研究者詳細 - 伊藤　隆徳

論文 - 伊藤　隆徳

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Significance of pretreatment alpha-fetoprotein in patients with compensated severe fibrosis after hepatitis C viral eradication.

Ishigami M, Honda T, Ishizu Y, Imai N, Ito T, Yamamoto K, Kawashima H

Journal of hepato-biliary-pancreatic sciences 30 巻 ( 6 ) 頁： 834 - 842 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Hepato Biliary Pancreatic Sciences

Background: We aimed to investigate the factors associated with improvement of liver functional reserve after sustained virological response using interferon-free, direct-acting antiviral combination treatment in patients with compensated, severe fibrosis. Methods: Between September 2014 and April 2020, 492 patients received direct-acting antiviral combination treatment in our hospital. Among them, 173 patients who had severe fibrosis based on a fibrosis-4 index ≥3.25, showed sustained virological response after treatment. We investigated the dynamic change in albumin-bilirubin score and the baseline factors associated with its improvement, 48 weeks after treatment. Results: The baseline significant factors associated with albumin-bilirubin ≦ −0.5 were lower albumin (HR: 15.625, 95% CI: 4.273–58.824, P <.001), higher hepatitis C virus RNA (HR: 4.995, 95% CI: 1.882–13.260, P =.001), and higher alpha-fetoprotein (HR: 1.033, 95% CI: 1.011–1.055, P =.003). Patients with alpha-fetoprotein ≧10 ng/mL showed significant improvement of albumin-bilirubin score from baseline to 48 weeks after treatment compared to those with alpha-fetoprotein <10 ng/mL (P <.001). Conclusions: Baseline serum alpha-fetoprotein might be a predictive factor for improvement of liver function after sustained virological response in patients with severe fibrosis.

DOI： 10.1002/jhbp.1309

Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis. Open Access

Yamamoto T, Mizuno K, Ito T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Ishikawa T, Kanamori A, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Ishii M, Sone M, Ando Y, Akiyama M, Ishigami M, Kawashima H

Investigational new drugs 41 巻 ( 3 ) 頁： 512 - 521 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Investigational New Drugs

Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.

DOI： 10.1007/s10637-023-01366-3

Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma.

Yamauchi R, Ito T, Yoshio S, Yamamoto T, Mizuno K, Ishigami M, Kawashima H, Yasuda S, Shimose S, Iwamoto H, Yamazoe T, Mori T, Kakazu E, Kawaguchi T, Toyoda H, Kanto T

Journal of gastroenterology 58 巻 ( 6 ) 頁： 565 - 574 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gastroenterology

Background: Combination therapy with anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for un-resectable hepatocellular carcinoma (uHCC). We aimed to identify predictive circulating biomarkers for the outcome/response of the combination therapy in uHCC patients. Methods: This prospective multicenter study enrolled 70 patients with uHCC who received atezolizumab and bevacizumab (Atez/Bev). We evaluated 47 circulating proteins in sera before and after 1 and 6 weeks of Atez/Bev therapy by multiplex bead-based immunoassay and ELISA. As controls, we analyzed the sera from 62 uHCC patients before treatment of lenvatinib (LEN) and healthy volunteers (HVs). Results: The disease control rate was 77.1%. Median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI] = 3.8–9.5). The pretreatment levels of osteopontin (OPN), angiopoietin-2, VEGF, S100–calcium-binding protein A8/S100–calcium-binding protein A9, soluble programmed cell death-1, soluble CD163, and 14 cytokines/chemokines were higher in patients with uHCC than in HVs. Among these, pretreatment OPN levels were higher in PD group than in non-PD group for Atez/Bev. The PD rate was higher in high OPN group than in low OPN group. Multivariate analysis identified high pretreatment OPN and high α‐fetoprotein levels as independent predictors of PD. In the sub-analysis of Child–Pugh class A patients, PFS was also shorter in the high OPN group than in the low OPN group. Pretreatment OPN level was not associated with treatment response for LEN. Conclusion: High serum OPN levels were associated with poor response to Atez/Bev in patients with uHCC.

DOI： 10.1007/s00535-023-01985-w

Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma. Open Access

Mizuno K, Imai N, Yamamoto T, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Kuzuya T, Ishigami M, Kawashima H

Cancers 15 巻 ( 10 ) 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancers

Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

DOI： 10.3390/cancers15102853

Distinct features of two lipid droplets types in cell nuclei from patients with liver diseases. Open Access

Imai N, Ohsaki Y, Cheng J, Zhang J, Mizuno F, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Ishizu Y, Honda T, Ishigami M, Wake H, Kawashima H

Scientific reports 13 巻 ( 1 ) 頁： 6851 2023年4月

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

Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

DOI： 10.1038/s41598-023-33977-4

Poor Diagnostic Efficacy of Noninvasive Tests for Advanced Fibrosis in Obese or Younger Than 60 Diabetic NAFLD patients. 国際共著 Open Access

Ito T, Nguyen VH, Tanaka T, Park H, Yeh ML, Kawanaka M, Arai T, Atsukawa M, Yoon EL, Tsai PC, Toyoda H, Huang JF, Henry L, Jun DW, Yu ML, Ishigami M, Nguyen MH, Cheung RC

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 21 巻 ( 4 ) 頁： 1013 - 1022.e6 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Gastroenterology and Hepatology

Background & Aims: Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized. Methods: We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM. Results: By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P = .001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P = .002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (>60 years), nonobese (BMI <25 kg/m<sup>2</sup>), and non-diabetic patients, although overall the best performance was observed with FIB-4 among nonobese (BMI<25) diabetic patients (AUROC, 0.92). The worst performance was observed in younger patients with T2DM for all NITs including FIB-4 (AUROC, 0.63–0.66). Conclusions: FIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients.

DOI： 10.1016/j.cgh.2022.05.015

Proteomic Analysis Reveals Changes in Tight Junctions in the Small Intestinal Epithelium of Mice Fed a High-Fat Diet. Open Access

Muto H, Honda T, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Maeda K, Ishikawa T, Adachi S, Sato C, Tsuji NM, Ishigami M, Fujishiro M, Kawashima H

Nutrients 15 巻 ( 6 ) 2023年3月

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

The impact of a high-fat diet (HFD) on intestinal permeability has been well established. When bacteria and their metabolites from the intestinal tract flow into the portal vein, inflammation in the liver is triggered. However, the exact mechanism behind the development of a leaky gut caused by an HFD is unclear. In this study, we investigated the mechanism underlying the leaky gut related to an HFD. C57BL/6J mice were fed an HFD or control diet for 24 weeks, and their small intestine epithelial cells (IECs) were analyzed using deep quantitative proteomics. A significant increase in fat accumulation in the liver and a trend toward increased intestinal permeability were observed in the HFD group compared to the control group. Proteomics analysis of the upper small intestine epithelial cells identified 3684 proteins, of which 1032 were differentially expressed proteins (DEPs). Functional analysis of DEPs showed significant enrichment of proteins related to endocytosis, protein transport, and tight junctions (TJ). Expression of Cldn7 was inversely correlated with intestinal barrier function and strongly correlated with that of Epcam. This study will make important foundational contributions by providing a comprehensive depiction of protein expression in IECs affected by HFD, including an indication that the Epcam/Cldn7 complex plays a role in leaky gut.

DOI： 10.3390/nu15061473

Prevalence, characteristics, and mortality outcomes of obese and nonobese MAFLD in the United States. 国際共著

Dao AD, Nguyen VH, Ito T, Cheung R, Nguyen MH

Hepatology international 17 巻 ( 1 ) 頁： 225 - 236 2023年2月

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

Background and aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) establishes new criteria for diagnosis of fatty liver disease independent of alcohol intake. We aimed to describe the prevalence and compare characteristics and mortality outcomes of persons with nonobese and obese MAFLD. Methods: Using data from 13,640 participants from the third National Health and Nutrition Examination Survey (NHANES III) 1988–1994, we identified participants with fatty liver on ultrasound who had MAFLD and analyzed them by the presence of obesity. Results: Overall prevalence of MAFLD was 19%; amongst those, 54% were obese and 46% were nonobese. Nonobese MAFLD was more common in participants older than 65 than in younger participants (56.8% vs. 43.2%, p < 0.0001). Nonobese MAFLD was more common in males (63.2% vs. 48.3%, p < 0.0001). Obese MAFLD was more common in females (51.7% vs. 48.3%, p < 0.0001). After adjusting for several demographic factors and alcohol use, older age [adjusted odds ratio (aOR) 1.02, 95% CI 1.00–1.02, p = 0.003] and being male (aOR: 1.65, 95% CI 1.25–2.17, p = 0.001) were independent risk factors for nonobese MAFLD. Nonobese MAFLD participants had a higher 20-year cumulative incidence for all-cause mortality compared to obese MAFLD participants (33.2% vs. 28.8%, p = 0.0137). However, nonobese MAFLD was not independently associated with mortality after adjusting for relevant confounders, while FIB-4 > 1.3 and cardiovascular disease were the strongest risk factors associated with increased mortality [adjusted hazard ratio (aHR) > 2.7 for both, p < 0.0001 for both]. Conclusions: Nonobese MAFLD constitutes about half of the MAFLD in the United States, especially among males and the elderly. Notably, nonobese MAFLD carries higher mortality than obese MAFLD. Screening and diagnosis of MAFLD should be considered in nonobese populations.

DOI： 10.1007/s12072-022-10436-2

Renal Outcomes With Tenofovir Alafenamide in Liver Transplant Recipients 国際共著 Open Access

Liu J.K., Vutien P., Huang D.Q., Ishigami M., Landis C.S., Nguyen M.H., Daniel P.C.Y.N., Ito T., Dang H., Maeda M., Leong J.

Clinical Gastroenterology and Hepatology 21 巻 ( 2 ) 頁： 538 - 540.e4 2023年2月

Endoscopic injection sclerotherapy with polidocanol for cardiac varices in children and adolescents. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Hinoki A, Sumida W, Shirota C, Tainaka T, Makita S, Yokota K, Uchida H, Ishigami M

Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 30 巻 ( 2 ) 頁： 109 - 112 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives De Pediatrie

Background: Like esophageal varices, cardiac varices are often treated with endoscopic variceal ligation (EVL). However, we previously reported that EVL for cardiac varices may be associated with a high risk of rebleeding from the ulcer if the O-ring spontaneously drops off early. The efficacy and safety of para-variceal endoscopic injection sclerotherapy (EIS) with polidocanol for the treatment of cardiac varices in children and adolescents were evaluated. Methods: Eleven patients under 18 years of age with portal hypertension who underwent para-variceal EIS with polidocanol for cardiac varices with red signs, which were considered to be at high risk of bleeding, were retrospectively reviewed. Results: One session of para-variceal polidocanol-EIS was performed for each of the 11 patients. One patient experienced temporary hypoxia due to aspiration of saliva when the tracheal intubation tube was removed after the procedure but recovered by endotracheal suctioning; there were no other adverse events. In six of the eight cases in which efficacy could be evaluated, eradication of cardiac varices was achieved. Conclusion: Para-variceal polidocanol-EIS may be considered instead of EVL for small cardiac varices with red signs in pediatric patients with cardiac varices.

DOI： 10.1016/j.arcped.2022.11.016

Clustering using unsupervised machine learning to stratify the risk of immune-related liver injury.

Yamamoto T, Morooka H, Ito T, Ishigami M, Mizuno K, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Yokota K, Hase T, Maeda O, Hashimoto N, Ando Y, Akiyama M, Kawashima H

Journal of gastroenterology and hepatology 38 巻 ( 2 ) 頁： 251 - 258 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gastroenterology and Hepatology Australia

Background and Aim: Immune-related liver injury (liver-irAE) is a clinical problem with a potentially poor prognosis. Methods: We retrospectively collected clinical data from patients treated with immune checkpoint inhibitors between September 2014 and December 2021 at the Nagoya University Hospital. Using an unsupervised machine learning method, the Gaussian mixture model, to divide the cohort into clusters based on inflammatory markers, we investigated the cumulative incidence of liver-irAEs in these clusters. Results: This study included a total of 702 patients. Among them, 492 (70.1%) patients were male, and the mean age was 66.6 years. During the mean follow-up period of 423 days, severe liver-irAEs (Common Terminology Criteria for Adverse Events grade ≥ 3) occurred in 43 patients. Patients were divided into five clusters (a, b, c, d, and e). The cumulative incidence of liver-irAE was higher in cluster c than in cluster a (hazard ratio [HR]: 13.59, 95% confidence interval [CI]: 1.70–108.76, P = 0.014), and overall survival was worse in clusters c and d than in cluster a (HR: 2.83, 95% CI: 1.77–4.50, P < 0.001; HR: 2.87, 95% CI: 1.47–5.60, P = 0.002, respectively). Clusters c and d were characterized by high temperature, C-reactive protein, platelets, and low albumin. However, there were differences in the prevalence of neutrophil count, neutrophil-to-lymphocyte ratio, and liver metastases between both clusters. Conclusions: The combined assessment of multiple markers and body temperature may help stratify high-risk groups for developing liver-irAE.

DOI： 10.1111/jgh.16038

The presence of high-risk varices after sclerotherapy in biliary atresia. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Shirota C, Tainaka T, Sumida W, Makita S, Takimoto A, Nakagawa Y, Takada S, Ishigami M, Uchida H, Kawashima H

Pediatrics international : official journal of the Japan Pediatric Society 65 巻 ( 1 ) 頁： e15454 2023年1月

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

Background: Esophagogastric varices (EGVs) may develop as a result of portal hypertension in children with biliary atresia (BA). Although endoscopic injection sclerotherapy (EIS) with ethanolamine oleate (EO) is reported useful for children, risk factors associated with the presence of high-risk EGVs after treatment remain unknown. Methods: The subjects were BA patients under 15 years of age who underwent EO-EIS. We retrospectively reviewed a total of 28 treatment sessions of EGVs with red signs and those larger than F2, which were considered to be at high risk of bleeding. Survival analysis was performed for the presence of high-risk EGVs at the time of follow-up endoscopy as the occurrence of an event. Results: Univariate analysis showed a significantly increased risk of the presence of high-risk EGVs post-EO-EIS in patients with increased liver stiffness (LS) and Mac-2 binding protein glycan isomer (M2BPGi), with hazard ratios of 1.48 and 1.15, respectively. The median presence-free period was significantly shorter in the LS ≥ 2.8 m/s patients than in those with LS <2.8 m/s (189 vs. 266 days). Similarly, the median presence-free period was significantly shorter in patients with M2BPGi ≥ 4.0 than in those with M2BPGi < 4.0 (182 vs. 203 days). The results of multivariate analysis revealed that the risk of the presence of high-risk EGVs was significantly higher only in the high-LS group, with a hazard ratio of 2.76. Conclusions: Increased LS is associated with risk of the presence of high-risk EGVs following EO-EIS in children with BA.

DOI： 10.1111/ped.15454

Bulevirtide and tenofovir combination therapy for hepatitis D virus infection: longer treatment and more diverse trial populations are needed. 国際共著

Ito T, Nguyen MH

The Lancet. Infectious diseases 23 巻 ( 1 ) 頁： 14 - 16 2023年1月

Astaxanthin Attenuates Nonalcoholic Steatohepatitis with Downregulation of Osteoprotegerin in Ovariectomized Mice Fed Choline-Deficient High-Fat Diet.

Zhao M, Ma L, Honda T, Kato A, Ohshiro T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Tsuji NM, Ishigami M, Fujishiro M

Digestive diseases and sciences 68 巻 ( 1 ) 頁： 155 - 163 2023年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Digestive Diseases and Sciences

Background: Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma. Aims: This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH. Methods: Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2. Results: The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells. Conclusions: Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH. Graphical Abstract: [Figure not available: see fulltext.].

DOI： 10.1007/s10620-022-07489-6

Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes. 国際共著 Open Access

Ito T, Nguyen MH

Journal of hepatocellular carcinoma 10 巻頁： 413 - 428 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

DOI： 10.2147/JHC.S347959

Differences in the Intestinal Microbiome Associated with Diarrhea during Lenvatinib Treatment for Hepatocellular Carcinoma. Open Access

Inukai Y, Yamamoto K, Honda T, Ito T, Imai N, Ishizu Y, Nakamura M, Kawashima H, Ishigami M

Digestive diseases (Basel, Switzerland) 41 巻 ( 1 ) 頁： 138 - 147 2023年

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

Introduction: Lenvatinib has been widely used for the treatment of advanced hepatocellular carcinoma (HCC). Some adverse events, including diarrhea, have been reported for lenvatinib. Diarrhea may be associated with the changes in the intestinal microbiome; however, the underlying mechanism has not been elucidated. Aim: In this study, we aimed to investigate the relationship between the intestinal microbiome and diarrhea caused by lenvatinib via analysis of fecal samples collected before treatment. Methods: A total of 21 patients with advanced HCC who were treated with lenvatinib were enrolled. Fecal samples were collected from patients. The patients were divided into diarrhea (n = 8) and nondiarrhea groups (n = 12). We compared the characteristics of patients, incidence of adverse events, composition of the intestinal microbiome, and enrichment of functional pathways between both groups using QIIME2 and PICRUSt2. Results: The median age of the two groups was 73 years. The nondiarrhea group comprised a relatively higher number of male patients than the diarrhea group; however, there were no significant differences in patient characteristics between both groups. The proportion of the microbiome was similar, and alpha and beta diversities were not significantly different between both groups. The relative abundance of order Bacteroidales, including Parabacteroides and Prevotella, was higher in the diarrhea group than in the nondiarrhea group. PICRUSt2 analysis showed some metabolic pathways, including butanoate (butyrate) metabolism, were enriched in the nondiarrhea group when compared with those in the diarrhea group. Conclusion: Differences in the intestinal microbiomes and their functions may influence the incidence of diarrhea during lenvatinib treatment.

DOI： 10.1159/000524298

Relationship between low-back pain and flexibility in children: A cross-sectional study. Open Access

Ito T, Sugiura H, Ito Y, Narahara S, Natsume K, Takahashi D, Noritake K, Yamazaki K, Sakai Y, Ochi N

PloS one 18 巻 ( 11 ) 頁： e0293408 2023年

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

Low-back pain is common among school-aged children. Decreased trunk flexibility in childhood influences low-back pain in adulthood. Previous studies examining the association between low-back pain and trunk flexibility in children are insufficient. Examining this association among elementary school children may help to better understand trunk flexibility in children with low-back pain and to modify the management of inflexibility. Therefore, this study aimed to identify the prevalence of low-back pain and its relationship with physical function among elementary school students. School-aged children aged 6–12 years were recruited in Japan between May 2018 and March 2023. Fingertip-to-floor distance, back muscle strength, pelvic tilt angle during gait, and the visual analog scale for low-back pain were measured. In addition, factors independently related to low-back pain were determined through logistic regression analysis. Low-back pain was reported in 9.6% of the 394 participants (boys, 191; girls, 203). All children with low-back pain presented with back pain when they moved; however, the pain was non-specific. Logistic regression analysis showed that the fingertip-to-floor distance was an independent risk factor for low-back pain (odds ratio, 0.921; p = 0.007). The odds ratios calculated in the logistic regression analysis confirmed that low-back pain frequency increased as the fingertip-to-floor distance decreased. The risk of low-back pain was associated with inflexibility, regardless of sex and muscle strength. These findings suggest that children with low-back pain must increase their trunk and lower extremity flexibility.

DOI： 10.1371/journal.pone.0293408

寄生虫感染による孤立性壊死性結節の一例

服部真代, 伊藤隆徳, 山本健太, 水野史崇, 佐藤浩司, 松原宏紀, 石津洋二, 石川卓哉, 古澤健司, 服部昌志, 川嶋啓揮

超音波検査技術抄録集 48 巻 ( 0 ) 頁： S207 - S207 2023年

Pipeline Esophagogastric Varices Secondary to Extrahepatic Portal Vein Obstruction Treated Endoscopically with the Assistance of Transileocolic Obliteration. Open Access

Yokoyama S, Ishizu Y, Honda T, Imai N, Ito T, Yamamoto K, Komada T, Hayashi M, Ishigami M

Internal medicine (Tokyo, Japan) 61 巻 ( 23 ) 頁： 3503 - 3511 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本内科学会

Endoscopic injection sclerotherapy (EIS) for esophagogastric varices (EGV) was attempted for a 29-yearold man with extrahepatic portal vein obstruction. However, pipeline varices characterized by a large blood flow volume were present, and the sclerosant did not accumulate sufficiently in them. Transileocolic obliteration (TIO) using coils was performed, but some EGVs and palisading veins remained. Thus, EIS was performed once again immediately after TIO. Since a reduction in the intravariceal blood flow was achieved by preceding TIO, effective injection of sclerosant into the vessels was possible. For pipeline varices difficult to treat endoscopically, combination therapy with TIO may be effective.

DOI： 10.2169/internalmedicine.9404-22

Factors associated with the progression of myosteatosis in patients with cirrhosis. Open Access

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Fujishiro M

Nutrition (Burbank, Los Angeles County, Calif.) 103-104 巻頁： 111777 2022年11月

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

Objectives: The presence of myosteatosis is one factor associated with poor prognosis for patients with cirrhosis; however, the factors contributing to worsening myosteatosis are, to our knowledge, unknown. The aim of this study was to clarify the changes in myosteatosis, and the factors involved in these changes. Methods: The present study enrolled 178 patients with cirrhosis who underwent computed tomography twice to measure changes in skeletal muscle attenuation (SMA) at the L3 level. Factors associated with SMA and those associated with changes in SMA were examined. Results: Using linear multiple regression analysis, age (β = –0.22), skeletal muscle index (SMI; skeletal muscle area divided by height squared; β = 0.25), and visceral and subcutaneous fat indices (VFI and SFI; the visceral and subcutaneous fat areas at the umbilical level divided by height squared; β = –0.08, β = –0.06, respectively) were identified as associated with SMA. The 100-d change in SMA was –0.21 ± 1.29 Hounsfield units (HU). Changes in SMI and SMA were positively associated (R = 0.183, P = 0.014), whereas those in VFI and SMA were negatively associated (R = –0.172, P = 0.022). No association was noted between the 100-d changes in SFI and SMA. In patients whose SMI increased and VFI decreased, the 100-d change in SMA was 0.24 ± 1.82 HU, which was marginally different from that in patients whose SMI decreased and VFI increased (–0.44 ± 1.32 HU, P = 0.077). Conclusions: In patients with cirrhosis, myosteatosis progressed, and decreases in SMI and increases in VFI were correlated with its progression.

DOI： 10.1016/j.nut.2022.111777

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