported questionnaire. The information on clinical remission was collected using medical records. The definition of mucosal healing (MH) and partial MH was Mayo endoscopic subscore of 0 or 0-1, respectively. Results Of the enrolled patients, 39.4% (109/277), 18.4% (51/277), 29.2% (81/277), and 13.0% (36/277) had blood types A, B, O, and AB, respectively. The mean current age, age at onset of UC, and body mass index were 51.3 years, 42.1 years, and 22.7 kg/m2, and the proportion of male patients was 59.2% (164/277). The proportion of patients with clinical remission, MH, partial MH, and prednisolone use were 58.1% (161/277), 25.6% (71/277), 63.2% (175/277), and 21.3% (59/277), respectively. Conclusions None of the blood types were associated with any of the variables in this study. Among Japanese patients with UC, ABO blood type might not be associated with clinical characteristics.

DOI： 10.7759/cureus.59787

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIMS: Although certain allergic diseases have been reported to be associated with the prevalence of functional dyspepsia (FD) and irritable bowel syndrome (IBS), it is unclear whether the presence of multiple allergic diseases further increases the prevalence of FD and IBS. The aim of this study is to determine this issue in young people. METHODS: A cohort of 8923 Japanese university students was enrolled and diagnoses of FD and IBS were confirmed using Rome III criteria. Allergic disorders diagnosed at medical institutions were obtained by means of a self-administered questionnaire. RESULTS: The prevalence of FD, IBS, and their overlap was found to be 1.9%, 6.5%, and 1.1%, respectively. Pollen allergy was independently positively correlated with FD, IBS, and overlap of FD and IBS. Allergic rhinitis was positively linked to IBS. Drug allergy was positively associated with FD. The presence of multiple allergic diseases was positively correlated with FD and IBS (FD: adjusted OR for 2 allergic diseases: 1.95 [95% CI, 1.24-2.98], P for trend = 0.003; and IBS: adjusted OR for 1 allergic disease: 1.40 [95% CI, 1.15-1.69], 2 allergic diseases 1.47 [95% CI, 1.12-1.91], and 3 or more allergic diseases: 2.22 [95% CI, 1.45-3.28], P for trend = 0.001). Additionally, the concomitant existence of multiple allergic diseases was also demonstrated to have a trend that correlated with the overlap of FD and IBS (P for trend = 0.018). CONCLUSION: Allergic disease multimorbidity is positively correlated with the prevalence of FD and IBS in a young population.

DOI： 10.5056/jnm23015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors. OBJECTIVE: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting. PATIENTS AND METHODS: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea). RESULTS: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival. CONCLUSIONS: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.

DOI： 10.1007/s11523-024-01061-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events. METHODS: A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices. RESULTS: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis. CONCLUSIONS: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

DOI： 10.1111/hepr.14049

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Double-stranded RNA-activated protein kinase R (PKR) is highly expressed in colorectal cancer (CRC). However, the role of PKR in CRC remains unclear. The aim of this study was to clarify whether C16 (a PKR inhibitor) exhibits antitumor effects and to identify its target pathway in CRC. We evaluated the effects of C16 on CRC cell lines using the MTS assay. Enrichment analysis was performed to identify the target pathway of C16. The cell cycle was analyzed using flow cytometry. Finally, we used immunohistochemistry to examine human CRC specimens. C16 suppressed the proliferation of CRC cells. Gene Ontology (GO) analysis revealed that the cell cycle-related GO category was substantially enriched in CRC cells treated with C16. C16 treatment resulted in G1 arrest and increased p21 protein and mRNA expression. Moreover, p21 expression was associated with CRC development as observed using immunohistochemical analysis of human CRC tissues. C16 upregulates p21 expression in CRC cells to regulate cell cycle and suppress tumor growth. Thus, PKR inhibitors may serve as a new treatment option for patients with CRC.

DOI： 10.1038/s41598-024-59671-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Rapidly aging societies have become a major issue worldwide including Japan. This study aimed to elucidate relative changes in the characteristics of inpatients in Japan related to this issue. METHODS: A total of 23 835 Japanese inpatients treated from 2010 to 2021 were enrolled (2010-2013, period I; 2014-2017, period II; 2018-2021, period III). Changes in clinical features were retrospectively analyzed based on ICD-10 diagnosis data. RESULTS: The percentage of patients aged over 75 years increased over time (period I, 38.0%; II, 39.5%, III, 41.4%). Emergency admissions comprised 27.5% of all in period I, which increased to 43.2% in period II and again to 44.5% in period III (P < 0.001). In period I, gastrointestinal disease, liver disease, pancreatic-biliary disease, and other disease types were noted in 47.4%, 29.5%, 19.2%, and 3.9%, respectively, while those values were 44.0%, 18.0%, 33.9%, and 4.1%, respectively, in period III (P < 0.001). The frequency of liver disease decreased by approximately 0.6-fold from periods I to III, while that of biliary-pancreatic disease increased by approximately 1.8-fold during that time. Both percentage and actual numbers of patients with biliary-pancreatic disease increased during the examined periods. Analysis of changes in the proportion of organs affected by malignancy during periods I, II, and III showed a marked increase in cases of biliary-pancreatic malignancy (11.6%, 19.5%, 26.6%, respectively) (P < 0.001). CONCLUSION: In association with the rapidly aging Japanese society, there has been an increasing frequency of biliary-pancreatic disease cases requiring hospitalization for treatment in the west Japan region of Shikoku.

DOI： 10.1111/jgh.16557

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The association between ulcerative colitis (UC) and erectile dysfunction (ED) has been previously reported. Numerous previous studies have also reported an association between gastrointestinal symptoms and ED. Constipation and diarrhea are common in patients with UC. However, the specific association between bowel movement frequency and ED remains unclear. The aim of this study is to investigate the association between bowel movement frequency and ED in 164 patients with UC. The definition of ED, moderate to severe ED, and severe ED was the Sexual Health Inventory for Men score <22, <12, and <8, respectively. Bowel movement frequency was divided into three categories: (1) high (More than once a day), (2) normal (once a day, reference), and low (less than one time/day). The definition of constipation was based on the Rome I criteria and/or medication for constipation. The prevalence of constipation and ED was 10.4% and 86.0%, respectively. The rate of high, normal, and low bowel movement frequency was 56.1%, 25.0%, and 18.9%, respectively. High bowel movement frequency was independently and positively associated with ED and moderate to severe ED (ED: adjusted odds ratio [OR] 4.42, 95% confidence interval [CI] 1.35-15.98; moderate to severe: adjusted OR 2.98, 95% CI 1.22-7.61). Low bowel movement frequency was independently and positively associated with moderate to severe ED and severe ED (moderate to severe: adjusted OR 3.96, 95% CI 1.27-13.08; severe: adjusted OR 3.20, 95% CI 1.08-9.86). No association between constipation and ED was found. In conclusion, in Japanese patients with UC, both high and low bowel movement frequency were independently and positively associated with ED.

DOI： 10.1038/s41443-024-00884-9

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < .001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c-index 0.606). PFS periods for those IMABALI-De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c-index 0.574). As compared with CRAFITY score, IMABALI-De score had better AIC and c-index results for both OS and PFS. CONCLUSION: The present results indicated that the proposed IMABALI-De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy.

DOI： 10.1002/cnr2.2042

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 79-year-old man received treatment for multiple intrahepatic hepatocellular carcinoma with atezolizumab + bevacizumab. However, he developed lower back pain attributed to spinal metastases upon tumor enlargement; thus, he was admitted to our hospital for a change from atezolizumab + bevacizumab to lenvatinib and radiation therapy for the spinal metastases. On the 11th day after starting lenvatinib treatment, a pulsatile aneurysm appeared in the tumor, detected using abdominal ultrasonography Micro B-flow imaging, which visualized blood flow at a high frame rate; this was diagnosed as a pseudoaneurysm. The patient refused treatment for the pseudoaneurysm; therefore, he was carefully followed up. Fortunately, the pseudoaneurysm disappeared on the 17th day. One month later, the tumor had become completely necrotic. Lenvatinib demonstrated effectiveness in inhibiting angiogenesis in the tumor, as evidenced by a decrease in tumor blood flow. This case report suggests that pseudoaneurysm formation within the tumor occurs early after the administration of lenvatinib; thus, clinicians must be aware of the potential risk of pseudoaneurysm rupture.

DOI： 10.1007/s12328-023-01914-7

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Several preliminary reports have suggested the utility of ultrasound attenuation coefficient measurements based on B-mode ultrasound, such as iATT, for diagnosing steatotic liver disease. Nonetheless, evidence supporting such utility is lacking. This prospective study aimed to investigate whether iATT is highly concordant with magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF) and could well distinguish between steatosis grades. METHODS: A cohort of 846 individuals underwent both iATT and MRI-PDFF assessments. Steatosis grade was defined as grade 0 with MRI-PDFF < 5.2%, grade 1 with 5.2% MRI-PDFF < 11.3%, grade 2 with 11.3% MRI-PDFF < 17.1%, and grade 3 with MRI-PDFF of 17.1%. The reproducibility of iATT and MRI-PDFF was evaluated using the Bland-Altman analysis and intraclass correlation coefficients, whereas the diagnostic performance of each steatosis grade was examined using receiver operating characteristic analysis. RESULTS: The Bland-Altman analysis indicated excellent reproducibility with minimal fixed bias between iATT and MRI-PDFF. The area under the curve for distinguishing steatosis grades 1, 2, and 3 were 0.887, 0.882, and 0.867, respectively. A skin-to-capsula distance of ≥ 25 mm was identified as the only significant factor causing the discrepancy. No interaction between MRI-logPDFF and MRE-LSM on iATT values was observed. CONCLUSIONS: Compared to MRI-PDFF, iATT showed excellent diagnostic accuracy in grading steatosis. iATT could be used as a diagnostic tool instead of MRI in clinical practice and trials. Trial registration This study was registered in the UMIN Clinical Trials Registry (UMIN000047411).

DOI： 10.1007/s00535-024-02096-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIMS: Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS) performed at the intrahepatic bile duct segment 3 (B3) is widely used for biliary drainage. Although performing post-puncture procedures is easier in the intrahepatic bile duct segment 2 (B2) when using a conventional oblique-viewing (OV) EUS scope, this method may cause transesophageal puncture and severe adverse events. We evaluated the safety and efficacy of B2 puncture using a novel OV-EUS scope. METHODS: In this single-center retrospective study, we prospectively enrolled and collected data from 45 patients who consecutively underwent EUS-HGS procedures with a novel OV-EUS scope between September 2021 and December 2022 at our cancer center. RESULTS: The technical success rates of B2-EUS-HGS and EUS-HGS were 93.3% (42/45) and 97.8% (44/45), respectively. The early adverse event rate was 8.9% (4/45) with no cases of scope changes or transesophageal punctures. The median procedure time was 13 minutes (range, 5-30). CONCLUSIONS: B2-EUS-HGS can be performed safely with the novel EG-740UT (Fujifilm) OV-scope without transesophageal puncture and with a high success rate. B2-EUS-HGS using this novel OV scope may be the preferred strategy for EUS-HGS.

DOI： 10.5946/ce.2023.129

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Unresectable recurrence after curative treatments for hepatocellular carcinoma (HCC) is a life-limited event. Although the IMbrave050 trial (IM050) showed a favorable reduction in recurrence with adjuvant immune-combination chemotherapy, inclusion criteria of the radiofrequency ablation (RFA) group were lower risk than that of the resection group. This study aimed to elucidate the clinical features of patients treated with RFA, which really need adjuvant-chemotherapy. METHODS: From 2000 to 2022, 528 patients with Child-Pugh A and HCC within the Milan criteria (MC), who met the IM050 criteria for RFA and undergone resection or RFA, were enrolled (71 years, HCV:HBV:HBV/HCV:alcohol:others = 337:44:5:53:89, multi-tumor = 138, RFA:resection = 309:219). Unresectable recurrence was defined as beyond the MC. Risk factors for recurrence beyond the MC were retrospectively evaluated. RESULTS: Multivariate Cox-hazard analysis showed HCV-positive (HR 1.49), AFP-L3 > 10% (HR 1.75), and DCP > 100 mAU/mL (HR1.80) as significant prognostic factors for recurrence beyond the MC (each P < 0.05). Summing of positive factors (1 point for each) was used for scoring (AD-ON score), which showed increased positive rates for micro-hepatic vein invasion (score 0:1:2:3 = 0%:1.1%:6.6%:15.8%), micro-portal vein invasion (0:1:2:3 = 2.0%:12.1%:14.1%:31.6%), and poor differentiation (0:1:2:3 = 6.0%:6.7%:15.3%:15.8%) in the resection group associated with a greater score (each P < 0.01). In patients treated with RFA, those with greater AD-ON scores showed shorter time to recurrence beyond the MC, recurrence-free time, and overall survival (score 0:1:2:3 = no-estimation:97:66:23 months, 35:27:20:12 months, and 91:82:67:52 months, respectively, each P < 0.05). CONCLUSION: HCC patients treated by RFA and with a high AD-ON score (≧2) should be considered for aggressive adjuvant-chemotherapy to prolong the period of recurrence beyond the MC.

DOI： 10.1007/s12328-024-01938-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

DOI： 10.1111/liv.15885

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記述言語：英語  

DOI： 10.1007/s10396-024-01423-1

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Constipation is a common gastrointestinal symptom in patients with ulcerative colitis (UC). Several studies on the general population have demonstrated a link between allergic diseases and constipation. However, evidence regarding the association between allergic diseases and constipation in UC is limited. This study aims to evaluate this issue in Japanese patients with UC. METHODS: This cross-sectional study recruited consecutive 387 patients with UC. We used a self-administered questionnaire to estimate the prevalence of physician-diagnosed allergic diseases. The definition of constipation was based on Rome I criteria and/or medication for constipation. RESULTS: The prevalence of constipation was 12.5%. The prevalence rates of asthma, atopic dermatitis, pollen allergy, food allergy, and drug allergy were 11.8%, 9.0%, 36.3%, 6.2%, and 8.3%, respectively. Allergic diseases were not associated with constipation (adjusted odds ratio [OR] with asthma (adjusted OR 0.98 [95% confidence interval [CI] 0.27-2.80]), atopic dermatitis (adjusted OR 0.67 [95% CI 0.10-2.56]), pollen allergy (adjusted OR 0.92 [95% CI 0.41-1.97]), food allergy (adjusted OR 0.76 [95% CI 0.11-2.95]), and drug allergy (adjusted OR 1.06 [95% CI 0.28-3.24]). Additionally, the number of allergic diseases was not associated with the prevalence of constipation. CONCLUSIONS: In Japanese UC patients, no association between allergic diseases and constipation was found.

DOI： 10.7759/cureus.55912

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 70-year-old woman presented with stage III pancreatic head cancer. After endoscopic sphincterotomy, a fully covered self-expandable metallic stent (FCSEMS) was placed in the common bile duct to manage jaundice. The patient developed a fever and abdominal pain 40 days after stent placement, with a suspected diagnosis of infected pancreatic pseudocyst. Purulent discharge from the papilla was observed during FCSEMS removal, and pancreatography revealed a pseudocyst connected to the main pancreatic duct. The pancreatic pseudocyst resolved after transpapillary drainage. Pancreatic pseudocysts should be suspected after biliary FCSEMS placement, and prompt removal and endoscopic drainage of the FCSEMS should be considered.

DOI： 10.2169/internalmedicine.3178-23

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to establish the shear wave measurement (SWM) cut-off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard. METHODS: We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61 kPa), F1 (≥2.61 kPa, <2.97 kPa, any fibrosis), F2 (≥2.97 kPa, <3.62 kPa, significant fibrosis), F3 (≥3.62 kPa, <4.62 kPa, advanced fibrosis), or F4 (≥4.62 kPa, cirrhosis). RESULTS: The median SWM values increased significantly with increasing fibrosis stage (p < 0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761-0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin-capsular distance; skin-capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut-off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89 kPa, respectively. CONCLUSIONS: This multicenter study in a large number of patients established SWM cut-off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut-off values will be applied to liver diseases in the future.

DOI： 10.1111/hepr.14026

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD. METHODS: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%. RESULTS: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses. CONCLUSION: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

DOI： 10.4093/dmj.2023.0200

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. OBJECTIVE: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC. PATIENTS AND METHODS: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years). RESULTS: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). CONCLUSIONS: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.

DOI： 10.1007/s11523-023-01029-6

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

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記述言語：日本語   出版者・発行元：(一社)日本消化管学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Socioeconomic status is a risk factor for poor disease prognosis. No studies of patients with ulcerative colitis (UC) have investigated the association between socioeconomic status and erectile dysfunction (ED), although UC is independently positively associated with ED. Therefore, the purpose of this survey to evaluate this issue in Japanese patients with UC. The study enrolled 165 patients with UC. Education status (low, middle, high) and household income (low, middle, high) were classified in three groups using self-administered surveys. The information regarding the Sexual Health Inventory for Men (SHIM) was obtained using self-administered questionnaires. The definition of mild to moderate or severe ED and severe ED was SHIM score <17 and SHIM score <8, respectively. The prevalence of mild to moderate or severe ED and severe ED was 64.9% and 47.9%, respectively. In crude analysis, household income was inversely associated with mild to moderate or severe ED and severe ED. After adjustment for age, current drinking, current smoking, exercise habit, body mass index, mucosal healing, and duration of UC, high household income was independently and inversely associated with mild to moderate or severe ED (adjusted odds ratio [OR] 0.23, 95% confidence interval [CI] [0.05, 0.93], p for trend = .038) and severe ED (adjusted OR 0.26, 95% CI [0.07, 0.85], p for trend = .024). In contrast, no association between education status and ED was found. In conclusion, household income was independently and inversely associated with ED in Japanese UC patients.

DOI： 10.1177/15579883241256833

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Immune checkpoint inhibitors may cause various types of organ damage as immune-related adverse events, of which, liver damage is the most common. Herein, we evaluated the clinicopathological features of immune checkpoint inhibitor-related liver injury and investigated the differences between immune checkpoint inhibitor-related liver injury and drug-induced liver injury or autoimmune hepatitis. METHODS: We selected patients with ≥ grade 3 liver injury who were diagnosed with immune checkpoint inhibitor-related liver injury (n=15). Liver biopsies were performed in 10 of the 15 cases. We also selected cases in which a liver biopsy was performed and drug-induced liver injury (n=7) or autoimmune hepatitis [n=21: acute exacerbation (n=13) was diagnosed and cases of acute onset (n=8), in which liver function test results corresponded to ≥ grade 3]. RESULTS: Portal fibrosis and periportal activity scores were significantly higher in the acute exacerbation autoimmune hepatitis group than in the other groups. Portal and lobular activity were not different between the groups. Plasma cell infiltration showed a higher trend in the autoimmune hepatitis group than in the other groups. Granuloma formations were seen in 90% of immune checkpoint inhibitor-related liver injury cases. The CD4/8 ratio was significantly lower in the immune checkpoint inhibitor-related liver injury group than in the other groups. Patients with bile duct injury had poorer response to corticosteroid therapy than those without. CONCLUSIONS: There are some obvious differences among immune checkpoint inhibitor-related liver injury, drug-induced liver injury, and autoimmune hepatitis in liver histology. Liver biopsy is helpful for the diagnosis and severity evaluation of liver injury.

DOI： 10.15403/jgld-5045

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

DOI： 10.1111/jgh.16439

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記述言語：日本語   出版者・発行元：日本消化器病学会-四国支部  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

DOI： 10.1038/s41598-023-36052-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.

DOI： 10.1002/ijc.34799

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN-treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev. CONCLUSIONS: Using a nonlinear mixed-effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN-treated patients with BCLC advanced stage or those receiving the full dose of LEN.

DOI： 10.1002/cam4.6726

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older. METHODS: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first-line treatment, respectively, were retrospectively analyzed. RESULTS: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01-86.0) and 83.0 (82.0-86.0) years (p=0.3), respectively. Males accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p=0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p=1.0). The median PFS in the LEN and Atez/Bev groups was 6.3 months and 7.2 months, respectively, which were not significantly different (p=0.2). The median OS was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p=0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of post-progression treatment (59.0% vs. 35.7%, p=0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p<0.001) compared to the LEN group. CONCLUSIONS: Atez/Bev showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of post-progression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first-line treatment even for elderly HCC patients. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13991

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009-2013, n = 86; period 2: 2014-2018, n = 132; period 3: 2019-2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1-3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin-bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.

DOI： 10.3390/cancers15215298

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記述言語：日本語   出版者・発行元：日本消化器病学会-甲信越支部  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The prognosis of cirrhosis is clearly stratified by liver function. Although direct-acting antiviral (DAA) has recently been used to eliminate hepatitis C virus (HCV), it is not clear whether liver function stratifies the prognosis of decompensated cirrhotic patients treated with DAA. METHODS: A total of 206 HCV-associated decompensated cirrhotic patients who started DAA from February 2019 to December 2021 at 31 Japanese hospitals were prospectively registered. RESULTS: The median age was 68, and the proportions of patients with Child-Pugh class A (CP-A), CP-B and CP-C were 10% (20/206), 76% (156/206) and 15% (30/206), respectively. Twenty-six patients died, and two patients underwent liver transplantation (LT); the 2- and 3-year LT-free survival rates were 90.0% and 83.2%, respectively. We examined factors associated with LT-free survival using 2 models including either CP class (Model 1) or MELD score (Model 2). In multivariate Cox proportional hazard analysis, CP class at 12 weeks after the end of treatment (EOT) in Model 1 and MELD score at 12 weeks after the EOT in Model 2 were significant factors, while baseline CP class or MELD score was not. Two-year LT-free survival rates were 100%, 91.6% and 60.4% for patients with CP-A, CP-B and CP-C at 12 weeks after the EOT and 95.2% and 69.6% for patients with MELD < 15 and MELD ≥ 15 at 12 weeks after the EOT, respectively. CONCLUSIONS: The prognosis of decompensated cirrhotic patients receiving DAA was stratified by liver function at 12 weeks after the EOT, not by baseline liver function.

DOI： 10.1007/s00535-023-02039-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: The study goal was to compare the outcomes of patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC]-B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic therapy. METHODS: A total of 358 patients with BCLC-B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first-line systemic therapy were included. RESULTS: The median progression-free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8-12.6) and 7.3 months (95% CI, 6.3-8.5), respectively (p = .019). In the propensity score-matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0-12.3) and 6.9 months (95% CI, 5.9-8.1), respectively (p = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up-to-seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0-11.8) and 6.3 months (95% CI, 5.5-7.3), respectively (p = .044). CONCLUSIONS: The use of Atezo/Bev as first-line systemic therapy in patients with BCLC-B HCC is expected to result in good PFS.

DOI： 10.1111/liv.15753

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: There is evidence regarding the association between dysmenorrhea and irritable bowel syndrome (IBS), although it is lacking in the Asian population. Therefore, the purpose of this study was to investigate the association between menstrual status and IBS in a young Japanese. METHODS: Overall, 4693 female college students were included in the analysis of this study. Information regarding lifestyle habits, menstrual status (irregularity, pain severity, and medication), and IBS (Rome III criteria) was obtained using a self-reported questionnaire. Age, body mass index, exercise habits, smoking, drinking habits, and anemia were analyzed as potential confounders. RESULTS: The prevalence of IBS was 6.1%. Moderate (adjusted odds ratio [OR]: 1.89 [95% confidence interval (CI): 1.27-2.91]) and heavy (adjusted OR: 2.14 [95% CI: 1.42-3.45]) menstrual pain was independently positively associated with IBS (p for trend = 0.001). Using medication sometimes (adjusted OR: 1.41 [95% CI: 1.09-1.84]) and often (adjusted OR: 1.60 [95% CI: 1.13-2.24]) was independently positively associated with IBS. There was no association between menstrual cycle and IBS. In subjects without functional dyspepsia, irregular menstrual cycle was independently positively associated with IBS. CONCLUSION: In the young Japanese population, menstrual pain and medications for menstrual pain may have a significant positive association with IBS.

DOI： 10.1159/000533264

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatitis B vaccine induces the production of antibodies against hepatitis B surface antigen (anti-HBs) and prevents hepatitis B virus (HBV) infection. However, 5-10% of individuals cannot develop anti-HBs even after multiple vaccinations (HB vaccine non-responders). We developed an intranasal vaccine containing both HBs antigen (HBsAg) and HB core antigen (HBcAg) and mixed it with a viscosity enhancer, carboxyl vinyl polymer (CVP-NASVAC). Here, we investigated the prophylactic capacity of CVP-NASVAC in HB vaccine non-responders. Thirty-four HB vaccine non-responders were administered three doses of intranasal CVP-NASVAC. The prophylactic capacity of CVP-NASVAC was assessed by evaluating the induction of anti-HBs and anti-HBc (IgA and IgG) production, HBV-neutralization activity of sera, and induction of HBs- and HBc-specific cytotoxic T lymphocytes (CTLs). After CVP-NASVAC administration, anti-HBs and anti-HBc production were induced in 31/34 and 27/34 patients, respectively. IgA anti-HBs and anti-HBc titers significantly increased after CVP-NASVAC vaccination. HBV-neutralizing activity in vitro was confirmed in the sera of 26/29 CVP-NASVAC-administered participants. HBs- and HBc-specific CTL counts substantially increased after the CVP-NASVAC administration. Mild adverse events were observed in 9/34 participants; no serious adverse events were reported. Thus, CVP-NASVAC could be a beneficial vaccine for HB vaccine non-responders.

DOI： 10.3390/vaccines11091479

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

肝硬変の治療の基本は栄養療法である.わが国のガイドラインでは,低アルブミン血症,Child-Pugh分類B/C,サルコペニアを合併する肝硬変を積極的な栄養療法の対象としている.サルコペニアの発症抑制に就寝前捕食や分岐鎖アミノ酸製剤が有効であり,亜鉛,カルニチンなどを併用した栄養療法が肝疾患患者の予後改善に必要である.一方,わが国ではウイルス性肝硬変が減少し,アルコール性肝硬変,脂肪性肝疾患の増加が著しい.肝疾患の病態に直接的な傷害を引きおこすアルコールについて,早急な対策が必要とされている.近年発売された飲酒量低減薬を含めたアルコール対策を,有効に実施する必要がある.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20230921450003&doc_link_id=%2Fck8syokb%2F2023%2F012009%2F003%2F0717-0725%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2023%2F012009%2F003%2F0717-0725%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

肝硬変の治療の基本は栄養療法である.わが国のガイドラインでは,低アルブミン血症,Child-Pugh分類B/C,サルコペニアを合併する肝硬変を積極的な栄養療法の対象としている.サルコペニアの発症抑制に就寝前捕食や分岐鎖アミノ酸製剤が有効であり,亜鉛,カルニチンなどを併用した栄養療法が肝疾患患者の予後改善に必要である.一方,わが国ではウイルス性肝硬変が減少し,アルコール性肝硬変,脂肪性肝疾患の増加が著しい.肝疾患の病態に直接的な傷害を引きおこすアルコールについて,早急な対策が必要とされている.近年発売された飲酒量低減薬を含めたアルコール対策を,有効に実施する必要がある.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20230921450003&doc_link_id=10.11405%2Fnisshoshi.120.717&url=https%3A%2F%2Fdoi.org%2F10.11405%2Fnisshoshi.120.717&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to evaluate the ability of a previously reported tumor marker (TM) score involving alpha-fetoprotein (AFP), fucosylated AFP (AFP-L3), and des gamma-carboxy prothrombin (DCP) as TMs in predicting the prognosis and therapeutic efficacy in hepatocellular carcinoma (HCC) patients administered atezolizumab plus bevacizumab (Atez/Bev) as first-line treatment. MATERIALS/METHODS: The study period covered September 2020 to December 2022 and involved 371 HCC patients treated with Atez/Bev. The values of the TMs AFP, AFP-L3, and DCP were measured upon introducing Atez/Bev. Elevations in the values of AFP (≥100 ng/mL), AFP-L3 (≥10%), and DCP (≥100 mAU/mL) were considered to indicate a positive TM. The number of positive TMs was summed up and used as the TM score, as previously proposed. Hepatic reserve function was assessed using the modified albumin-bilirubin grade (mALBI). Predictive values for prognosis were evaluated retrospectively. RESULTS: A TM score of 0 was shown in 81 HCC patients (21.8%), 1 in 110 (29.6%), 2 in 112 (29.9%), and 3 in 68 (18.3%). The median overall survival (OS) times for TM scores 0, 1, 2, and 3 were not applicable [NA] (95% CI NA-NA), 24.0 months (95% CI 17.8-NA), 16.7 months (95% CI 17.8-NA), and NA (95% CI 8.3-NA), respectively (p < 0.001). The median progression-free survival (PFS) times for TM scores 0, 1, 2, and 3 were 16.5 months (95% CI 8.0-not applicable [NA]), 13.8 months (95% CI 10.6-21.3), 7.7 months (95% CI 5.3-8.9), and 5.8 months (95% CI 3.0-7.6), respectively (p < 0.001). OS was well stratified in mALBI 1/2a and mALBI 2a/2b. PFS was well stratified in mALBI 2a/2b, but not in mALBI 1/2a. CONCLUSIONS: The TM score involving AFP, AFP-L3, and DCP as TMs was useful in predicting the prognosis and therapeutic efficacy in terms of OS and PFS in HCC patients administered Atez/Bev as first-line treatment.

DOI： 10.3390/cancers15174348

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate the association between nocturia and constipation in patients with ulcerative colitis (UC). Constipation has recently been recognized as an important symptom in patients with UC. Although nocturia has been associated with constipation in the general population, the association between nocturia and constipation in UC patients is uncertain. METHODS: Consecutive series of 290 Japanese patients with UC, Information on constipation, nocturia, and lifestyle habits was obtained using self-administered questionnaires. The definition of constipation was based on Rome I criteria and/or current medication for constipation. Patients were divided into three groups based on nighttime urination: 1) no nocturia, 2) mild nocturia (nocturnal urination - one), and 3) serious nocturia (nocturnal urination - two or more). Multivariate logistic regression was used to evaluate the association between nocturia and constipation. RESULTS: Among all of the UC patients, the prevalence of mild nocturia, serious nocturia, and constipation was 35.2%, 26.9%, and 12.4%, respectively. The prevalence of constipation in the none, mild, and serious nocturia groups was 8.2%, 10.8%, and 20.5%, respectively. After adjustment for confounders such as age, sex, current drinking, current smoking, body mass index, and steroid use, nocturia severity was independently and positively associated with constipation (adjusted odds ratio for mild nocturia: 1.55 [95% confidence interval: 0.57-4.28], serious nocturia: 3.19 [95% confidence interval: 1.09-9.81], p for trend = 0.035). CONCLUSIONS: The severity of nocturia is positively associated with constipation, and physicians should consider the interrelationships between nocturia and constipation in managing UC patients.

DOI： 10.1016/j.urology.2023.07.035

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. METHODS: From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score -1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. RESULTS: There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4-7] vs. 5.5 [95% CI: 3.4-7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3-11] vs. 8.8 [95% CI: 6.1-12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). DISCUSSION: This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC.

DOI： 10.1159/000530028

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bevacizumab inhibits vascular endothelial growth factor-A (VEGF-A), though is known to increase bleeding risk as an adverse event (AE). This study examined whether atezolizumab/bevacizumab (Atez/Bev) for unresectable hepatocellular carcinoma (uHCC) can be used for patients with esophageal-gastric varices (EGV). METHODS: From October 2020 to December 2022, 506 uHCC patients (median 74 years) underwent an upper gastrointestinal endoscopy examination were enrolled, after exclusion of those with portal vein tumor thrombus (PVTT). Patients with EGV (≧ F1) were defined as EGV positive, and the cohort was divided into non-EGV (n = 355) and EGV (n = 151). Before introducing Atez/Bev, endoscopic treatment was performed, when necessary. Prognosis was evaluated, retrospectively. RESULTS: The EGV group had significantly worse hepatic function, lower platelet count, elevated alpha-fetoprotein, and lower rate of extrahepatic metastasis, and lower rate of first-line use (each P < 0.05) than the other. However, progression-free survival (PFS) was also not a significantly difference between the EGV and non-EGV groups in analyses with (PFS rate at 6/12/18 months: 60%/38%/30% vs. 65%/46%/34%, P = 0.29) or without inverse probability weighting adjustment [median: 10.6 months (95% CI 8.3-14.0) vs. 10.5 months (95% CI 7.8-13.7), P = 0.79]. As for AEs, diarrhea was more frequent in the EGV group (≧ G3: 2.0% vs. 0.3%, P = 0.036), while no significant difference was noted for EGV hemorrhage (≧ G3: 1.3% vs. 0.6%, P = 0.345). Of 28 patients who underwent endoscopic treatments before introducing Atez/Bev, none showed EGV-associated hemorrhage. CONCLUSIONS: Atez/Bev might be an effective therapeutic option in patients with EGV, when appropriate endoscopic treatment for EGV is performed.

DOI： 10.1007/s00535-023-02026-2

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. MATERIALS AND METHODS: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. RESULTS: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). CONCLUSION: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

DOI： 10.1016/j.ejca.2023.05.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Central neuropathic pain (CNeP) is difficult to treat and has diverse etiology, including spinal cord injury (CNePSCI), Parkinson's disease (CNePPD), and central post-stroke pain (CPSP). The safety and efficacy of mirogabalin have been demonstrated in short-term trials, including patients with CNePSCI. The objective of our study was to confirm the safety/efficacy of mirogabalin in patients with CNePPD and CPSP, and obtain long-term data for CNePSCI. METHODS: This 52-week, open-label extension of a previous randomized controlled study was conducted across Japan, Korea, and Taiwan. Patients with CNePSCI, CNePPD, or CPSP received twice daily (BID) 5-10 mg mirogabalin for a 4-week titration period, after which the dosage was maintained for 47 weeks at a maximum of 15 mg BID, followed by a 1-week taper period receiving the same dose but only administered once daily. The primary endpoint was safety, assessed primarily by incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed in a post hoc analysis of data obtained by the short-form McGill Pain Questionnaire (SF-MPQ). RESULTS: Of the 210 patients enrolled, 106, 94, and 10 had CNePSCI, CPSP, and CNePPD, respectively. The mean overall age of patients was 62.9 years, and most patients were male and of Japanese ethnicity. TEAEs occurred in 84.8% of patients, the most common being somnolence (16.7%), peripheral edema (12.4%), edema (11.4%), nasopharyngitis (11.0%), and dizziness (7.6%). Most TEAEs were mild. Severe and serious TEAEs occurred in 6.2% and 13.3% of patients, respectively. All patient groups experienced reductions in SF-MPQ visual analog scores for pain: mean ± standard deviation changes from baseline at week 52 were -2.3 ± 21.13 mm (CNePSCI), -17.0 ± 24.99 mm (CPSP), and -17.1 ± 35.32 mm (CNePPD). CONCLUSION: Mirogabalin was generally safe, well tolerated, and effective for treatment of CNeP in this long-term study. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03901352.

DOI： 10.1007/s40122-023-00513-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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%); modified albumin-bilirubin (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), 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 < 0.001), mALBI grade (≥2a) (HR 3.451, 95% CI 1.580-7.538, p = 0.002), and MVL (HR 2.119, 95% CI 1.150-3.904, p = 0.016). Patients with MVL (MVL group, n = 91) showed worse PFS than those without (non-MVL group, n = 138) (median PFS 5.3 vs. 7.6 months, p = 0.025), while the MVL group showed worse OS (p = 0.038), though neither reached the median survival time. CONCLUSION: MVL may be a clinical factor related to poor prognosis in patients receiving Atez/Bev treatment for u-HCC.

DOI： 10.1159/000527402

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

＜文献概要＞栄養食事療法は肝硬変の基本的治療である.「肝硬変診療ガイドライン2020」では,サルコペニアの評価を含めた栄養アセスメントを速やかに行い,就寝前軽食や分岐鎖アミノ酸製剤を含めた栄養療法を早期から提供することを推奨している.また,肝硬変患者は高率にサルコペニアを合併し,その予後を悪化させる要因となるため,SARC-Fや指輪っか法による拾い上げが重要である.肝硬変患者に対する運動療法の重要性は指摘されているが,安全性への懸念などから,その研究は端緒についたばかりである.日本肝臓学会は肝疾患患者に対する運動療法,栄養療法などを包括した多職種連携プログラムである「肝臓リハビリテーション」の確立に向けて検討を開始している.

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The chronological pattern of extrahepatic lymphatic vessel progression in the course of chronic liver disease has not been clarified. This study aimed to clarify the chronological changes in lymphatic vessels with liver disease progression. METHODS: This was a prospective cross-sectional study that enrolled a total of 199 patients. The maximum diameter of the cisterna chyli (CC) or terminal thoracic duct (tTD) was measured using computed tomography or ultrasonography, respectively. Changes in the maximum diameters of the CC and tTD were evaluated with patients with chronic liver disease as the pilot set (n = 138). Subsequently, we examined whether CC/tTD could be used to re-allocate unclassified patients by the Baveno-VII criteria to appropriately diagnose clinically significant portal hypertension (CSPH) in the pilot and validation sets. RESULTS: In the pilot set, a scatter-plot showed that both CC and tTD were narrowed as terminal features in chronic liver disease after dilation. Because there was a significant correlation between the CC diameter and hepatic venous pressure gradient (r = 0.724) in unclassified patients, the diagnostic value of CC and tTD for CSPH was good (AUC: 0.961 and 0.913, respectively). After re-allocation, 68 and 27 unclassified patients were reduced to 4 and 5 in the pilot and validation sets, respectively. CONCLUSION: Both the CC and tTD narrow in the course of liver disease after dilation. Moreover, the maximum diameter of the CC and tTD can be used to re-allocate patients who are unclassified according to the Baveno-VII criteria. CLINICAL TRIAL NUMBER: UMIN trial no. 000044857.

DOI： 10.1007/s12072-023-10563-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.14309/ajg.0000000000002382

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The aMAP score is a prediction model for hepatocellular carcinoma (HCC) risk in chronic hepatitis patients. This study was conducted to elucidate the utility of this model for predicting initial recurrence of HCC in patients within the Milan criteria after undergoing curative treatment. METHODS: Patients with naïve HCC within the Milan criteria (n = 1,020) and treated from January 2000 to August 2022 were enrolled. The cohort was divided into two groups according to the aMAP score (high ≥60, low &lt;60) and then compared for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Comparisons between the high and low groups showed that etiology (HBV:HCV:HBV+HCV:NBNC = 41:79:2:37 vs. 65:589:11:196, p &lt; 0.001), AST (36 vs. 46 IU/L, p &lt; 0.001), and multiple HCC occurrence (15% vs. 22%, p = 0.026) were significantly different. Additionally, median RFS (59.8 vs. 30.9 months; p &lt; 0.001) and median OS (154.1 vs. 83.4 months, p &lt; 0.01) were greater in the low group. As for patients with HCC due to chronic viral hepatitis, there was a significant difference in median RFS between the groups (59.8 vs. 30.6 months, p &lt; 0.001), especially for HCV-positive patients (53.1 vs. 27.2 months, p = 0.002). In patients with HCC due to a nonviral cause, the difference in median RFS between the low (70.9 months) and high (32.0 months) groups was not significant. DISCUSSION: Findings of this retrospective study indicate a significant association of elevated aMAP with worse RFS in patients with HCC caused by chronic viral hepatitis, especially those with HCV. The aMAP score is considered useful to predict not only HCC-carcinogenesis risk but also risk of recurrence following curative treatment.

DOI： 10.1159/000530987

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

According to the World Health Organization (WHO), an estimated 296 million people are chronically infected with hepatitis B virus (HBV). Approximately 15-25% of these people develop complications such as advanced chronic liver diseases (ACLDs). Mortality due to HBV-related complications accounted for an estimated 882,000 deaths in 2019. Potent preventive vaccines have already restricted new HBV infections, and several drugs are available to treat chronic HBV infections. However, the positive impacts of these drugs have been recorded in only a few patients with chronic HBV infection. These drugs do not show long-term efficacy and cannot halt the progression to complications. Thus, more effective and evidence-based therapeutic strategies need to be urgently developed for patients with chronic HBV infection. CHB is a pathological entity induced by HBV that progresses due to impaired host immunity. This indicates the inherent limitations of antiviral-drug-based monotherapy for treating patients with chronic HBV infection. Additionally, commercially available antiviral drugs are not available to patients in developing and resource-constrained countries, posing a challenge to achieving the following WHO goal: "Elimination of Hepatitis by 2030". As such, this review aimed to provide insights regarding evidence-based and effective management strategies for chronic HBV infection.

DOI： 10.3390/biomedicines11071944

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: We aimed to compare vibration-controlled transient elastography (VCTE) with shear wave elastography (SWE) without previous analysis and generate regression equations between VCTE and new point SWE using combination-elastography. METHODS: Overall, 829 patients with chronic liver disease were enrolled in this study. Patients with a skin-liver capsule distance > 25 mm were excluded. The reproducibility of VCTE and SWE was confirmed in a phantom study and a clinical study. Considering that combination-elastography allows measurement based on strain elastography, a similar analysis was performed for the liver fibrosis index (LFI), which is a quantitative value for evaluation of liver fibrosis calculated using strain elastography image features. Regression equations between the VCTE and SWE values were obtained based on linear regression analysis. RESULTS: In the phantom study and clinical study, there was a strong correlation between VCTE and SWE [r = 0.995 (p < 0.001) and r = 0.747 (p < 0.001), respectively). The regression equation between VCTE and SWE was VCTE (kPa) = 1.09 × point SWE (kPa) - 0.17. The Bland-Altman plots revealed no statistically significant bias. Meanwhile, there was no correlation between VCTE and LFI (r = 0.279). There was a statistically significant bias between VCTE and LFI in the Bland-Altman plots. The inter-operator reliability showed a good intraclass correlation coefficient of 0.760 (95% confidence interval: 0.720-0.779). CONCLUSION: Liver stiffness measured using point SWE was comparable to that measured using VCTE.

DOI： 10.1007/s10396-023-01333-8

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The present study focused on geriatric nutritional risk index (GNRI), which is based on body weight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC). MATERIALS/METHODS: Five hundred twenty-five HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled [Child-Pugh A:B:C=484:40:1, BCLC 0:A:B:C:D=7:25:192:283:18]. Prognosis was evaluated retrospectively using GNRI. RESULTS: Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival (PFS) based on GNRI indicating normal, mild-decline, moderate-decline, and severe-decline was 8.3, 6.7, 5.3 and 2.4 months, respectively, while median overall survival (OS) was 21.4, 17.0, 11.5 and 7.3 months, respectively (both P<0.001). The concordance index (c-index) values of GNRI for predicting prognosis (PFS/OS) were superior to those of Child-Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a sub-analysis, muscle volume loss (MVL) was observed in 37.5% in 256 patients with CT data available. Along with GNRI decline, frequency of MVL became progressively larger (normal vs. mild vs. moderate vs. severe=17.6% vs. 29.2% vs. 41.2% vs. 57.9%, P<0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95%CI 0.649-0.781) (specificity/sensitivity=0.644/0.688). CONCLUSION: These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and MVL complication in HCC patients treated with Atez/Bev. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13934

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. MATERIALS/METHODS: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D=1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. RESULTS: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, P=0.557) or OS (13.6 months, P=0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD=3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD=1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3=2:15:10), general fatigue (21.8%) (grade 1:2:3=3:13:6), protein in urine (16.8%) (grade 1:2:3=0:4:13), and hypertension (13.9%) (grade 1:2:3=1:8:5). CONCLUSION: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment.

DOI： 10.1159/000531316

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

DOI： 10.1038/s41598-023-36052-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Evidence regarding the association between exercise habits and irritable bowel syndrome (IBS) remains scarce in a young population. It is also unknown whether the existence of an exercise partner affects this issue. The purpose of this study was to explore the association between exercise habits that include an exercise partner and IBS in a young Japanese population. METHODS: This study enrolled 8923 Japanese university students and examined exercise frequency and intensity, and exercise partners using self-administered questionnaires. IBS and functional dyspepsia were defined according to the Rome III criteria. RESULTS: The prevalence of IBS in this survey was 6.5%. Moderate frequency exercise was inversely related with IBS [adjusted odds ratio (aOR): 0.65 (95% confidence interval, CI: 0.51-0.83), P for trend = 0.005]. Moderate and high exercise intensities were independently and inversely related with IBS, respectively [aORs were moderate: 0.76 (95% CI: 0.61-0.95) and high: 0.62 (95% CI: 0.48-0.78), P for trend = 0.001]. Exercising with a group or with friends instead of alone was independently inversely related with IBS [aOR with groups: 0.53 (95% CI: 0.40-0.70) and with friends: aOR 0.71 (95% CI: 0.54-0.93)]. After excluding subjects with overlapping IBS and functional dyspepsia, an inverse association between high intensity of exercise or exercise in a group and IBS remained significant. CONCLUSION: The frequency and intensity of exercise may be independently inversely related with IBS in a young Japanese population. Also, exercise with others may be important for preventing IBS.

DOI： 10.1097/MEG.0000000000002561

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記述言語：日本語   出版者・発行元：日本消化器病学会-四国支部  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy. METHODS: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n = 268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n = 162). RESULTS: The median progression-free survival times in the first- and later-line groups were 7.7 months (95% confidence interval [CI], 6.7-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006-1.690; P = 0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5 months (95% CI, 6.8-13.8) and 6.8 months (95% CI, 5.0-9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7 months (95% CI, 6.3-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.022). CONCLUSION: The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.

DOI： 10.1111/jgh.16225

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記述言語：英語  

DOI： 10.1002/jcsm.13268

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein report a 63-year-old man who presented with left lower jaw pain and was diagnosed with hepatocellular carcinoma with bone metastases post-examination. All tumors grew after immunotherapy with atezolizumab and bevacizumab, and his jaw pain worsened. After palliative radiation therapy, however, the tumors shrank markedly, with no recurrence seen after stopping immunotherapy. To our knowledge, this is the first case in which a radiotherapy- and immunotherapy-mediated abscopal effect facilitated tumor shrinkage and immunotherapy discontinuation.

DOI： 10.2169/internalmedicine.1844-23

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

DOI： 10.1111/hepr.13925

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An open-level, randomized and treatment-controlled clinical trial has shown that a therapeutic vaccine containing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) (NASVAC) is endowed with antiviral and liver protecting capacity and is safer than pegylated interferon (Peg-IFN) in patients with chronic hepatitis B (CHB). The present study provides information about the role of the hepatitis B virus (HBV) genotype in this phase III clinical trial. From a total of 160 patients enrolled in this trial, the HBV genotypes of 133 patients were characterized, and NASVAC induced a stronger antiviral effect (HBV DNA reduction below 250 copies per mL) than Peg-IFN. The antiviral effects and alanine aminotransferase levels were not significantly different among different HBV genotypes in NASVAC-treated patients. However, a significantly higher proportion of genotype-D patients receiving NASVAC showed better therapeutic effects, compared to genotype-D patients receiving Peg-IFN, with a marked difference of 44%. In conclusion, NASVAC seems to be a better alternative to Peg-IFN, especially in patients with HBV genotype-D patients. This reflects the attractiveness of NASVAC in countries where genotype D is highly prevalent. The mechanisms underlying the effect of HBV genotype are being studied in a new clinical trial.

DOI： 10.3390/vaccines11050962

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This retrospective study aimed to investigate the impact of proton pump inhibitor treatment (PPI) and antibiotic treatment on the therapeutic outcomes of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). METHODS: The present study included a total of 441 HCC patients who were treated with Atez/Bev in 20 Japanese institutions from September 2020 to April 2022. We adopted the inverse probability of treatment weight to adjust for imbalance in the baseline characteristics of patients with and without PPI treatment as well as patients with and without antibiotic treatment. RESULTS: The progression-free survival (PFS) and overall survival (OS) of patients with and without PPI treatment did not differ to a statistically significant extent. In the weighted cohort, the difference in PFS and OS between the patients with and without PPI did not reach statistical significance (median PFS, 7.0 vs. 6.5 months, p = 0.07; 1-year survival rate 66.3% and 73.8%, p = 0.9). The PFS and OS in patients with antibiotic treatment were worse in comparison to patients without antibiotic treatment (median PFS, 3.8 vs. 7.0 months, p = 0.007; 1-year survival rate 58.8% and 70.3%, p = 0.01). In the weighted cohort, the PFS and OS of the two groups did not differ to a statistically significant extent (median PFS, 3.8 vs. 6.7 months, p = 0.2; 1-year survival rate, 61.8% and 71.0%, p = 0.6). CONCLUSIONS: The therapeutic outcomes of Atez/Bev in HCC patients did not differ between patients with and without PPI treatment or between patients with and without antibiotic treatment.

DOI： 10.1111/hepr.13905

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

【緒言】がん病態栄養専門管理栄養士の配置による、がん患者の入院中の栄養状態に及ぼす効果について明らかにすることを目的とした。【方法】2015年4月1日から2021年3月31日に当院に入院した胃がん患者858名を対象とし、がん病態栄養専門管理栄養士の配置体制がなかった配置前群376名と配置後群482名の食事摂取割合および体重変化率を後ろ向きに比較検討した。【結果】退院時食事摂取割合は、配置前群56.7±23.2%から配置後群62.2±25.0%と有意に増加した(p=0.001)。また、入院中の体重変化率は配置前群-3.1±4.6%から配置後群-2.3±4.6%と有意な体重減少の抑制を認めた(p=0.015)。【考察】がん病態栄養専門管理栄養士を配置することにより、胃がん患者の入院治療に伴う食事摂取量の低下ならびに体重減少を抑制し、がん患者の円滑な治療の推進に寄与できる可能性が示唆された。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The association between disease activity and erectile dysfunction (ED) in patients with inflammatory bowel disease (IBD) is inconsistent, although IBD, including ulcerative colitis (UC), is reported as a risk factor for ED. AIM: The purpose of this study was to explore this association in Japanese patients with UC. METHODS: In this study, we enrolled 165 Japanese male patients with UC. Information regarding the Sexual Health Inventory for Men (SHIM) score, medication, and severity of UC was obtained from medical records, self-administered questionnaires, and reports from physicians. The definition of ED and severe ED is a SHIM score <17 and <8, respectively. OUTCOMES: No association between severity of UC and ED was found in Japanese patients. Aging is independently positively associated with ED in patients with UC. RESULTS: The prevalence of severe ED and ED was 47.9% and 64.9%, respectively. In this study, mucosal healing, clinical remission, duration of UC, disease extent, and medication were not associated with the prevalence of ED. Older age (≥63 years of age) was independently positively associated with ED (adjusted odds ratio, 12.93; 95% CI: 4.51-43.00) and severe ED (adjusted odds ratio, 9.02; 95% CI: 3.66-23.91). CLINICAL IMPLICATIONS: Disease severity of UC might not be associated with the prevalence of ED in patients with UC. STRENGTHS AND LIMITATIONS: This is the first study to investigate the association between several factors regarding UC activity and ED. The limitation of this study is the definition of ED based on SHIM scores. CONCLUSION: No association between severity of UC and ED was found in Japanese patients. As expected, aging may be independently positively associated with ED in patients with UC.

DOI： 10.1093/sexmed/qfad024

PubMed

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The best first-line treatment for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class B remains unknown. The aim of the present study was to perform a real-world analysis on a large sample of patients with unresectable HCC with CP B treated with atezolizumab plus bevacizumab Vs Lenvatinib. METHODS: The study population included patients affected by advanced (BCLC-C) or intermediate (BCLC-B) HCC patients not suitable for locoregional therapies from both the Western and Eastern world (Italy, Germany, Republic of Korea and Japan), who received atezolizumab plus bevacizumab or Lenvatinib as first-line treatment. All the study population presented a CP class of B. The primary endpoint of the study was the overall survival (OS) of CP B patients treated with Lenvatinib compared to atezolizumab plus bevacizumab. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analyzed with log-rank tests. Finally, an interaction test was performed for the main baseline clinical characteristics. RESULTS: 217 CP B HCC patients were enrolled in the study: 65 (30%) received atezolizumab plus bevacizumab, and 152 (70%) received lenvatinib. The mOS for patients receiving Lenvatinib was 13.8 months (95% CI: 11.6-16.0), compared to 8.2 months (95% CI 6.3-10.2) for patients receiving atezolizumab plus bevacizumab as first-line treatment (atezolizumab plus bevacizumab Vs Lenvatinib: HR 1.9, 95% CI 1.2-3.0, p = 0.0050). No statistically significant differences were highlighted in terms of mPFS. The multivariate analysis confirmed that patients receiving Lenvatinib as first-line treatment have a significantly longer OS compared to patients receiving atezolizumab plus bevacizumab (HR 2.01; 95% CI 1.29-3.25, p = 0.0023). By evaluating the cohort of patients who received atezolizumab plus bevacizumab, we found that Child B patients with ECOG PS 0, or BCLC B stage or ALBI grade 1 were those who had benefited from the treatment thus showing survival outcomes no significantly different compared to those receiving Lenvatinib. CONCLUSION: The present study suggests for the first time a major benefit from Lenvatinib compared to atezolizumab plus bevacizumab in a large cohort of patients with CP B class HCC.

DOI： 10.1007/s00432-023-04678-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Atezolizumab plus bevacizumab has recently been approved as a new first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). OBJECTIVE: We performed a real-world study to evaluate the impact of the IMbrave150 trial inclusion criteria on the safety and efficacy of treatment outside of clinical trials. METHODS: We analyzed patients treated with atezolizumab plus bevacizumab for unresectable HCC from four different countries. No specific inclusion and exclusion criteria were applied, except for the absence of previous systemic therapies for HCC. The entire population was split into two groups according to concordance with the inclusion criteria as reported in the IMbrave150 trial in 'IMbrave150-in' and 'IMbrave150-out' patients, and safety and efficacy in the two groups of patients were evaluated. RESULTS: Overall, 766 patients were included in the analysis: 561/766 (73%) in the 'IMbrave150-in' group and 205/766 (27%) in the 'IMbrave150-out' group. Median overall survival (OS) and median progression-free survival (PFS) were 16.3 versus 14.3 months (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.35-0.65; p < 0.0001] and 8.3 versus 6.0 months (HR 0.79, 95% CI 0.63-0.99; p = 0.0431) in 'IMbrave150-in' and 'IMbrave150-out' patients, respectively. Multivariate analysis confirmed that patients included in the 'IMbrave150-in' group had significantly longer OS compared with patients included in the 'IMbrave150-out' group (HR 0.76, 95% CI 0.47-0.97; p = 0.0195). In 'IMbrave150-in' patients, the albumin-bilirubin (ALBI) grade was not associated with OS, whereas in 'IMbrave150-out' patients, those with ALBI grade 1 reported a significant benefit in terms of OS compared with those with ALBI grade 2 (16.7 vs. 5.9 months; HR 4.40, 95% CI 2.40-8.08; p > 0.0001). No statistically significant differences were reported in the 'IMbrave150-in' and 'IMbrave150-out' groups in terms of safety profile. CONCLUSION: Adherence to the IMbrave150 trial inclusion criteria favorably impacts the prognosis of patients receiving atezolizumab plus bevacizumab. Among patients who did not meet the IMbrave150 inclusion criteria, those with ALBI grade 1 could benefit from the treatment.

DOI： 10.1007/s11523-023-00953-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: It is unclear whether prognosis differs by age for early-stage hepatocellular carcinoma (HCC). We aimed to examine prognosis and recurrence after radiofrequency ablation (RFA) for early-stage HCC and to determine its prognostic factors for different age groups. METHODS: This retrospective study enrolled 1079 patients with initial early-stage HCC treated with RFA at two institutions. All patients in this study were divided into four groups: <70 years old (group1, n = 483), 70-74 years old (group2, n = 198), 75-79 years old (group3, n = 201), and ≥80 years old (group4, n = 197). Prognostic factors were evaluated by comparing survival and recurrence rates between each group. RESULTS: The median survival time and 5-year survival rates for each group were 113 months and 70.8% in group1, 99.2 months and 71.5% in group2, 91.3 months and 66.5% in group3, and 71 months and 52.6% in group 4, respectively. Group4 had a significantly shorter survival than the other groups (p < 0.05). There were no significant differences in recurrence-free survival among the groups. In group4, the most common cause of death was nonliver-related disease (69.4%). In all groups, modified albumin-bilirubin index grade was a factor contributing to prolonged prognosis, but only in group4 performance status (PS) was a significant factor (hazard ratio, 2.46; 95% confidence interval, 1.16-3.00; p = 0.009). CONCLUSION: For early-stage HCC in the elderly, preoperative evaluation of PS and management of other diseases could contribute to a prolonged prognosis.

DOI： 10.1111/hepr.13896

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

【背景/目的】門脈圧亢進症合併症例の予後改善やサルコペニア進展阻止のため栄養介入をすべき症例の臨床像は未だ明らかではない.栄養介入を開始すべき臨床像を明らかとする.【対象/方法】2021年12月までに当院で診断した初発肝癌患者408例.肝予備能評価にはmALBIを用い,門脈圧亢進症(PHT)は食道胃静脈瘤F2以上/治療歴ありとした.BTR4.4以下をアミノ酸インバランス(AAI)と規定して後方視的に生命予後を解析した.【結果】多変量解析で75歳以上,mALBI 2b以下,MVL,PHTが予後因子であった.AAIを予測するALBIは-2.586(AUC 0.789)であった.【結語】PHTがあれば,Child-Pugh AでもmALBI 1から2aへの過渡期にAAIがすでに起こりはじめており,MVLへの進展を防ぐために栄養介入を積極的に行うべきである.(著者抄録)

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: This study aimed to compare the image quality in the hepatobiliary phase images of gadoxetic acid-enhanced liver magnetic resonance imaging using parallel imaging (PI) and compressed sensing (CS) reconstruction, using variable CS factors with the standard method using the PI technique. METHODS: In this study, 64 patients who underwent gadoxetic acid-enhanced liver magnetic resonance imaging at 3.0 T were enrolled. Hepatobiliary phase images were acquired 6 times using liver acquisition with volume acceleration (LAVA) and CS reconstruction with 5 CS factors 1.4, 1.6, 1.8, 2.0, and 2.5 (LAVA-CS 1.4, 1.6, 1.8, 2.0, and 2.5) and standard LAVA (LAVA-noCS). For objective analysis, the signal intensity ratios (SIRs) of the liver-to-spleen (SIRliver/spleen), liver-to-portal vein (SIRliver/portal vein), and liver-to-fat (SIRliver/fat) were estimated. For subjective analysis, 2 radiologists independently evaluated the quality of all the images. RESULTS: The objective analysis demonstrated no significant difference in all evaluation parameters of all the images. Subjective analysis revealed that the scores of all evaluation items were higher for LAVA-noCS images than for LAVA-CS images, and only LAVA-CS 1.4 did not significantly differ from LAVA-noCS in all evaluation items (P = 1.00 in 2 readers). CONCLUSIONS: A CS factor of 1.4 in the hepatobiliary phase image with combined PI and CS can reduce the scan time without degrading the image quality compared with the standard method.

DOI： 10.1097/RCT.0000000000001451

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Introduction

There is a pressing need to develop novel drugs for treating patients with chronic hepatitis B (CHB), as commercially available antiviral drugs are endowed with safety and efficacy concerns.

Methods

A phase III clinical trial was conducted with a therapeutic vaccine containing two antigens of the hepatitis B virus (HBV; named NASVAC) in 78 patients with CHB expressing both HBV DNA and elevated levels of alanine aminotransferase (ALT) in the blood. Five years after the end of treatment (EOT), 60 NASVAC-recipient patients were enrolled in this long-term follow-up study to evaluate the safety, antiviral potential, and liver-protective capacity of NASVAC.

Results

NASVAC exhibited an excellent safety profile 5 years after EOT. The levels of HBV DNA in the sera were reduced in 55 of the 60 patients, and 45 of them were negative for HBV DNA in the sera. ALT levels were also normalized in 40 of the 60 patients 5 years after EOT. None of the patients receiving NASVAC developed liver cirrhosis or cancer.

Discussion

The present study is the first to exhibit long-term follow-up data of a finite immune therapy for CHB that is safe and endowed with potent antiviral and liver-protecting capacities.

DOI： 10.3389/fmed.2023.1032531

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c+ M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.

DOI： 10.3390/ijms24032509

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been demonstrated in patients treated with sorafenib and lenvatinib. The aim of this real-world study is to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. METHODS: The overall cohort of this multicentric study included 871 consecutive HCC patients from 4 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). RESULTS: For only 773 patients, data regarding lymphocyte counts and albumin levels were available, so only these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic (ROC) analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p < 0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p < 0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49 , p < 0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate (ORR) between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate (DCR) was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). CONCLUSION: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.

DOI： 10.1159/000528818

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with viral hepatitis-related chronic liver disease (CLD) under surveillance for hepatocellular carcinoma (HCC) are often diagnosed with pancreatic cancer (PC) at an early stage. However, the long-term outcomes of these patients are unclear. We aimed to clarify the long-term outcomes of patients with PC with viral hepatitis-related CLD using a chart review. Data collection included the Union for International Cancer Control (UICC) stage at PC diagnosis, hepatitis B virus and hepatitis C virus status, and long-term outcomes. The distribution of the entire cohort (N = 552) was as follows: early stage (UICC 0-IB; n = 52, 9.5%) and non-early stages (UICC IIA-IV; n = 500, 90.5%). At diagnosis, the HCC surveillance group (n = 18) had more patients in the early stages than the non-surveillance group (n = 534) (50% vs. 8.0%), leading to a higher indication rate for surgical resection (72.2% vs. 29.8%) and a longer median survival time (19.0 months vs. 9.9 months). We confirmed that patients with viral hepatitis-related CLD under HCC surveillance were diagnosed with PC at an early stage. Because of the higher indication rate for surgical resection in these patients, they had favorable long-term outcomes for PC.

DOI： 10.3390/cancers15030561

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.14309/ajg.0000000000001982

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

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掲載種別：研究論文（学術雑誌）  

Aim: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. Methods: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. Results: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. Conclusions: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

DOI： 10.1111/hepr.13925

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11405/nisshoshi.120.717

PubMed

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掲載種別：研究論文（学術雑誌）  

Background and Aim: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy. Methods: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n = 268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n = 162). Results: The median progression-free survival times in the first- and later-line groups were 7.7 months (95% confidence interval [CI], 6.7–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006–1.690; P = 0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5 months (95% CI, 6.8–13.8) and 6.8 months (95% CI, 5.0–9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7 months (95% CI, 6.3–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.022). Conclusion: The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.

DOI： 10.1111/jgh.16225

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: For intermediate-stage hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC]-B) cases, transarterial chemoembolization (TACE) is recognized as the standard treatment, while systemic therapy is recommended for TACE-unsuitable HCC. However, because the curative potential is not high, this study was conducted to elucidate the potential outcomes of surgical resection (SR) for BCLC-B HCC cases. MATERIALS/METHODS: From January 2000 to July 2022, 70 patients with BCLC-B HCC treated with surgery as the initial treatment were enrolled (median age 67.5 years, beyond up-to-7 criteria 44). Forty-five were treated with SR only (SR group), while twenty-five underwent that with complemental radiofrequency ablation (RFA) (Comb group). Recurrence-free survival (RFS) and overall survival (OS) were retrospectively evaluated in both groups. RESULTS: The median albumin-bilirubin (ALBI) score was better in the SR as compared with the Comb group (-2.74 vs. -2.52, p = 0.02), while there were no significant differences between them for median RFS (17.7 vs. 13.1 months; p = 0.70) or median OS (66.6 vs. 72.0 months p = 0.54). As for those beyond up-to-7 criteria, there were no significant differences for median RFS (18.2 vs. 13.0 months; p = 0.36) or median OS (66.5 vs. 72.0 months; p = 0.57). An acceptable five-year cumulative survival rate (&gt;50%) was obtained in both groups (54% vs. 64%). CONCLUSION: This retrospective study found no significant differences for RFS or OS between the present SR and Comb groups with BCLC-B HCC. When possible to perform, the outcome of SR for BCLC-B is favorable, with a five-year survival rate greater than 50%.

DOI： 10.3390/cancers15010236

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Drug-induced liver injury (DILI) is a severe and life-threatening immune-mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese population that predict the onset of DILI after using a certain class of drugs such as Kampo products (Japanese traditional medicines). METHODS: A total of 287 subjects diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome-wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed. RESULTS: We found a significant association (P = 9.41 × 10-10 ) of rs146644517 (G > A) with Kampo product-related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo-DILI cases contained HLA-B*35:01, whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75-24.46; P = 2.98 × 10-6 , corrected P = 4.17 × 10-5 ) and it increased to 13.55 compared with the DILI cases not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root (ougon in Japanese), rhubarb (daiou), Gardenia fruit (sanshishi), and Glycyrrhiza (kanzou), were significantly associated with HLA-B*35:01. CONCLUSIONS: HLA-B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo-induced DILI in the Japanese population. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13874

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Deep attenuation transducers (DAX) are capable of imaging at diagnostic depths of up to 40 cm. The feasibility of DAX for liver stiffness measurement (LSM) has not been reported clinically. We aimed to assess the feasibility and reliability of DAX for LSM. METHODS: Overall, 219 patients with chronic liver disease were enrolled. The success rate (acquired after ≥ 10 valid measurements) and inadequate measurements (interquartile range/median ≥ 0.3) for DAX were compared with those of conventional convex (c-convex) probes and M and XL probes of vibration-controlled transient elastography. RESULTS: LSM was successfully performed for all patients using DAX through all degrees of skin-to-liver capsular distance (SCD). Especially in patients with an SCD ≥ 30 mm, the difference in the rate of acquisition of 10 valid measurements was remarkable: M probe (8/33, 24.2%), XL probe (26/33, 78.8%), c-convex probe (33/43, 76.7%), and DAX (44/44, 100%). In patients with an SCD ≥ 30 mm, the inadequate measurement rate of M probe (1/8, 12.5%), XL probe (8/26, 30.8%), and c-convex probe (6/33, 18.2%) was higher than that of DAX (1/43, 2.3%). The areas under the curve for diagnosis of F4 with shear wave speed by c-convex and DAX were 0.916 and 0.918, respectively. Between DAX and c-convex probes, the intraclass correlation coefficient of 0.937 (95% CI 0.918-0.952) was excellent. Bland-Altman plots revealed that there was no statistically significant bias. CONCLUSION: Liver stiffness measured by DAX is feasible and reliable for all patient populations, while the XL probe is limited to use in obese patients.

DOI： 10.1007/s10396-022-01270-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND OBJECTIVES: Patients with spinal cord injury (SCI) commonly experience central neuropathic pain (CNeP), which is challenging to treat. Mirogabalin is effective for peripheral neuropathic pain, but evidence for CNeP is lacking. METHODS: This randomized, double-blind, placebo-controlled, phase 3 study investigated mirogabalin efficacy and safety for treatment of CNeP in patients with traumatic SCI. Adult patients from 120 sites throughout Japan, Korea, and Taiwan, were randomized (1:1) to receive placebo or mirogabalin (5 mg twice daily [BID] for 1 week, 10 mg BID for 1 week, and 10 or 15 mg BID for 12 weeks). Patients with moderate renal impairment received half the dosage. The primary efficacy endpoint was change from baseline in the weekly average daily pain score (ADPS) at Week 14. Secondary endpoints included ADPS responder rates, Short-Form McGill Pain Questionnaire (SF-MPQ), average daily sleep interference score (ADSIS), and Neuropathic Pain Symptom Inventory (NPSI). Adverse events were monitored for safety. RESULTS: Each treatment group comprised 150 patients. Mirogabalin elicited a statistical and clinically relevant improvement in change from baseline in the weekly ADPS at Week 14 (least-squares mean difference [95% confidence interval [CI]] vs placebo -0.71 [-1.08, -0.34], p=0.0001). Responder rates at Week 14 were higher for mirogabalin vs placebo (odds ratio [95% CI] 1.91 [1.11, 3.27] for the ≥30% responder rate; 2.52 [1.11, 5.71] for the ≥50% responder rate). Statistical improvements (i.e., least-squares mean difference [95% CI] vs placebo) were also observed in SF-MPQ (-2.4 [-3.8, -1.1]), ADSIS -0.71 (-1.04, -0.38), and NPSI -7.7 (-11.1, -4.4) scores. Most treatment-emergent adverse events were mild; no serious adverse drug reactions were reported. DISCUSSION: Mirogabalin elicited clinically relevant decreases in pain and was well-tolerated, suggesting that mirogabalin is a promising treatment for patients with CNeP due to SCI.

DOI： 10.1212/WNL.0000000000201709

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < 0.001). Regarding response rates, the disease control rate of patients who developed treatment-related hypertension (94.2%) was significantly higher than those who did not (79.1%) (p = 0.009). CONCLUSIONS: Treatment-related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev.

DOI： 10.1002/cam4.5535

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting. METHODS: Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea). RESULTS: 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab. Objective response rate (ORR) was 38.6% for patients receiving lenvatinib, and 27.3% for patients receiving atezolizumab plus bevacizumab (p < 0.01; odds ratio 0.60). For patients who achieved complete response (CR), overall survival (OS) was not reached in both arms, but the result from univariate Cox regression model showed 62% reduction of death risk for patients treated with atezolizumab plus bevacizumab (p = 0.05). In all multivariate analyses, treatment arm was not found to be an independent factor conditioning OS. Comparing ORR achieved in the two arms, there was a statistically significant difference in favor of lenvatinib compared to atezolizumab plus bevacizumab in all subgroups except for Eastern patients, Child-Pugh B patients, presence of portal vein thrombosis, α-feto-protein ≥ 400 ng/mL, presence of extrahepatic disease, albumin-bilirubin (ALBI) grade 2, and no previous locoregional procedures. CONCLUSION: Lenvatinib achieves higher ORR in all patient subgroups. Patients who achieve CR with atezolizumab plus bevacizumab can achieve OS so far never recorded in HCC patients. This study did not highlight any factors that could identify patient subgroups capable of obtaining CR.

DOI： 10.1007/s00432-022-04512-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Recent meta-analysis showed that ulcerative colitis (UC) is a risk factor for cardiovascular disease (CVD). Dyslipidemia is a well-established risk factor for CVD. However, evidence regarding inflammatory bowel disease (IBD), including UC and lipid profiles, is limited. Additionally, no study has assessed the association between endoscopic activity and lipid profiles in patients with IBD. Therefore, we aimed to clarify the association between mucosal healing (MH) and lipid profiles in patients with UC. METHODS: A total of 221 Japanese patients with UC were enrolled in this analysis. Total cholesterol (T-chol), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were divided into tertiles (high, moderate, and low) based on the distributions, respectively. Self-administered questionnaire was used to obtain information regarding medication for dyslipidemia. Complete MH and MH are based on Mayo endoscopic subscore 0 and 0-1, respectively. RESULTS: The percentage of complete MH was 30.8%. In patients without medication for dyslipidemia, high HDL-C (>66 mg/dL) was significantly positively associated with complete MH (adjusted odds ratio [OR] 2.58, 95% CI: 1.04-6.64, p for trend = 0.037). In patients with nonproctitis, a positive association between HDL-C and complete MH was found (adjusted OR 3.54, 95% CI: 1.22-11.01, p for trend = 0.020). T-chol and TG were not associated with MH, regardless of medication for dyslipidemia. CONCLUSIONS: Complete MH was significantly positively associated with HDL-C in UC patients without medication for lipid. The disease extent might affect the association between complete MH and HDL-C.

DOI： 10.1159/000527353

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < 0.001). The neo-GPS, compared with the GPS, had a lower Akaike information criterion (1207 vs. 1,211, respectively) and a higher c-index (0.677 vs. 0.652, respectively) regarding to overall survival. In a subgroup analysis of patients considered to have a good prognosis as confirmed using a Child-Pugh score of 5 (p = 0.001), a neutrophil-to-lymphocyte ratio <3 (p = 0.001), or an α-fetoprotein level < 100 ng/mL (p < 0.001), those with a high neo-GPS (≥1) had a statistically poorer overall survival than those with a low neo-GPS. CONCLUSIONS: The neo-GPS can predict prognosis in advanced unresectable HCC patients treated with Atez/Bev.

DOI： 10.1002/cam4.5495

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction This study investigated the relationship between nutritional status, as determined by the prognostic nutritional index (PNI), and outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). Methods The study analyzed 485 HCC patients treated with Atez/Bev. Results There were 342 patients with a low PNI (<47) and 143 with a high PNI (≥47). The median follow-up duration was 9.4 (6.0-14.3) months. Multivariate Cox hazards analysis showed that an α-fetoprotein level ≥100 ng/mL (hazard ratio (HR), 2.217; 95% confidence interval (CI), 1.588-3.095; p<0.001) and PNI ≥47 (HR, 0.333; 95% CI, 0.212-0.525; p<0.001) were independently associated with overall survival. Multivariate analysis showed that an α-fetoprotein level ≥100 ng/mL (HR, 1.690; 95% CI, 1.316-2.170; p<0.001) and PNI ≥47 (HR, 0.696; 95% CI, 0.528-0.918; p=0.010) were independently associated with progression-free survival. Cumulative overall and progression-free survival rates differed significantly by PNI (p<0.001 and p<0.002, respectively). In a subgroup analysis using inverse probability weighting (IPW) adjustment in patients with albumin-bilirubin grade 1 (n=173), univariate Cox hazards analysis showed that a PNI ≥47 (HR, 0.502; 95% CI, 0.260-0.991; p=0.047) was significantly associated with overall survival. Spline curve analysis revealed that a PNI of approximately 34-48 is an appropriate cutoff for predicting good overall and progression-free survival. Discussion/Conclusion The PNI, a biomarker of nutritional status, can predict prognosis in patients with HCC treated with Atez/Bev, even those who are considered to have a good prognosis due to good liver function.

DOI： 10.1159/000527676

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Restless legs syndrome (RLS) is a common sleep disorder in the Western population. The prevalence of restless legs syndrome in the Japanese population is 4.6%. Inflammatory and/or immune alteration might be associated with the development of restless legs syndrome. Ulcerative colitis is a chronic inflammatory bowel disease. Evidence regarding the association between ulcerative colitis and the prevalence of restless legs syndrome is limited. Herein, we investigated the association between clinical outcomes and the prevalence of restless legs syndrome in Japanese patients with ulcerative colitis. This was a cross-sectional study using baseline data from a prospective cohort study. Subjects in this study were 273 patients with ulcerative colitis. The definition of restless legs syndrome was achieved using a self-administered questionnaire based on the diagnostic criteria for restless legs syndrome in an epidemiological study approved by the Executive Committee of the International Restless Leg Syndrome Study Group in 2002. Clinical outcomes were clinical remission and mucosal healing. The association between clinical remission and mucosal healing and the prevalence of restless legs syndrome was assessed by multivariate logistic regression analyses. The percentage of clinical remission and mucosal healing was 58.4% and 63.1%, respectively. The prevalence of restless legs syndrome in this cohort was 4.7%. Clinical remission (adjusted odds ratio 0.23, 95% confidence interval 0.05-0.93) and mucosal healing (adjusted odds ratio 0.23, 95% confidence interval 0.05-0.90) were independently inversely associated with restless legs syndrome. No association between serum haemoglobin and restless legs syndrome was found. In conclusion, clinical remission and mucosal healing were independently and inversely associated with the prevalence of restless legs syndrome in Japanese patients with ulcerative colitis.

DOI： 10.1111/jsr.13691

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. METHODS: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point. RESULTS: The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. CONCLUSION: Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.

DOI： 10.1016/j.ejca.2022.11.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device. METHODS: A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints. RESULTS: Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 log10  IU/ml (p < 0.05) and -0.2677 log10  IU/ml (p < 0.05), respectively. Anti-HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP-NASVAC treatment. CONCLUSIONS: Anti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB.

DOI： 10.1111/hepr.13851

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記述言語：英語  

DOI： 10.1007/s12072-022-10446-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The SURF trial showed that surgical resection (SR) and percutaneous ultrasonographic guided radiofrequency ablation (RFA) had equal therapeutic effects for small hepatocellular carcinoma (HCC). However, consensus regarding which treatment is appropriate for initial recurrent early-stage HCC remains lacking. This study aimed to elucidate therapeutic efficacy differences between SR and RFA for initial recurrent early-stage HCC. MATERIALS/METHODS: From 2000 to 2021, 371 patients with recurrent early-stage HCC (≤3 cm, ≤3 nodules) after undergoing initial curative treatment with SR or RFA were enrolled (median age 72 years; males 269; Child-Pugh A:B, n = 328:43; SR:RFA, n = 36:335). Recurrence-free survival (RFS) and overall survival (OS) were retrospectively evaluated. RESULTS: Although the median albumin-bilirubin (ALBI) score was better in the SR than the RFA group (-2.90 vs. -2.50, p &lt; 0.01), there were no significant differences between them in regard to RFS (median 28.1 months, 95% CI 23.4-50.0 vs. 22.1 months, 95% CI 19.3-26.2; p = 0.34), OS (78.9 months, 95% CI 49.3-not applicable vs. 71.2 months 95% CI, 61.8-84.7; p = 0.337), or complications (8.3% vs. 9.3%; p = 1.0). In sub-analysis for RFS and OS according to ALBI grade revealed no significant differences between the SR and RFA groups (ALBI 1/2 = 28.2/17.5 vs. 24.0/23.4 months; p = 0.881/0684 and ALBI 1/2 = 78.9/58.9 vs. 115.3/52.6 months, p = 0.651/0.578, respectively). CONCLUSION: This retrospective study found no significant differences in regard to RFS or OS between patients in the SR and the RFA groups for initial recurrence of early-stage HCC after undergoing curative treatment. These results showing equal therapeutic efficacy of SR and RFA confirm the findings of the SURF trial.

DOI： 10.3390/cancers14225524

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記述言語：日本語   出版者・発行元：(株)メディカルアイ  

50歳代女性。貧血の精査加療目的に当院受診となった。造影CT検査でMeckel憩室を背景とした慢性炎症が疑われたが活動性出血源はなく、腹部超音波検査にて終末回腸に全周性の壁肥厚と同部位に血流シグナルを認め、Meckel憩室出血と診断し、腹部鏡下小腸切除術を施行した。病理ではMeckel憩室と起始部に潰瘍あり、異所性粘膜はないことから潰瘍から出血したと考えた。術後貧血なく経過している。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The association between body mass index (BMI) and irritable bowel syndrome (IBS) has been inconsistent in the Asian population. Also, no evidence regarding this issue in the young population exists. The aim of the present study is to investigate the association between BMI and IBS based on the Rome III criteria in young Japanese people. METHODS: This study was a cross-sectional study consisted of 8923 Japanese university students. The definition of IBS was based on the Rome III criteria. BMI was divided into four categories (quartiles) on the basis of the study subjects' distribution (lowest, low, moderate, and high [reference]). The definition of lean, normal, and overweight was BMI < 18.5 kg/m2, 18.5 ≤ BMI < 25 kg/m2 (reference), and 25 ≤ BMI kg/m2, respectively. Age, sex, drinking, smoking, exercise habit, anemia, and sports injury were selected a priori as potential confounding factors. RESULTS: The prevalence of IBS was 6.5%, with females having a significantly higher prevalence than males (6.0% vs. 7.2%, p = 0.029). In females, being overweight was independently positively associated with IBS after adjustment (adjusted odds ratio [OR]: 1.81 [95% confidence interval (CI): 1.13-2.79]). In contrast, in males, no association between being lean or overweight and IBS was found. CONCLUSIONS: Among the young Japanese population, being overweight might be independently positively associated with prevalence of IBS in females but not in males.

DOI： 10.1007/s00384-022-04267-8

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は70歳男性.アルコール性肝硬変の経過中にアルコール性肝炎を合併し入院した.血尿を伴うネフローゼ症候群を呈しており,禁酒,利尿剤と栄養療法の導入により蛋白尿は改善した.顕微鏡的血尿が残存したため腎生検を実施し,血栓性微小血管障害症(TMA)と診断した.血漿ADAMTS13活性低下とvon Willebrand factor(VWF)抗原高値がみられ,肝星細胞減少によるADAMTS13産生低下がTMAの原因と想定された.ADAMTS13補充目的に新鮮凍結血漿(FFP)の投与,内皮細胞障害に対してトロンボモジュリン製剤(rTM)を開始した.FFPの漸減,中止後もADAMTS13活性の低下はみられず,腎機能が維持された.肝硬変の経過中に血尿が出現した場合,ADAMTS13活性低下とVWF抗原とのインバランスがある場合はTMAを疑い,FFPやrTMの投与を考慮する必要があると考えられた.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00263&link_issn=&doc_id=20221111010001&doc_link_id=10.2957%2Fkanzo.63.473&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.63.473&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は70代女性.COVID19ワクチン2回目を接種2日後に黄疸が出現し,急性肝障害のため入院となった.各種ウイルスマーカーは陰性,抗核抗体陽性,抗平滑筋抗体陽性,IgG高値であった.肝生検組織では,肝実質に広範な壊死・炎症がみられた.門脈域にも炎症細胞浸潤がみられたが,線維化やinterface hepatitisは明らかでなかった.COVID19ワクチンに対するリンパ球刺激試験が陽性であり,当初は自己免疫機序の関与が示唆された薬物性肝障害と診断した.しかし,肝庇護療法では肝機能検査異常は改善せず,副腎皮質ステロイド投与を開始し改善した.改善後の肝生検ではロゼット形成,interface hepatitisや形質細胞浸潤が確認され,COVID19ワクチンに誘発された自己免疫性肝炎(AIH)と診断した.COVID19ワクチン投与後に発症したAIHの症例は極めてまれであり報告する.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00263&link_issn=&doc_id=20221111010003&doc_link_id=10.2957%2Fkanzo.63.491&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.63.491&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本安定同位体・生体ガス医学応用学会  

脂質中の飽和脂肪酸は,肝脂肪毒性を有し肝病態に強く関与する.食事由来脂肪酸は,これまで13C標識試薬の経口投与を主とした小腸脂肪酸吸収試験が行われてきたが,胃の排出能や消化時間のバイアスを受け評価を困難にしていた.我々は,上部消化管内視鏡に胃を介さず13C標識試薬を投与することで,ヒト小腸におけるより正確な脂肪酸吸収評価法を確立した.同法を用いた13C呼気試験は,門脈圧亢進症を伴う肝硬変患者における小腸飽和脂肪酸吸収異常を証明し,非アルコール性脂肪肝炎(non-alcoholic steatohepatitis:NASH)患者における小腸パルミチン酸吸収亢進と病態進展への関与を見出した.肝臓は,食事由来脂質だけでなく,消化管ホルモン,腸内細菌叢など腸管から様々な影響を強く受ける臓器であり,その関係性は腸肝軸(Gut-Liver axis)と評される.今後,簡便かつ安全性の高い13C呼気試験を用いた腸管脂質吸収動態研究は,種々の肝疾患の病態解明においてさらに重要となることが予想される.(著者抄録)

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記述言語：日本語   出版者・発行元：(株)メディカルアイ  

肝内多発腫瘤で紹介された50歳代男性。造影超音波検査(CEUS)で、動脈優位相で辺縁及び中心部が濃染、門脈相で中心部の濃染持続、周囲実質と同程度の造影効果がみられ排血路が描出され、後血管相で欠損像を呈した。腫瘍生検にて肝血管肉腫と診断した。CEUSを施行し得た肝血管肉腫の報告は稀であるため報告する。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence of inflammatory bowel disease (IBD) is increasing; hence, effective treatments are warranted. The therapeutic effect of human carbonic anhydrase I (hCA I) in IBD remains unknown. Therefore, we investigated whether oral tolerization to hCA I would induce antigen-specific protection from intestinal inflammation in vivo. Severe combined immunodeficient mice received hCA I, keyhole limpet hemocyanin (KLH), or phosphate-buffered saline (PBS) orally for 7 days. Colons and mesenteric lymph nodes (MLNs) were collected 4 weeks after cell transfer. Additionally, the mechanisms underlying the therapeutic effects were investigated. The comparison between the effects of well-established drugs and hCA I oral administration was investigated. Oral administration of hCA I ameliorated colitis remarkably. hCA I reached the cecum and ameliorated colitis more effectively than mesalazine and similarly to prednisolone. Compared with PBS treatment, hCA I treatment reduced interleukin (IL)-17a, IL-6, and retinoic acid-related orphan receptor gamma t (RORγt) expression in the colon or MLNs; moreover, hCA I markedly reduced IL-6, IL-17, and interferon-gamma (IFN-γ) levels in the MLN. Oral administration of hCA I induced immune tolerance and suppressed colitis in vivo. Thus, hCA I administration could be proposed as a new treatment option for IBD.

DOI： 10.1038/s41598-022-22455-y

PubMed

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記述言語：日本語   出版者・発行元：日本メディカルセンター  

＜文献概要＞エラストグラフィには,臓器に対して一定の力を加えた際に生じる歪み(stiffness)を「硬さ」として計測した"strain elastography"と,剪断波(shear wave)が臓器の中を伝播する速度を「硬さ」として計測した"shear wave elastography"に大きく分けられる.本稿ではstrain elastographyであるReal-time Tissue Elastography(RTE)の特徴と,shear wave elastography(SWE)であるtransient elastographyの違いについて概説する.

DOI： 10.19020/cg.0000002416

CiNii Research

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1002/cam4.5337

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.

DOI： 10.3390/biomedicines10102540

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: In patients with compensated advanced chronic liver disease (cACLD), the invasive measurement of hepatic venous pressure gradient is the best predictor of hepatic decompensation. This study aimed at developing an alternative risk prediction model to provide a decompensation risk assessment in cACLD. METHODS: Patients with cACLD were retrospectively included from 9 international centers within the Portal Hypertension Alliance in China (CHESS) network. Baseline variables from a Japanese cohort of 197 patients with cACLD were examined and fitted a Cox hazard regression model to develop a specific score for predicting hepatic decompensation. The novel score was validated in an external cohort (n = 770) from 5 centers in China, Singapore, Korea, and Egypt, and was further assessed for the ability of predicting clinically significant portal hypertension in a hepatic venous pressure gradient cohort (n = 285). RESULTS: In the derivation cohort, independent predictors of hepatic decompensation were identified including Stiffness of liver, Albumin, Varices, and platElets and fitted to develop the novel score, termed "SAVE" score. This score performed significantly better (all P < 0.05) than other assessed methods with a time-dependent receiver operating characteristic curve of 0.89 (95% confidence interval [CI]: 0.83-0.94) and 0.83 (95% CI: 0.73-0.92) in the derivation and validation cohorts, respectively. The decompensation risk was best stratified by the cutoff values at -6 and -4.5. The 5-year cumulative incidences of decompensation were 0%, 24.9%, and 69.0% in the low-risk, middle-risk, and high-risk groups, respectively ( P < 0.001). The SAVE score also accurately predicted clinically significant portal hypertension (AUC, 0.85 95% CI: 0.80-0.90). DISCUSSION: The SAVE score can be readily incorporated into clinical practice to accurately predict the individual risk of hepatic decompensation in cACLD.

DOI： 10.14309/ajg.0000000000001873

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Socioeconomic status is a risk factor for worse outcomes in many diseases. However, evidence on the association between socioeconomic status and clinical outcome in patients with ulcerative colitis (UC) is limited. In the clinical setting, the therapeutic goal for UC is to achieve mucosal healing (MH). Thus, the aim of this study is to examine the association between socioeconomic status and MH in patients with UC. METHODS: The study population consisted of 298 patients with UC. Education status and household income were divided into three groups based on a self-administered questionnaire. MH and complete MH were defined as a Mayo endoscopic subscore of 0-1 and 0, respectively. The association of socioeconomic status with MH and complete MH was assessed by multivariate logistic regression analysis. Patients with UC were divided into a younger group (<51 years old) and an older group (≥51 years old) based on median age. RESULTS: The percentage of MH and complete MH was 62.4% and 25.2%, respectively. In all patients, socioeconomic status was not associated with MH and complete MH, respectively. In the older group, education but not household income was independently positively associated with MH and complete MH. In contrast, in the younger group, no association between socioeconomic status and MH and complete MH was found. CONCLUSION: In older Japanese patients with UC, education status but not household income was independently positively associated with MH and complete MH.

DOI： 10.1136/bmjgast-2022-001000

PubMed

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：日本語   出版者・発行元：日本消化器病学会-四国支部  

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記述言語：日本語   出版者・発行元：日本消化器病学会-四国支部  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Four decades have passed since the first usage of the therapeutic vaccine in patients with chronic hepatitis B (CHB). However, there is no approved regimen of vaccine therapy for the treatment of CHB. This is mainly attributable to faulty conception, an improper understanding of the cellular and molecular mechanisms of CHB, and the impaired design of vaccine therapy for CHB. With the advent of new techniques and a better understanding of cellular and molecular mechanisms underlying the genesis of CHB, the limitations and failures of previous regimens of therapeutic vaccines have been primarily understood. Additionally, the importance of immune therapy for treating millions of CHB patients and achieving the target of "Elimination of Hepatitis by 2030" has been focused on in the international arena. This has been amplified by the apparent limitation of commercially available antiviral drugs that are infinite in duration, endowed with safety concerns, and unable to cure liver damage due to their minimal immune modulation capacities. The proposed review article comprehensively discusses each of these points and proposes evidence-based approaches for viable types of vaccine therapy for the treatment of CHB.

DOI： 10.3390/vaccines10101644

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 (<3.5 g/L = 1 point), lactate dehydrogenase (≥245 U/L = 1 point), neutrophil-to-lymphocyte ratio (≥4.8 = 1 point), aspartate aminotransferase-to-alanine aminotransferase ratio (≥1.44 = 1 point), and total bilirubin level (≥1.3 mg/dl = 1 point). Patients were divided into the low-score group (0, 1, or 2 points) and the high-score group (3, 4, or 5 points). RESULTS: There were 89 (22.0%), 141 (34.8%), 106 (26.2%), 49 (12.1%), 16 (4.0%), and 4 (1.0%) patients with scores of 0, 1, 2, 3, 4, 5, respectively. The progression-free survival (PFS) in the low-score group was significantly longer than that in the high-score group (median 7.8 vs. 3.5 months, p < 0.001). The median overall survival (OS) of the low-score group was not reached at the time cutoff, with a 1-year survival rate of 75.5%, whereas the median OS of the high-score group was 8.5 months, showing a significant difference (p < 0.001). A high HCC-GRIm score was a significant unfavorable factor associated with the PFS and OS in multivariate analyses (p = 0.002 and p < 0.001, respectively). CONCLUSIONS: The HCC-GRIm score serves as a novel prognostic score for HCC patients treated with Atez/Bev.

DOI： 10.1002/cam4.5294

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The novel 2-D shear wave elastography (2D-SWE) can measure two ultrasound parameters: shear wave dispersion (SWD) and shear wave speed (SWS). We investigated the ability of 2D-SWE in measuring spleen stiffness using ultrasound multiparametric imaging. METHODS: This cross-sectional study included patients with chronic liver disease who underwent esophagogastroduodenoscopy and ultrasonographic examinations of the spleen between September 2018 and December 2021. In total, 157 patients were enrolled in this study: 81 and 67 patients were included in the pilot set for hepatic venous pressure gradient (HVPG) measurements and validation cohort without HVPG measurements, respectively. To confirm reproducibility between the two examiners, an additional 30 patients were enrolled. RESULTS: The Bland-Altman plots revealed no significant bias in the SWD as measured by two examiners. The splenic SWS (r = 0.752) and SWD (r = 0.444) were correlated with the HVPG. Regarding high-risk varices, as per the Youden index, the cut-off value for splenic SWS was 3.30 m/s, with a sensitivity of 85.7%, specificity of 92.5%, positive predictive value of 85.7%, and negative predictive value of 92.4% in the pilot set. In the validation set, good diagnostic performance by the splenic SWS was observed. However, SWD did not perform as well as SWS. CONCLUSIONS: The splenic SWS, measured using ultrasound multiparametric imaging, was closely correlated with the HVPG. Thus, SWS is a useful predictive marker for high-risk varices.

DOI： 10.1111/hepr.13841

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Adverse events (AEs) of urinary protein from monoclonal antibodies against vascular endothelial growth factor (VEGF) are factors that often inhibit systemic therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate risk factors of urinary protein in the early period (<12 weeks) of atezolizumab plus bevacizumab treatment (Atez/Bev). MATERIALS/METHODS: From 2020 to June 2022, 193 uHCC patients treated with Atez/Bev at our affiliated hospitals were enrolled (median 73 years, 158 males, 183 Child-Pugh A, BCLC-0: A: B: C=1: 7: 73: 112). AEs related to urinary protein (≥G2) within 12 weeks were defined as significant and related clinical features were analyzed retrospectively. RESULTS: In analyses of risk factors of urinary protein-related AEs during the first 12 weeks after starting Atez/Bev using a logistic regression method, univariate analysis showed positive for hypertension [odds ratio (OR) 3.54, 95%CI: 1.28-9.80, P=0.015] and baseline urinary protein urine creatinine ratio (UPC: ≥0.16) (OR 2.52, 95%CI: 1.09-5.83, P=0.031) as pre-treatment clinical factors, while elevation of urinary protein in the early period (baseline to three weeks) with delta UPC per three weeks (ΔUPC/3W) (≥0.23) (OR 15.80, 95%CI: 6.15-40.50, P<0.001) was a clinical factor after starting treatment. Multivariate analysis of only baseline clinical factors revealed positive for history of hypertension as the only predictive factor (OR 3.20, 95%CI: 1.14-8.95, P=0.027), while only ΔUPC/3W (≥0.23) (OR 14.40, 95%CI: 4.91-42.00, P<0.001) were noted in multivariate analysis including ΔUPC/3W. Predictive factors for ΔUPC/3W (≥0.23) (OR 3.50, 95%CI: 1.23-99.90, P=0.019) were hypertension and UPC (≥0.16) (OR 6.12, 95%CI 2.61-14.30, P<0.001) in multiple analysis. CONCLUSION: Urinary protein-related AEs are frequently observed during Atez/Bev treatment in uHCC patients with elevated ΔUPC/3W (≥0.23), and ΔUPC/3W (≥0.23) is often seen in patients with hypertension and/or UPC (≥0.16).

DOI： 10.1159/000526521

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Predicting the survival of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/bev) remains a challenge. This study aims to validate the modified albumin-bilirubin grade and α-fetoprotein score (mALF score). METHODS: This retrospective, multicenter study included 426 HCC patients receiving Atez/Bev. Each patient was randomized 3:2 to a training set (n = 255) and a validation set (n = 171). We investigated prognostic factors in the training set and developed an easily applicable mALF score, which was evaluated in the validation set. RESULTS: We built the mALF score using baseline mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37-4.05, p = 0.002) and α-fetoprotein ≥ 100 ng/ml (HR 2.61, 95% CI 1.49-4.55, p < 0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9-90.8) in patients who meet neither of the criteria (mALF 0 points, n = 101), 61.7% (95% CI 44.5-74.9) in patients who meet either of the two criteria (mALF 1 point, n = 109), and 24.6% (95% CI 9.0-44.3) in patients who meet both criteria (mALF 2 points, n = 45); the difference was statistically significant (p < 0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0-8.0), and 3.8 months (95% CI 3.0-5.2), respectively, which amounted to a significant difference (p < 0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points = 94.2%/62.1%/46.3%, p < 0.001; median PFS, 0/1/2 points = 9.3/6.7/4.7 months, p = 0.018). CONCLUSION: The mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.

DOI： 10.1007/s12072-022-10406-8

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Patients often do not respond truthfully to physicians' interviews concerning alcohol. Few reports regarding the level of alcohol dependence in patients with chronic liver disease (CLD) have been presented. This study aimed to elucidate severity distribution in patients with CLD using the alcohol use disorders identification test (AUDIT). METHODS: From March to June 2022, 2034 Japanese outpatients with CLD, including 415 cases associated with hepatitis C virus, 436 with hepatitis B virus, 173 with alcohol-related liver disease (ARLD), and 1010 with other factors, were interviewed using AUDIT. Clinical features related to alcohol use in these patients were then retrospectively evaluated. RESULTS: In all patients, an AUDIT score 8-14 (harmful use) was noted in 5.8% of hepatitis C virus, 8.9% of hepatitis B virus, 24.3% of ARLD, and 4.4% of other groups, respectively (P < 0.001), while a score ≥15 (dependency) was noted in 3.4%, 3.0%, 27.7%, and 1.9%, respectively (P < 0.001). When the country was divided into regions, the percentages remained similar. Comparisons between patients with and without an AUDIT score ≥8 (n = 1412), performed after exclusion of those without related data (n = 622), showed no significant differences for hepatic reserve function, while those with harmful alcohol use were significantly younger (66 vs. 70 years, P = 0.006) and had a larger percentage of men (80.4% vs. 45.1%, P < 0.001). CONCLUSION: Harmful alcohol and alcohol dependency were observed in approximately 10% of patients with viral or non-viral CLD, after excluding patients with ARLD. Assessment of alcohol intake by use of the AUDIT questionnaire as well as adequate intervention should be considered necessary.

DOI： 10.1111/hepr.13835

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The use of Glasgow prognostic score (GPS), calculated using the serum C-reactive protein and albumin levels, to predict the outcomes of patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib was investigated in this study. METHODS: A total of 508 patients with Child-Pugh class A HCC treated with lenvatinib were included in this study. RESULTS: The median overall and progression-free survivals were 20.4 months [95% confidence interval (CI), 17.7-23.2 months] and 7.5 months (95% CI, 6.8-8.5 months), respectively. The median overall survivals of patients with a GPS of 0, 1, and 2 were 28.5, 16.0, and 9.1 months, respectively (P < 0.001). When adjusted for age, sex, performance status, etiology, α-fetoprotein, macroscopic vascular invasion, extrahepatic spread, history of sorafenib therapy, and GPS, a GPS of 1 [hazard ratio (HR), 1.664; 95% CI, 1.258-2.201; P < 0.001] and a GPS of 2 (HR, 2.664; 95% CI, 1.861-3.813; P < 0.001) were found to be independently associated with overall survival. The median progression-free survivals of patients with a GPS of 0, 1, and 2 were 8.8, 6.8, and 3.8 months, respectively (P < 0.001). When adjusted for the same factors of overall survival, a GPS of 2 (HR, 2.010; 95% CI, 1.452-2.784; P < 0.001) was found to be independently associated with progression-free survival. As the albumin-bilirubin with tumor node metastasis score increased, the proportion of patients with a GPS of 1 or 2 increased (P < 0.001). CONCLUSIONS: GPS can be used to predict survival in patients with unresectable HCC who were treated with lenvatinib.

DOI： 10.1097/MEG.0000000000002398

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aims: Functional dyspepsia (FD) may be a common digestive disease worldwide and reduces the quality of life of patients. However, only a few studies have investigated the association between eating behavior and FD. The purpose of this cross-sectional study is to examine the association between eating behavior and prevalence of FD in a young Japanese cohort. Methods: In this study, we enrolled 8923 Japanese university students. FD is diagnosed based on the Rome III criteria. Eating habits and frequency of meals were investigated using a self-administered questionnaire. Results: The FD subjects had a younger mean age, a lower body mass index, and a lower proportion of men compared to the non-FD subjects. An independent positive association between skipping breakfast and/or lunch and FD was found (adjusted ORs were 1.60 [95% CI, 1.10-2.32] for breakfast and 2.52 [95% CI, 1.04-5.18] for lunch). Skipping dinner, extra meals (snacks) or midnight snacks was not associated with FD. The prevalence of FD in subjects eating 1, 2, and 3 meals per day was 4.8%, 2.2%, and 1.7%, respectively. The frequency of meals was independently inversely associated with prevalence of FD (adjusted ORs were 1 per day: 2.72 [95% CI, 1.19-5.42], and 2 per day: 1.69 [95% CI, 1.16-2.43], P for trend = 0.001). Conclusions: In the young Japanese people, the frequency of meals may be independently inversely associated with prevalence of FD. In particular, skipping breakfast and/or lunch was associated with the prevalence of FD.

DOI： 10.5056/jnm21146

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Previous reports suggest that null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. METHODS: Blood samples of 270 DILI cases from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week (DDW)-Japan score as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. RESULTS: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and DDW-Japan scores was not observed. CONCLUSIONS: GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13812

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記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

DOI： 10.1016/j.cyto.2022.155901

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to investigate the utility of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score in hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). METHODS: This retrospective cohort study included a total of 297 patients receiving Atez/Bev from September 2020 to November 2021 at 21 different institutions and hospital groups in Japan. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. RESULTS: The patients were assigned CRAFITY scores of 0 points (n = 147 [49.5%]), 1 point (n = 111 [37.4%]), and 2 points (n = 39 [13.1%]). AFP ≥ 100 ng/mL and CRP ≥ 1.0 mg/dL were significantly associated with progression-free survival (PFS) and overall survival (OS). The median PFS in the CRAFITY score 0, 1, and 2 groups was 11.8 months (95% confidence interval [CI] 6.4-not applicable [NA]), 6.5 months (95% CI 4.6-8.0), and 3.2 months (95% CI 1.9-5.0), respectively (p < 0.001). The median OS in patients with CRAFITY score 0, 1 and 2 was not reached, 14.3 months (95% CI 10.5-NA), and 11.6 months (95% CI 4.9-NA), respectively. The percentage of patients with grade ≥ 3 liver injury, any grade of decreased appetite, any grade of proteinuria, any grade of fever, and any grade of fatigue was lowest in patients with a CRAFITY score of 0, followed by patients with CRAFITY scores of 1 and 2. CONCLUSIONS: The CRAFITY score is simple and could be useful for predicting therapeutic outcomes and treatment-related adverse events.

DOI： 10.1007/s12072-022-10358-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/a-1858-4826

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with chronic hepatitis B (CHB) represent a living and permanent reservoir of hepatitis B virus (HBV). Millions of these CHB patients will eventually develop complications such as liver cirrhosis, hepatic failure, and hepatocellular carcinoma if they are not treated properly. Accordingly, several antiviral drugs have been developed for the treatment of CHB, but these drugs can neither eradicate all forms of HBV nor contain the progression of complications in most patients with CHB. Thus, the development of new and novel therapeutics for CHB remains a pressing need. The molecular and cellular mechanisms underlying the pathogenesis of CHB indicate that immune dysregulations may be responsible for HBV persistence and progressive liver damage in CHB. This provided the scientific and ethical basis for the immune therapy of CHB patients. Around 30 years have passed since the initiation of immune therapies for CHB in the early 1990s, and hundreds of clinical trials have been accomplished to substantiate this immune treatment. Despite these approaches, an acceptable regimen of immune therapy is yet to be realized. However, most immune therapeutic agents are safe for human usage, and many of these protocols have inspired considerable optimism. In this review, the pros and cons of different immune therapies, observed in patients with CHB during the last 30 years, will be discussed to derive insights into the development of an evidence-based, effective, and patient-friendly regimen of immune therapy for the treatment of CHB.

DOI： 10.1007/s00535-022-01890-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < 0.001), and diarrhea (10.5% vs. 4.6%, p = 0.012) were greater, while that of general fatigue was lower (22.8% vs. 26.3%, p = 0.008). Comparisons of therapeutic best response using modified response evaluation criteria in solid tumors (mRECIST) did not show significant differences between the present groups (Atez/Bev vs. lenvatinib: CR/PR/SD/PD = 6.1%/39.1%/39.1%/15.6% vs. 0%/48.0%/38.0%/14.0%, p = 0.285). In patients of discontinuation of treatments, 48.2% switched to lenvatinib, 10.6% continued beyond PD, 8.2% received another systemic treatment, 5.9% underwent transcatheter arterial chemoembolization (TACE), 3.5% received hepatic arterial infusion chemotherapy (HAIC), and 1.2% underwent surgical resection in Atez/Bev-group, while 42.2% switched to Atez/Bev, 4.4% continued beyond PD, 4.4% received another systemic treatment, 2.2% nivolumab, 6.7% received TACE, and 2.2% received HAIC in lenvatinib-group. Following adjustment with inverse probability weighting (IPW), Atez/Bev-group showed better PFS (0.5-/1-/1.5-years: 56.6%/31.6%/non-estimable vs. 48.6%/20.4%/11.2%, p < 0.0001) and OS rates (0.5-/1-/1.5-years: 89.6%/67.2%/58.1% vs. 77.8%/66.2%/52.7%, p = 0.002). CONCLUSION: The present study showed that u-HCC patients who received Atez/Bev as a first-line treatment may have a better prognosis than those who received lenvatinib.

DOI： 10.1002/cam4.4854

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Objectives: Sleep disturbance due to muscle cramps or hepatic encephalopathy in patients with chronic liver disease (CLD) can lead to a reduced quality of life. The Pittsburgh sleep quality index (PSQI) is commonly used for evaluating sleep disturbance; however, this questionnaire is time-consuming owing to the large number of questions. As the usefulness of the Athens insomnia scale (AIS) in patients with CLD is not sufficiently known, the present study aimed to determine whether the AIS and Epworth sleepiness scale (ESS) could be used as simple alternative questionnaires for evaluating sleep disturbances in patients with CLD. Materials and Methods: A total of 117 patients with CLD were retrospectively evaluated. Patients with overt hepatic encephalopathy were excluded. All patients were examined using the AIS, PSQI, and ESS, and their responses to these questionnaires were statistically analyzed. Results: The number of patients diagnosed with sleep disturbance using the AIS, PSQI, and ESS were 39 (33.3%), 37 (31.6%), and 9 (7.7%), respectively. There was no correlation between PSQI and ESS scores (r = 0.011, p = 0.910); in contrast, the AIS scores showed a significant correlation with the PSQI scores (r = 0.689, p &lt; 0.001). When the PSQI was considered as the standard for evaluating sleep disturbance, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the AIS were 76.9%, 91.0%, 81.1%, and 88.8%, respectively. In the sleep medication group, the sensitivity, specificity, PPV, and NPV of the AIS were 100%, 70%, 78.6%, and 100%, respectively. Conclusions: This is the first report to indicate that the AIS is an alternative questionnaire to the PSQI and that it can be a useful tool for detecting cirrhosis-related complications in patients with CLD.

DOI： 10.3390/medicina58060741

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u-HCC) patients classified as Child-Pugh A (CP-A). This study aimed to elucidate the prognosis of patients treated with Atez/Bev, especially CP-A and -B cases. MATERIALS/METHODS: From September 2020 to March 2022, 457 u-HCC patients treated with Atez/Bev were enrolled (median age 74 years, male:female = 368:89, CP-A:CP-B = 427:30, Child-Pugh score [CPS] 5:6:7:8:9 = 271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated. RESULTS: There were no significant differences between CP-A and -B patients in regard to best response (CR:PR:SD:PD = 16:91:194:81 vs. 0:7:13:8, p = 0.739; objective response rate/disease control rate = 28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value < 0.10 for comparisons between patients with CP-A and -B showed that the progression-free survival (PFS) rate for CP-A cases was better (6-/12-/18-month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non-estimable [NE], p < 0.001), as was overall survival (OS) rate (6-/12-/18-month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p < 0.001). Median PFS (mPFS) and median OS (mOS) for the CPS-5 were 9.5 months/NE, and 5.1/14.0 months for the CPS-6 (both p < 0.001). Furthermore, for modified albumin-bilirubin grade (mALBI)-1/2a/2b, mPFS was 9.4/8.5/5.3 months (p < 0.001) and mOS was NE/17.8/13.4 months (p < 0.001). CONCLUSION: Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u-HCC patients, whereas for CP-B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.

DOI： 10.1111/hepr.13797

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Liver-related death is preceded by clinical decompensation; therefore, the risk stratification of decompensation in compensated advanced chronic liver disease (cACLD) is extraordinary significant. METHODS: The international, multicenter study included three cohorts from January 2009 to August 2021. In training cohort, the unfavorable Baveno VI criteria patients were used to develop the novel CHESS criteria to stratify decompensation risk. The Algorithm based on Baveno VI criteria plus CHESS criteria (ABC model) was validated in validation cohort, and used to diagnose clinically significant portal hypertension (CSPH) in hepatic venous pressure gradient (HVPG)-performed cohort. RESULTS: A total of 1377 cACLD patients were enrolled. In training cohort, multivariate analysis revealed that liver stiffness measurement (LSM), platelet count (PLT), albumin, alanine aminotransferase (ALT) and varices were the independent risk factors for hepatic decompensation. The novel CHESS criteria was produced (0.036 × LSM [kPa]) + (- 0.013 × PLT [109/L]) + (- 0.068 × Albumin [g/L])) + (- 0.016 × ALT [U/L]) + (0.651 × Varices [present: 1, absent: 0]), and < - 4.4, - 4.4 to - 3.1 and > - 3.1 indicated the low risk, medium risk, and high risk of decompensation, with a 3 year-time-dependent area under the curve (tAUC) of 0.851 (0.800-0.901). In validation cohort, the 3 year-tAUC of ABC model was 0.843 (0.742-0.943). Notably, in HVPG cohort, the high risk group was used to rule in CSPH with a positive predictive value of 93.0%. CONCLUSIONS: The ABC model can stratify the risk of decompensation in cACLD. HVPG evaluation can be waived in both low risk and high risk cACLD patients as they can be managed by Baveno VI criteria and non-selective β-blockers intervention, respectively, and the remaining medium risk patients need further HVPG evaluation.

DOI： 10.1007/s12072-022-10345-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < 0.001). Median progression-free survival was 7.5 (95% CI, 6.7-8.1) months. Multivariate analysis showed that age, CAR ≥ 0.108 (HR, 1.644; 95% CI, 1.324-2.043), and non-hepatitis B, non-hepatitis C etiology (HR, 0.726) were independently associated with progression-free survival. Cumulative progression-free survival differed significantly between patients with low versus high CAR (p < 0.001). CAR values were significantly higher as Japan Integrated Staging score increased (p < 0.001). In conclusion, CAR can predict outcomes in patients with unresectable HCC treated with lenvatinib.

DOI： 10.1038/s41598-022-12058-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

For patients with cirrhosis, no definitive predictor of the efficacy and prognosis of tolvaptan treatment exists. We assessed the cisterna chyli's utility as an optimal marker. We retrospectively enrolled 172 patients with cirrhosis. The effect of tolvaptan was evaluated using post-treatment survival time. The overall response to tolvaptan was 52.3%. The median cisterna chyli diameter was 4.1 mm. Of 172 patients, 100 were included in the pilot set and 72 in the validation set. According to the Youden index, the cisterna chyli diameter's cutoff value was 4 mm, with a sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of 92%, 83%, 86%, 91%, 5.43, and 0.09, respectively, in the pilot set. The area under the curve of the cisterna chyli diameter for evaluating tolvaptan's effect was 0.911 and 0.988 in the pilot and validation sets, respectively. During multivariate analysis, cisterna chyli narrowing and furosemide treatment were significant predictive factors for tolvaptan's insufficient effect. Cumulative liver transplantation-free survival rates were significantly higher in patients with cisterna chyli dilatation than in those without (p = 0.028). Our findings suggest a strong association of cisterna chyli with tolvaptan treatment response in patients with cirrhosis and hepatic edema.

DOI： 10.1038/s41598-022-11889-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Chronic hepatitis B (CHB) is a highly complicated pathological process in which the disease is initiated by the hepatitis B virus (HBV); however, host immune responses are primarily responsible for variable extents of liver damage. If the patients with CHB remain untreated, many CHB patients will eventually develop complications like cirrhosis of the liver (LC) and hepatocellular carcinoma (HCC). In 2019, an estimated 882,000 patients died due to HBV-related complications worldwide. Accordingly, several drugs with antiviral properties have been used to treat CHB patients during the last four decades. However, the treatment outcome is not satisfactory because viral suppression is not usually related to the containment of progressive liver damage. Although proper reconstruction of host immunity is essential in CHB patients, as of today, there is no acceptable immune therapeutic protocol for them. These realities have exposed new, novel, and innovative therapeutic regimens for the management of CHB patients. This review will update the scope and limitation of the different innovative antiviral and immune therapeutic approaches for restoring effective host immunity and containing the virus in CHB patients to block progression to LC and HCC.

DOI： 10.3390/vaccines10050746

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The potential health benefits of laughter are recognized in relation to several chronic diseases. However, no study has yet investigated the association between laughter and functional dyspepsia (FD). The purpose of this study was to investigate this issue in a young Japanese population. METHODS: This study was conducted on 8923 Japanese university students. Information on the frequency of laughter and types of laughter-inducing situations, digestive symptoms (Rome III criteria) were obtained through a self-administered, web-based questionnaire. RESULTS: The percentage of respondents who laughed out loud almost every day was 64.3%. On the other hand, 1.8% of the subjects reported that they rarely laughed. No association was found between the total frequency of laughter and FD. Laughing while talking with family and friends almost every day was significantly inversely associated with FD (adjusted odds ratio (OR): 0.47 (95% confidence interval (CI): 0.28-0.81); p for trend was 0.003). On the other hand, laughing while watching TV or videos and laughing while looking at comics or magazines independently showed a positive correlation with FD (TV or videos: adjusted OR, 1-5 times a week: 1.74 (95% CI: 1.16-2.60); comics or magazines: adjusted OR, 1-5 times a week: 1.78 (95% CI: 1.08-2.81)). CONCLUSION: In this young Japanese population, no association between laughter frequency and FD was observed although laughing while talking with friends and family was independently and inversely associated with FD.

DOI： 10.3390/ijerph19095686

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Luseogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Unhealthy eating behavior is associated with diabetes, hypertension, and obesity. However, evidence regarding the effect of medications, including SGLT2 inhibitors, on unhealthy eating behavior is limited. This study investigated the association between unhealthy eating behavior and the laboratory and physical findings of Japanese patients with type 2 diabetes given luseogliflozin once daily for 24 weeks. METHODS: Twenty-nine patients with type 2 diabetes mellitus were enrolled in a 24-week prospective, open-label, single-arm pilot study. The information regarding unhealthy eating behaviors (eating fast, late dinner, nighttime snack, skipping breakfast, and eating until full) was obtained using self-reported questionnaires. RESULTS: The baseline rate of eating fast, late dinner, nighttime snack, skipping breakfast, and eating until full was 51.7%, 24.1%, 24.1%, 10.3% and 55.2%, respectively. After administration of luseogliflozin, fasting plasma glucose, HbA1c, aspartate aminotransferase (ALT), weight, body mass index, and waist measurement all decreased significantly. High-density lipoprotein cholesterol and hematocrit increased significantly. In the healthy eating behavior group, the improvements of fasting plasma glucose and ALT, but not other variables, were attenuated. HbA1c level was significantly improved in patients with eating fast, while other unhealthy eating behaviors attenuated the effect of luseogliflozin for HbA1c. The effect of leseogliflozin on the relationship between eating behavior and weight reduction was inconsistent after administration luseogliflozin. CONCLUSION: Luseogliflozin might be more effective for controlling plasma glucose in patients with type 2 diabetes who have a tendency to eat fast, but it might have less effect on those with other unhealthy eating habits.

DOI： 10.1007/s13300-022-01261-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aims: Evidence regarding the association between body mass index (BMI) and functional dyspepsia (FD) in the Asian population is limited. Further, no study has evaluated this issue in young people in Asian and Western populations. Thus, we aim to investigate this issue among young Japanese people. Methods: The study subjects comprised of 8923 Japanese university students. BMI was divided into 4 categories (quartiles) on the basis of the study subjects' distribution (lowest, low, moderate, and high [reference]). The definition of lean, normal, overweight, and obese was BMI < 18.5 kg/m2, 18.5 ≤ BMI < 25 kg/m2 (reference), 25 kg/m2 ≤ BMI < 30 kg/m2, and 30 kg/m2 ≤ BMI, respectively. The definition of FD was based on the Rome III criteria. Results: The prevalence of FD was 1.9% in this cohort. The lowest BMI was independently associated with FD after adjustment (adjusted odds ratio [OR], 2.88; 95% confidence interval [CI], 1.46-3.67); P for trend = 0.001). The lowest BMI was independently associated with FD in women but not in men (OR, 2.94; 95% CI, 1.59-5.77; P for trend = 0.001). Leanness was independently associated with FD in total and in women but not in men (total: adjusted OR, 2.01; 95% CI, 1.40-2.86) and women (OR, 2.19; 95% CI, 1.35-3.45). However, interaction analysis showed no significant difference for sex. Conclusions: Among young Japanese people, BMI may be independently inversely associated with FD. Leanness may be an independent associated factor for FD in the young Japanese women.

DOI： 10.5056/jnm21076

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1002/cam4.4763

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: To investigate whether fibrosis-4 index can help stratify the risk of diabetes mellitus in subjects with fatty liver disease. METHODS: Based on fatty liver disease and fibrosis-4 index (cutoff value, 1.3), we retrospectively divided 9,449 subjects, who underwent at least two annual health checkups, into four groups stratified by gender: normal, high fibrosis-4 indexwithout fatty liver disease, low fibrosis-4 index with fatty liver disease, and high fibrosis-4 index with fatty liver disease groups. RESULTS: Onset rates for diabetes mellitus in the normal, high fibrosis-4 index without fatty liver disease, low fibrosis-4 index with fatty liver disease, and high fibrosis-4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8%, and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3%, and 7.0%, respectively, in women. Compared with the normal group, the high fibrosis-4 index without fatty liver disease, low fibrosis-4 index with fatty liver disease, and high fibrosis-4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female subjects. Moreover, in both genders, high fibrosis-4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis-4 index with fatty liver disease group: adjusted harzard ratio, 95% confidence interval: 4.03, 2.19-7.42 [men] and 6.40, 1.77-23.14 [women]). CONCLUSIONS: Subjects with fatty liver disease and high fibrosis-4 index had a higher risk of diabetes mellitus onset. Therefore, fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention.

DOI： 10.1111/jdi.13812

PubMed

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: The albumin-to-globulin ratio (AGR) is a recognized chronic inflammation marker. No evidence regarding the relationship between AGR level and ulcerative colitis (UC) exists. The aim of this study was to evaluate the association between AGR and clinical outcomes among Japanese subjects with UC. Methods: The study subjects consisted of 273 Japanese individuals with UC. AGR was divided into 4 categories (low, moderate, high, and very high). The definition of complete mucosal healing (MH) was based on the Mayo endoscopic subscore of 0. Clinical remission (CR) was defined as no rectal bleeding and no abnormally high stool frequency (<3 times per day). Results: The percentage of MH was 26.4%. High AGR and very high AGR were significantly positively correlated with CR (adjusted odds ratio [OR], 5.85; 95% confidence interval [CI], 2.52-14.18 and adjusted OR, 4.97; 95% CI, 2.14-12.04) and complete MH (adjusted OR, 4.03; 95% CI, 1.56-11.51 and adjusted OR, 5.22; 95% CI, 1.97-14.89), respectively after adjustment for confounding factors (P for trend=0.001). Only in the low C-reactive protein (CRP) group (≤0.1 mg/dL), very high AGR was significantly positively correlated with complete MH but not CR (adjusted OR, 4.38; 95% CI, 1.06-21.77; P for trend=0.017). In the high CRP group, no correlation between AGR and complete MH was found. Conclusion: Among Japanese patients with UC, AGR may be independently positively correlated with complete MH. In particular, among UC patients with low CRP, AGR might be a useful complementary marker for complete MH.

DOI： 10.3393/ac.2021.01032.0147

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM. METHODS: This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.

DOI： 10.1007/s13300-022-01239-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The accuracy of attenuation coefficients and B-mode ultrasound for distinguishing between S0 (healthy, < 5% fat) and S1-3 (steatosis ≥ 5%) livers compared to a controlled attenuation parameter is unclear. This meta-analysis aimed to comprehensively assess the diagnostic performance of B-mode ultrasound imaging for evaluating steatosis of ≥ 5%. We searched the PubMed, Embase, and Web of Science databases for studies on the accuracy of B-mode ultrasound for differentiating S0 from S1-3 in adults with chronic liver disease. A bivariate random-effects model was performed to estimate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and diagnostic odds ratios (DORs). Subgroup analyses by attenuation coefficient, conventional B-mode ultrasound findings, and B-mode ultrasound findings without semi-quantification methods were performed. Liver steatosis was scored as follows: S0, < 5%; S1, 5-33%; S2, 33-66%; and S3, > 66%. Nineteen studies involving 3240 patients were analyzed. The pooled sensitivity and specificity of B-mode ultrasound for detecting S1 were 0.70 (95% confidence interval [CI], 0.63-0.77) and 0.86 (95% CI 0.82-0.89), respectively. The pooled PLR, NLR, and DOR were 4.90 (95% CI 3.69-6.51), 0.35 (95% CI 0.27- 0.44), and 14.1 (95% CI 8.7-23.0), respectively. The diagnostic accuracy was better in patients with attenuation coefficients (area under the curve [AUC], 0.89; sensitivity, 0.75; specificity, 0.86) than in those with conventional B-mode findings (AUC, 0.80; sensitivity, 0.59; specificity, 0.83). In particular, the diagnostic value was better when the attenuation coefficient guided by B-mode ultrasound was utilized. To screen patients with steatosis of ≥ 5%, attenuation coefficient should be used.

DOI： 10.1007/s10396-022-01196-5

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction-associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM. MATERIALS AND METHODS: We retrospectively assessed 9,459 participants who underwent two or more annual health check-ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non-overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants). RESULTS: The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre-diabetes (P < 0.01). CONCLUSIONS: Fatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.

DOI： 10.1111/jdi.13772

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate whether neutrophil-to-lymphocyte ratio (NLR) can predict outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). METHODS: A total of 249 patients with unresectable HCC treated with Atez/Bev were included. We analyzed survival and discontinuation of this therapy in this cohort. RESULTS: Cumulative overall survival at 2, 4, 6, and 8 months was 97.6%, 94.9%, 88.9%, and 82.8%, respectively. Cumulative overall survival differed significantly between patients with low (<3.0) versus high (≥3.0) NLR (P = 0.001). Conversely, cumulative progression-free survival did not differ between patients with low versus high NLR. The distribution of response was 1.5% for complete response, 17.1% for partial response, 60.5% for stable disease, and 21.0% for progressive disease. Responses were not different between patients with low and high NLR. Regarding adverse events, immune-related liver injury of any grade and grade of at least 3, decreased appetite of any grade, grade of at least 3 proteinuria, and other adverse events of any grade differed significantly between patients with low and high NLR. There were 56, 18, and 2 patients who discontinued Atez/Bev therapy due to progression of disease, adverse event, and other reasons, respectively. The cumulative discontinuation rate for Atez/Bev therapy due to adverse events differed significantly between patients with low versus high NLR (P = 0.022). Cox proportional hazards modeling analysis with inverse probability weighting showed that NLR of at least 3.0 was significantly associated with overall survival (hazard ratio, 3.369; 95% confidence interval, 1.024-11.080). CONCLUSIONS: NLR can predict outcomes in patients with unresectable HCC treated with Atez/Bev.

DOI： 10.1097/MEG.0000000000002356

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Direct-acting antiviral (DAA) therapy enables a high rate of sustained virologic response (SVR) in patients with hepatitis C virus associated cirrhosis. However, the impact of DAA therapy on liver-related events in patients with cirrhosis is unclear. METHODS: A total of 350 patients with compensated and decompensated cirrhosis administered DAA therapy at 29 Japanese hospitals were enrolled (Child-Pugh class A [CP-A]: 195 patients, CP-B: 131 patients and CP-C: 24 patients). RESULTS: The SVR rates of patients with CP-A, CP-B and CP-C were 96.9%, 93.1% and 83.3%, respectively (p = 0.006). Seventy patients developed hepatocellular carcinoma (HCC), and male sex, previous HCC treatment, platelet counts < 10.0 × 104/µl, alpha-fetoprotein levels ≥ 5.0 ng/ml and CP-C were identified as significant factors in the multivariate analysis. The cumulative HCC occurrence/recurrence rates at 1 year were 6.6%/45.2%. The cumulative rate of decompensated cirrhotic events requiring hospital admission at 1 year was 9.1%. In the multivariate analysis, CP-B and CP-C were identified as significant factors. During the median observation period of 14.9 months, 13 patients died and one patient received liver transplant. The overall survival rates at 1 year were 98.4% in patients with CP-A, 96.4% in those with CP-B and 85.6% in those with CP-C (CP-A vs. CP-B: p = 0.759, CP-A vs. CP-C: p = 0.001 and CP-B vs. CP-C: p = 0.005). CONCLUSIONS: HCC development and mortality in patients with CP-B were not different from those with CP-A. On the other hand, in patients with CP-C, the development of HCC and decompensated cirrhotic events requiring hospital admission, and death were frequent. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN000036150).

DOI： 10.1007/s00535-021-01845-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A simple serum biomarker for clinical outcome in patients with ulcerative colitis (UC) remains an unmet need. Some studies have shown an association between C-reactive protein (CRP)-albumin ratio (CAR) and prognosis in patients with inflammatory bowel disease (IBD), but evidence regarding the association between CAR and UC remains limited. We evaluated the association between CAR and clinical outcome in Japanese patients with UC. METHODS: Subjects were 273 Japanese patients with UC. Clinical remission was defined as absence of both abnormally high stool frequency (< 3 per day) and rectal bleeding. Mucosal healing (MH) was defined as Mayo endoscopic subscore (MES) 0. Moderate to severe endoscopic activity was defined as MES 2-3. Subjects were divided according to CAR into tertiles (low, moderate, and high). RESULTS: The proportions of patients with clinical remission, MH, and moderate to severe endoscopic activity were 57.9%, 26.0%, and 37.0%, respectively. High CAR was significantly positively associated with moderate to severe endoscopic activity but not MH or clinical remission after adjustment (adjusted odds ratio [OR] 2.18 [95% confidence interval (CI) (1.11-4.35)], p for trend 0.023), but only in patients with long disease duration (> 7 years) (adjusted OR 2.95 [95% CI (1.06-8.79)], p for trend 0.023). CAR was not associated with clinical remission or MH. CONCLUSIONS: CAR may be significantly positively associated with moderate to severe endoscopic activity but not clinical remission or MH in Japanese patients with UC. In patients with long UC duration, CAR might be a useful serum marker for disease activity.

DOI： 10.1186/s12876-022-02113-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The present study focused on the association of early bevacizumab (Bev) interruption with the clinical outcome of atezolizumab plus bevacizumab. METHODS: This retrospective study included 239 patients with advanced hepatocellular carcinoma receiving atezolizumab/Bev from September 2020 to June 2021 at 16 different institutions in Japan. We conducted a 9-week landmark analysis to investigate the association of Bev interruption due to adverse events with the therapeutic efficacy. RESULTS: The median age was 73.0 (68.0-80.0) years old, with 195 (81.6%) men. The objective response rate was significantly higher in patients without Bev interruption than in those with it (34.5% vs. 17.3%, p = 0.038). The median progression-free survival (PFS) was 6.5 months (95% confidence interval [CI] 4.5-9.7) and 9.0 months (95% CI 7.1-not applicable) in patients with and without Bev interruption, respectively, with statistical significance (p = 0.021). The 12-month overall survival (OS) rates in patients with and without Bev interruption were 49.4% (CI 27.7%-67.9%) and 82.2% (95% CI 70.3%-89.6%), respectively, showing a significant difference (p = 0.004). The presence of Bev interruption was a significant factor associated with the PFS (p = 0.021) and OS (p = 0.008). A multivariate analysis showed that modified albumin-bilirubin 2b (p < 0.001) and later-line treatment (p = 0.018) were unfavorable factors associated with Bev interruption. Liver injury, appetite loss, protein urea, and ascites or hepatic edema were more frequently found in patients with Bev interruption than in those without it. CONCLUSIONS: Early Bev interruption was an unfavorable factor associated with the PFS and OS. Good liver function and treatment settings may be associated with maintaining Bev treatment.

DOI： 10.1111/hepr.13748

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Functional dyspepsia (FD) is a very common disease worldwide. Dysmenorrhea impairs quality of life among females of reproductive age. Although dysmenorrhea is associated with irritable bowel syndrome (IBS), no study has yet evaluated the association between dysmenorrhea and FD. METHODS: This study's subjects consisted of 4693 female Japanese university students. We defined FD according to the Rome III criteria. Subjects completed a self-reported questionnaire regarding menstrual irregularity, menstrual pain, and medication for menstrual pain. Age, body mass index, drinking, smoking, exercise habit, anemia, and first-year student status were selected as potential confounding factors. RESULTS: The prevalence of FD, epigastric pain syndrome (EPS), and postprandial distress syndrome (PDS) was 2.5%, 0.6%, and 2.1%, respectively. Heavy menstrual pain was independently positively associated with FD and PDS but not EPS (adjusted ORs: FD, 3.18 [95% CI: 1.60-6.89] and PDS, 2.93 [95% CI: 1.56-7.93] for heavy menstrual pain, p for trend = 0.001 and 0.004, respectively). Using medication for menstrual pain often was independently positively associated with FD, EPS, and PDS, respectively, (adjusted ORs: FD, 2.41 [95% CI: 1.50-3.83], EPS, 2.93 [95% CI: 1.04-7.93], PDS, 2.44 [95% CI: 1.46-4.01]). Irregular menstrual cycle was not associated with FD or with subtype of FD. CONCLUSION: Among the young female Japanese population, menstrual pain might be independently positively associated with FD and PDS but not EPS. The use of medication for menstrual pain might be independently positively associated with FD including subtype of FD.

DOI： 10.1111/nmo.14324

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Millions of people of the world suffer from chronic hepatitis B (CHB), a pathological entity in which the patients are chronically infected with hepatitis B virus (HBV) and express hepatitis B surface antigen (HBsAg) and HBV DNA, as well as evidence of liver damages. Considerable numbers of CHB patients develop cirrhosis of the liver and hepatocellular carcinoma if untreated. Two groups of drugs (interferons and nucleoside analogs) are used to treat CHB patients, but both are endowed with considerable adverse effects, increased costs, extended duration of therapy, and limited efficacy. Thus, there is a pressing need to develop new and innovative therapeutics for CHB patients, and many such drugs have been developed during the last four decades. Some of these drugs have inspired considerable optimism to be a game-changer for the treatment of CHB. Here, we first discuss why ongoing therapeutics such as interferon and nucleoside analogs could not stand the test of time. Next, we dissect the scope and limitation of evolving therapies for CHB by dissecting the cellular and molecular mechanisms of some of these innovative therapeutics.

DOI： 10.3390/livers2010001

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/id9.0000000000000028

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1111/hepr.13674

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: Patients often do not respond truthfully to physicians' interviews concerning alcohol. Few reports regarding the level of alcohol dependence in patients with chronic liver disease (CLD) have been presented. This study aimed to elucidate severity distribution in patients with CLD using the alcohol use disorders identification test (AUDIT). Methods: From March to June 2022, 2034 Japanese outpatients with CLD, including 415 cases associated with hepatitis C virus, 436 with hepatitis B virus, 173 with alcohol-related liver disease (ARLD), and 1010 with other factors, were interviewed using AUDIT. Clinical features related to alcohol use in these patients were then retrospectively evaluated. Results: In all patients, an AUDIT score 8–14 (harmful use) was noted in 5.8% of hepatitis C virus, 8.9% of hepatitis B virus, 24.3% of ARLD, and 4.4% of other groups, respectively (P < 0.001), while a score ≥15 (dependency) was noted in 3.4%, 3.0%, 27.7%, and 1.9%, respectively (P < 0.001). When the country was divided into regions, the percentages remained similar. Comparisons between patients with and without an AUDIT score ≥8 (n = 1412), performed after exclusion of those without related data (n = 622), showed no significant differences for hepatic reserve function, while those with harmful alcohol use were significantly younger (66 vs. 70 years, P = 0.006) and had a larger percentage of men (80.4% vs. 45.1%, P < 0.001). Conclusion: Harmful alcohol and alcohol dependency were observed in approximately 10% of patients with viral or non-viral CLD, after excluding patients with ARLD. Assessment of alcohol intake by use of the AUDIT questionnaire as well as adequate intervention should be considered necessary.

DOI： 10.1111/hepr.13835

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

DOI： 10.2169/internalmedicine.8736-21

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The objective of the present study was to assess the safety and efficacy of a therapeutic vaccine containing both HBsAg and HBcAg (NASVAC) in patients with chronic hepatitis B (CHB) three years after the end of treatment (EOT) as a follow-up of a phase III clinical trial. NASVAC was administered ten times by the nasal route and five times by subcutaneous injection. A total of 59 patients with CHB were enrolled. Adverse events were not seen in any of the patients. Out of the 59 CHB patients, 54 patients exhibited a reduction in HBV DNA, compared with their basal levels. Although all the patients had alanine transaminase (ALT) above the upper limit of normal (&gt;42 IU/L) before the commencement of therapy, the levels of ALT were within the ULN level in 42 patients. No patient developed cirrhosis of the liver. The present study, showing the safety and efficacy of NASVAC 3 years after the EOT, is the first to report follow-up data of an immune therapeutic agent against CHB. NASVAC represents a unique drug against CHB that is safe, of finite duration, can be administered by the nasal route, is capable of reducing HBV DNA and normalizing ALT, and contains hepatic fibrosis.

DOI： 10.3390/vaccines10010045

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Advanced Hepatocarcinoma (HCC) is an important health problem worldwide. Recently, the REFLECT trial demonstrated the non-inferiority of Lenvatinib compared to Sorafenib in I line setting, thus leading to the approval of new first-line standard of care, along with Sorafenib. AIMS AND METHODS: With aim to evaluate the optimal choice between Sorafenib and Lenvatinib as primary treatment in clinical practice, we performed a multicentric analysis with the propensity score matching on 184 HCC patients. RESULTS: The median overall survival (OS) were 15.2 and 10.5 months for Lenvatinib and Sorafenib arm, respectively. The median progression-free survival (PFS) was 7.0 and 4.5 months for Lenvatinib and Sorafenib arm, respectively. Patients treated with Lenvatinib showed a 36% reduction of death risk (p = 0.0156), a 29% reduction of progression risk (p = 0.0446), a higher response rate (p < 0.00001) and a higher disease control rate (p = 0.002). Sorafenib showed to be correlated with more hand-foot skin reaction and Lenvatinib with more hypertension and fatigue. We highlighted the prognostic role of Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), bilirubin, alkaline phosphatase and eosinophils for Sorafenib. Conversely, albumin, aspartate aminotransferase (AST), alkaline phosphatase and Neutrophil-Lymphocyte Ratio (NLR) resulted prognostic in Lenvatinib arm. Finally, we highlighted the positive predictive role of albumin > Normal Value (NV), ECOG > 0, NLR < 3, absence of Hepatitis C Virus positivity, and presence of portal vein thrombosis in favor of Lenvatinib arm. Eosinophil < 50 and ECOG > 0 negatively predicted the response to Sorafenib. CONCLUSION: SLenvatinib showed to better perform in a real-word setting compared to Sorafenib. More researches are needed to validate the predictor factors of response to Lenvatinib rather than Sorafenib.

DOI： 10.1111/hepr.13718

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.

DOI： 10.1111/jgh.15745

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple. MATERIAL/METHODS: From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child-Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). RESULTS: Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). CONCLUSION: Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.

DOI： 10.1111/hepr.13734

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Monocytes play an important role in innate immunity. Some epidemiological evidence indicates an association between peripheral blood monocytes and ulcerative colitis (UC). The association between peripheral blood monocytes and mucosal healing (MH), however, remains unclear. We evaluated this issue in patients with UC. METHODS: Study subjects consisted of 272 Japanese patients with UC. Monocyte counts were taken in the morning after overnight fasting. Monocyte count was divided into tertiles based on the distribution of values among all study subjects. Information on clinical remission was obtained from medical records. MH was assessed using the Mayo endoscopic subscore. RESULTS: The mean monocyte count was 360.1 ± 155.3/mm3. Rates of clinical remission, MH, and complete MH were 61.0%, 66.2%, and 27.9%, respectively. High monocyte count was significantly inversely associated with clinical remission, MH, and complete MH (adjusted odds ratio [OR] 0.45 [95% confidence interval [CI]: 0.23-0.89], OR 0.45 [95% CI: 0.23-0.89], and OR 0.48 [95% CI: 0.23-0.97], respectively). Patients were also classified according to C-reactive protein (CRP) levels; in the low CRP group (<0.1 mg/dL), high monocyte count was independently inversely associated with complete MH but not with clinical remission or MH (OR 0.33 [95% CI: 0.10-0.92], P for trend = 0.027). In the high CRP group, there was no association between monocyte count and clinical outcomes. DISCUSSION: Our findings suggest that peripheral blood monocyte count can be used as a serum supplemental marker for MH in UC patients with low CRP levels.

DOI： 10.14309/ctg.0000000000000429

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan-Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.

DOI： 10.1038/s41598-021-01465-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Sleep disorder is common in patients with chronic liver disease (CLD). Liver-related silent complications, including muscle cramps, covert hepatic encephalopathy (HE), and sarcopenia, often reduce the quality of life of patients with CLD and have been reported to cause sleep disorders. In this study, we clarified the prevalence of liver-related complications associated with sleep disorders in patients with CLD. METHODS: We conducted a multicenter cohort study of 271 patients with CLD. The Athens Insomnia Scale, muscle cramps questionnaires, and Stroop test were used to assess insomnia, muscle cramps, and covert HE, respectively. In addition, sarcopenia, dynapenia, and myopenia were diagnosed according to the guidelines of the Japan Society of Hepatology. RESULTS: In total, 136 patients (50.2%) had sleep disorders. Serum albumin and hemoglobin levels and prothrombin time activity were significantly lower in patients with sleep disorders than in those without sleep disorders. On univariate and multivariate analyses adjusted with inverse probability weighting, muscle cramps, covert HE, and dynapenia were associated with a sleep disorder. Sleep disorder was categorized as follows: cramp, covert HE, dynapenia, multiple complications, and others. In total, 106 of 136 patients (77.9%) with sleep disorder had at least one liver-related complication, whereas 75 patients had multiple liver-related complications. CONCLUSION: Sleep disorder in patients with CLD was classified into four categories (muscle cramp, covert HE, dynapenia, and others). Questionnaire for sleep disorder might be an easy primary step for surveillance of high-risk patients with silent complications associated CLD.

DOI： 10.1111/hepr.13731

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A phase III clinical trial in treatment-naïve patients with chronic hepatitis B (CHB) revealed the safety and considerable therapeutic efficacy of a vaccine containing both hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) (NASVAC) at the end of treatment (EOT) and 24 weeks after EOT. Two years after EOT, we checked HBV DNA, alanine aminotransferase (ALT), and hepatitis B e antigen (HBeAg). The data reveal that 33 of 66 NASVAC-recipient CHB patients became negative for HBV DNA in the blood two years after EOT. The ALT levels were within the upper limit of normal (ULN) in 37 patients, although all 66 CHB patients had elevated ALT (above ULN) before the start of therapy. Out of the total twelve HBeAg-positive patients, eight patients became negative for HBeAg. None of the patients developed cirrhosis of the liver within this period. NASVAC is a finite treatment regimen with sustained antiviral and liver-protecting properties. This study is the first to report follow-up data of immune therapy for CHB. NASVAC, an immune therapy of finite duration, is endowed with sustained antiviral and liver protection properties in CHB patients.

DOI： 10.3390/pathogens10111440

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

ABSTRACT: Most patients with pancreatic cancer are ineligible for curative resection at diagnosis, resulting in poor prognosis. This study aimed to evaluate the prognostic factors in patients with unresectable pancreatic cancer.We retrospectively collected clinical data from 196 patients with unresectable pancreatic cancer who received palliative chemotherapy (N = 153) or palliative care alone (N = 43) from January 2011 to December 2013. Patients' background data and overall survival were analyzed using the Cox proportional hazard regression model.In patients receiving palliative chemotherapy (gemcitabine-based regimen, 88.2%) and palliative care alone, the median (range) ages were 68 (43-91) and 78 (53-90) years, and metastatic diseases were present in 80% (N = 123) and 86% (N = 37), respectively. Multivariate analysis in the palliative chemotherapy patients showed that liver metastasis (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.58-3.20, P < .001), neutrophil-to-lymphocyte ratio (>4.5 vs ≤4.5; HR 3.45, 95% CI 2.22-5.36, P < .001), and cancer antigen 19-9 (CA19-9) (≥900 vs <900 U/mL; HR 1.45, 95% CI 1.02-2.05, P = .036) were independent prognostic factors. In those receiving palliative care alone, lung (HR 3.27, 95% Cl 1.46-7.35, p = 0.004) and peritoneum (HR 2.50, 95% CI 1.20-5.18, P = .014) metastases and the C-reactive protein-to-albumin ratio (≥1.3 vs <1.3; HR 3.33, 95% Cl 1.51-7.35, P = .003) were independent prognostic factors. Furthermore, patients with multiple factors had worse prognosis in both groups. Median survival time of palliative chemotherapy patients with risk factors 0, 1, 2, and 3 were 13.1 (95% CI 8.0-16.9), 9.4 (95% CI 7.9-10.1), 6.6 (95% CI 4.9-7.8), and 2.5 (95% CI 1.7-4.0) months, respectively. Similarly, median survival time was 5.7 (95% CI 1.3 -8.0), 2.1 (95% CI 1.5-3.9), and 1.3 (95% CI 0.6-1.7) months, respectively, for palliative care alone patients with risk factor 0, 1, and 2 to 3.Prognostic markers for pancreatic cancer were neutrophil-to-lymphocyte ratio, liver metastasis, and CA19-9 in patients undergoing palliative chemotherapy and C-reactive protein-to-albumin ratio and lung/peritoneum metastases in patients undergoing palliative care alone. These simple markers should be considered when explaining the prognosis and therapeutic options to patients.

DOI： 10.1097/MD.0000000000027591

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Evidence regarding the association between sleep disturbance and functional dyspepsia (FD) remains limited in the young population. AIMS: This study aimed to investigate the association between sleep disturbance and FD including subgroups among Japanese young people. METHODS: Study subjects were 8923 university students. FD was defined according to the Rome III criteria. Subjects with FD were further categorized as having postprandial distress syndrome (PDS) or epigastric pain syndrome (EPS). Subjects completed a self-reported questionnaire assessing self-reported sleep duration, sleep disturbance, difficulty falling asleep, deep sleep disorder, nocturnal awakening, early awakening, and daytime sleepiness. RESULTS: The prevalence of FD was 1.9%. After adjustment, all types of sleep disturbances were independently positively associated with FD (total sleep disturbance: OR 4.11 [95% CI: 2.89-5.78], difficulty falling asleep: OR 3.97 [95% CI: 2.53-6.01], deep sleep disorder: OR 4.85 [95% CI: 3.06-7.40], nocturnal awakening: OR 4.35 [95% CI: 1.90-8.67], early awakening: OR 4.50 [95% CI: 1.97-8.97], and daytime sleepiness: OR 2.83 [95% CI: 1.25-5.56]). While nocturnal awakening and daytime sleepiness were not associated with EPS, the other types of sleep disturbance were independently positively associated with EPS and PDS. No association between self-reported sleep duration and FD was found. CONCLUSIONS: Sleep disturbance may be independently positively associated with the prevalence of FD among Japanese young people. Nocturnal awakening and daytime sleepiness were not associated with EPS; the other types of sleep disturbance were independently positively associated with EPS and PDS.

DOI： 10.1007/s10620-021-07260-3

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-四国支部  

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記述言語：日本語   出版者・発行元：(株)南江堂  

＜文献概要＞▼わが国の肝硬変・肝細胞がん患者の多くが高齢者である.▼高用量の利尿薬投与は電解質異常や腎機能増悪の危険性があり,高齢者ではtolvaptanの適用を利尿薬の増量前から検討する.▼高齢者に対する腹水排液は少量から開始し,輸液,アルブミン投与を併用する.▼サルコペニア合併例は分岐鎖アミノ酸製剤を含む栄養療法と運動療法を行う.ただし,運動は軽微な運動から段階的に強度を上げることが望ましい.▼加齢に伴う認知機能低下と肝性脳症の鑑別はしばしば困難である.▼高齢者の肝細胞がんでは,より侵襲の少ない治療が推奨される.個々の症例におけるperformance statusや合併疾患を考慮して,ガイドラインに沿った治療が可能か検討する.

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00974&link_issn=&doc_id=20211004160015&doc_link_id=10.15106%2Fj_naika128_843&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_naika128_843&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Aim: Spleen stiffness measurement (SSM) is useful for assessing portal hypertension. It is unclear whether SSM values are appropriate because vibration-controlled transient elastography (VCTE) does not generate B-mode images. This study aimed to confirm whether the controlled attenuation parameter (CAP) measured in the spleen can predict the accuracy of SSM. Methods: This retrospective study enrolled 349 patients who underwent SSM using VCTE from January 2012 to December 2020. Consecutive patients were classified into the pilot set (SSM and hepatic venous pressure gradient [HVPG] were measured) and the validation set (SSM was measured without HVPG). In the pilot set, scatter plots with a nonparametric contour line were created. Logistic regression analysis was performed to predict outliers outside the 50% contour line. Results: The values of CAP could distinguish the outliers in scatter plots between the HPVG and SSM in both univariate and multivariate analyses (cutoff, 118 dB/m). The correlation of SSM with HVPG (r = 0.718; P < 0.001) was significantly better in the low CAP (≤118 dB/m) group than in the high CAP (>118 dB/m) group (r = 0.330; P < 0.001). The area under the receiver operating characteristic curve of SSM in predicting high-risk varices was better in the low CAP group than in all patients or in the high CAP group in the pilot set (0.881, 0.854, and 0.843, respectively) and in the validation set (0.893, 0.821, and 0.814, respectively). Conclusion: For patients with CAP <118 dB/m, SSM is a feasible predictor of HVPG.

DOI： 10.1002/jgh3.12647

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Open Exploration Publishing  

<jats:p>With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.</jats:p>

DOI： 10.37349/emed.2021.00058

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To validate an appropriate spleen size measurement technique for the prediction of high-risk esophagogastric varices. METHODS: This retrospective cross-sectional study included 369 patients who underwent ultrasonography and computed tomography (CT) of the spleen and esophagogastroduodenoscopy between January 2018 and December 2020. Maximum spleen length, width, and craniocaudal length were measured in a longitudinal view. The two-dimensional (2D) spleen index (maximum length × maximum width in the longitudinal view) was calculated. A three-dimensional (3D) spleen index was then defined as follows: 2D spleen index × maximum length in the transverse view. The similarity in spleen volume measured by CT and ultrasonography (spleen index) was assessed by the correlation coefficient. The diagnostic accuracies of the spleen index, platelet/spleen length, and platelet/spleen index were calculated to determine the overall diagnostic accuracy. RESULTS: Compared to the other spleen indices, our 3D spleen index was significantly better correlated with spleen volume on CT (r = 0.91, 95% confidence interval 0.89-0.92, p < 0.001). Receiver-operating characteristic curve analyses revealed no significant difference between the 3D and 2D indices (p = 0.228) but did show a significant difference between the 3D and one-dimensional indices (p = 0.020). Although the area under the curve for the platelet count combined with the spleen index or length was higher than that for our 3D index, there was no significant difference between platelet count and spleen index or length (p = 0.078). CONCLUSIONS: Platelet/spleen length has a reasonable ability to predict high-risk esophagogastric varices, even though measurement of two or three factors can be correlated with spleen volume.

DOI： 10.1111/hepr.13716

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

＜Key Point＞・「肝硬変診療ガイドライン2020」の栄養療法フローチャートは、実際の栄養指導で利用しやすい流れに改訂された。・蛋白低栄養状態、Child-Pugh分類BまたはC、サルコペニアのいずれかがある肝硬変患者には、分岐鎖アミノ酸を含めた栄養療法を行う。・肝硬変患者の栄養療法では、就寝前軽食や分割食を積極的に取り入れる。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.

DOI： 10.1038/s41598-021-96089-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

ABSTRACT: Rapid response systems (RRS) have been introduced worldwide to reduce unpredicted in-hospital cardiac arrest (IHCA) and in-hospital mortality. The role of advance care planning (ACP) in the management of critical patients has not yet been fully determined in Japan.We retrospectively assessed the characteristics of all inpatients with unpredicted IHCA in our hospital between 2016 and 2018. Yearly changes in the number of RRS activations and the incidence of unpredicted IHCA with or without code status discussion were evaluated from 2014 to 2018. Hospital standardized mortality ratios were assessed from the data reported in the annual reports by the National Hospital Organization.A total of 81 patients (age: 70.9 ± 13.3 years) suffered an unpredicted IHCA and had multiple background diseases, including heart disease (75.3%), chronic kidney disease (25.9%), and postoperative status (cardiovascular surgery, 18.5%). Most of the patients manifested non-shockable rhythms (69.1%); survival to hospital discharge rate was markedly lower than that with shockable rhythms (26.8% vs 72.0%, P < .001). The hospital standardized mortality ratios was maintained nearly constant at approximately 50.0% for 3 consecutive years. The number of cases of RRS activation markedly increased from 75 in 2014 to 274 patients in 2018; conversely, the number of unpredicted IHCA cases was reduced from 40 in 2014 to 18 in 2018 (P < .001). Considering the data obtained in 2014 and 2015 as references, the RRS led to a reduction in the relative risk of unpredicted IHCA from 2016 to 2018 (ie, 0.618, 95% confidence interval 0.453-0.843). The reduction in unpredicted IHCA was attributed partly to the increased number of patients who had discussed the code status, and a significant correlation was observed between these parameters (R2 = 0.992, P < .001). The reduction in the number of patients with end-stage disease, including congestive heart failure and chronic renal failure, paralleled the incidence of unpredicted IHCA.Both RRS and ACP reduced the incidence of unpredicted IHCA; RRS prevents progression to unpredicted IHCA, whereas ACP decreases the number of patients with no code status discussion and thus potentially reducing the patient subgroup progressing to an unpredicted IHCA.

DOI： 10.1097/MD.0000000000026856

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記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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記述言語：英語  

We report a case of rupture of a synchronous metastatic liver tumor secondary to a thymoma. A 56-year-old woman was referred to our hospital with acute abdomen. Computed tomography (CT) revealed a 10 cm diameter tumor in the left lateral segment of the liver, together with ascites, which was suggestive of intra-abdominal bleeding. She was in stable condition and hemostasis was confirmed by angiography. CT also revealed a mass in the anterior mediastinum. Elective laparoscopic left lateral segmentectomy was performed to make a pathological diagnosis and for radical resection. No peritoneal dissemination was observed and the liver tumor was curatively resected. The patient subsequently underwent thymectomy. The pathological diagnoses were thymoma with the liver metastasis. Currently, at 30 months post-treatment, she has had no tumor recurrence. Rupture of a metastatic liver tumor secondary to a thymoma is a rare condition; careful preoperative management and aggressive treatment might improve the patient's prognosis.

DOI： 10.1093/jscr/rjab341

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the impact on survival of modified albumin-bilirubin (mALBI) grade versus Child-Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child-Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944-3.141 and HR, 2.178; 95%CI, 1.591-2.982]. In patients with a Child-Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083-3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child-Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child-Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child-Pugh classification in patients with unresectable HCC who received lenvatinib therapy.

DOI： 10.1038/s41598-021-93794-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome. METHODS: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS). RESULTS: The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277). CONCLUSIONS: Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.

DOI： 10.1111/liv.15014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocellular carcinoma has been considered to disseminate through the tumor blood drainage area. To improve curation rates, treatment should cover this area as it may contain satellite lesions. This retrospective study aimed to investigate whether radiofrequency ablation (RFA) completely covering the blood drainage area can improve the overall and disease-free survival. We enrolled 526 patients who underwent computed tomography during hepatic arteriography following RFA from April 2001 to May 2019. Patients were categorized into a covered group in which the blood drainage area was completely covered by RFA and a noncovered group in which coverage was incomplete. The primary endpoint was the overall survival rate; secondary outcomes included disease-free survival rate, distant intrahepatic and local recurrence rate, and changes in the Child-Pugh score. There were no significant differences in baseline characteristics between the two groups. Cumulative overall survival rates were significantly higher in the covered group than in the noncovered group (hazard ratio, 0.63; 95% confidence interval, 0.48-0.84; P = 0.002). On multivariate Cox proportional hazard model analysis, age <65 years, Child-Pugh class A, and coverage of the entire drainage area were independent protective factors. Child-Pugh worsened in 11 (4.2%) patients in the covered group compared to 18 (6.7%) patients in the noncovered group. Conclusion: RFA covering the complete drainage area improved overall survival without decreasing liver function.

DOI： 10.1002/hep4.1703

PubMed

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