Faculty Profiles - ITO Takanori

Papers - ITO Takanori

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Patients with low muscle mass have characteristic microbiome with low potential for amino acid synthesis in chronic liver disease. Open Access

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

Scientific reports Vol. 12 ( 1 ) page： 3674 2022.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Sarcopenia is thought to be related to the microbiome, but not enough reports in chronic liver disease (CLD) patients. In addition to the differences in microbiome, the role of the microbiome in the gut is also important to be clarified because it has recently been shown that the microbiome may produce branched-chain amino acids (BCAAs) in the body. In this single-center study, sixty-nine CLD patients were divided by skeletal muscle mass index (SMI) into low (L-SMI: n = 25) and normal (N-SMI: n = 44). Microbiome was analyzed from stool samples based on V3-4 region of bacterial 16S rRNA). L-SMI had a lower Firmicutes/Bacteroidetes ratio than N-SMI. At the genus level, Coprobacillus, Catenibacterium and Clostridium were also lower while the Bacteroides was higher. Predictive functional profiling of the L-SMI group showed that genes related to nitrogen metabolism were enriched, but those related to amino acid metabolism, including BCAA biosynthesis, were lower. The genes related to 'LPS biosynthesis' was also higher. The microbiome of CLD patients with low muscle mass is characterized not only by high relative abundance of gram-negative bacteria with LPS, but also by the possibility of low potential for amino acid synthesis including BCAAs.

DOI： 10.1038/s41598-022-07810-3

Absence of large portal collateral vessels is associated with spontaneous improvement of cirrhotic portal vein thrombosis.

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

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 52 ( 2 ) page： 199 - 209 2022.2

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

Aim: Portal vein thrombosis (PVT) is a major complication in patients with liver cirrhosis (LC). In some cases, PVT decreases spontaneously, but the factors that predict this are still not fully understood. Methods: This was a retrospective, multicenter study that included 77 consecutive patients with cirrhotic PVT. Forty-eight patients did not undergo anticoagulation and 29 patients did between the time of the first diagnosis of PVT and the follow-up radiological imaging undertaken 1–6 months later. A complete disappearance and 25% shrinkage of PVT was defined as complete remission (CR) and partial remission (PR), respectively. Portosystemic collateral vessels larger than 9 mm in diameter were defined as large collateral vessels. Results: Complete remission + PR was found in 37.5% of the anticoagulation-naïve patients. On univariate analysis, the absence of large collateral vessels, absence of PVT in the main trunk of the portal vein, a high platelet count, and a low FIB-4 index were significant factors associated with CR + PR. On multivariate analysis, the absence of large collateral vessels was the unique factor associated with CR + PR of PVT (odds ratio 5.9; 95% confidence interval, 1.73–20.1). The CR + PR rate for anticoagulated patients was 44.8%. However, no predictors for a good treatment effect of anticoagulation for PVT were identified. Conclusions: Spontaneous improvement of PVT in patients with LC can be expected when large collateral vessels are absent. For these patients, the option of observing them without anticoagulation can be considered in expectation of spontaneous reduction of PVT.

DOI： 10.1111/hepr.13725

Immune-related Liver Injury is a Poor Prognostic Factor in Patients with Nonsmall Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Yamamoto T, Ito T, Hase T, Ishigami M, Mizuno K, Yamamoto K, Imai N, Ishizu Y, Honda T, Shibata H, Hatta T, Yogo N, Yasuda S, Toyoda H, Abe T, Kawashima H, Hashimoto N, Fujishiro M

Cancer investigation Vol. 40 ( 2 ) page： 189 - 198 2022.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Cancer Investigation

It remains unclear whether severe liver immune-related adverse events (liver-irAEs) can affect the prognosis in nonsmall cell lung carcinoma (NSCLC) patients. Of the 365 NSCLC patients treated with immune checkpoint inhibitors (ICIs), 19 suffered from severe liver-irAEs (grade ≥3). The median time-to-onset of liver-irAEs was 53 days postinjection of the first ICI. The progression-free survival and overall survival of the liver-irAEs group (median 69 and 262 days, respectively) were significantly worse than the nonliver-irAEs group (128 and 722 days; P = 0.010 and P = 0.007; respectively). In conclusion, liver-irAEs were associated with poor prognosis in NSCLC patients.

DOI： 10.1080/07357907.2021.1994586

The influence of hepatitis C virus eradication on hepatocarcinogenesis in patients with hemophilia. Open Access

Inukai Y, Imai N, Yamamoto K, Ito T, Ishizu Y, Honda T, Okamoto S, Kanematsu T, Suzuki N, Matsushita T, Ishigami M, Fujishiro M

Annals of hepatology Vol. 27 ( 1 ) page： 100545 2022.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Annals of Hepatology

Introduction and objectives: Hepatitis C virus (HCV) infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. Although recent progress in direct-acting-antivirals has facilitated a high rate of sustained virological response (SVR), the clinical influence of HCV eradication in hemophilia patients remains unclear. This study aimed to compare the clinical outcomes of SVR against HCV in patients with and without hemophilia. Patients and methods: The study enrolled 699 patients who achieved SVR after HCV antiviral treatment. Patients were divided into two groups: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). We evaluated patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR. Results: Compared with the NH group, patients in the H-group were significantly younger and had a lower hepatic fibrosis score. No difference was found in the incidence of liver-related disease or overall death between the two groups over a mean follow-up period of 7 years. Four patients in the H group and 36 patients in the NH group were diagnosed with HCC after SVR. Multivariate analysis showed that male sex, age, and cirrhosis were significant risk factors for HCC incidence. There was no significant difference in the cumulative incidence of HCC after propensity-score matching adjusting for the risk factors of HCC between the two groups. Conclusion: Hemophilia is not a significant risk factor for hepatocarcinogenesis after SVR against HCV.

DOI： 10.1016/j.aohep.2021.100545

Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study. Reviewed

Matsumoto K, Ohfuji S, Abe M, Komori A, Takahashi A, Fujii H, Kawata K, Noritake H, Tadokoro T, Honda A, Asami M, Namisaki T, Ueno M, Sato K, Kakisaka K, Arakawa M, Ito T, Tanaka K, Matsui T, Setsu T, Takamura M, Yasuda S, Katsumi T, Itakura J, Sano T, Tamura Y, Miura R, Arizumi T, Asaoka Y, Uno K, Nishitani A, Ueno Y, Terai S, Takikawa Y, Morimoto Y, Yoshiji H, Mochida S, Ikegami T, Masaki T, Kawada N, Ohira H, Tanaka A

Journal of gastroenterology Vol. 57 ( 1 ) page： 19 - 29 2022.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Gastroenterology

Background: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case–control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case–control study to identify the environmental factors associated with the development of PBC in Japan. Methods: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. Results: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01–2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07–1.92), ever smoking (OR, 1.70; 95% CI, 1.28–2.25), and hair dye use (OR, 1.57; 95% CI, 1.15–2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99–19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077–0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52–68.0) in the model for medical and familial factors. Conclusions: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.

DOI： 10.1007/s00535-021-01836-6

Mortality of inactive hepatitis B virus carriers in Japan is similar to that of the general population.

Kumada T, Toyoda H, Yasuda S, Ito T, Tanaka J

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 52 ( 1 ) page： 81 - 92 2022.1

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

Aims: Data on the long-term outcomes of individuals with hepatitis B virus (HBV) infection who are hepatitis envelope antigen (HBeAg)-negative inactive carriers (ICs) are limited due to small numbers. We compared the long-term prognosis of well-defined ICs with that of age- and gender-matched general population controls. Methods: A total of 526 HBeAg-negative patients who demonstrated alanine aminotransferase (ALT) level ≤40 U/L and HBV DNA level ≤4.3 log IU/ml at least three times within 1 year after the start of follow-up were enrolled as ICs. Inactive carriers were divided into two groups: Group A (n = 332), whose ALT level was ≤30 U/L and HBV DNA level was ≤3.3 log IU/ml, and Group B (remaining patients, n = 194). We determined the long-term prognosis of ICs and compared it with that of general population controls. We also analyzed factors associated with hepatitis B surface antigen (HBsAg) clearance and phase transition in ICs. Results: There were no significant differences in hepatocellular carcinoma development or all-cause, liver-related, or non–liver-related mortality between Groups A and B. There was no significant difference in all-cause mortality between ICs and the general population. Low HBsAg level (≤3.0 log IU/ml) and the presence of fatty liver were associated with HBsAg clearance and high alpha-fetoprotein level was associated with phase transition. Conclusions: The long-term prognosis of well-defined ICs was similar to that of general population controls. In addition, the ICs had a high HBsAg clearance rate and low phase transition rate.

DOI： 10.1111/hepr.13723

Changes in Body Composition Predict the Time to Treatment Failure of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma: A Pilot Retrospective Study.

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

Nutrition and cancer Vol. 74 ( 9 ) page： 3118 - 3127 2022

Language：English Publishing type：Research paper (scientific journal) Publisher：Nutrition and Cancer

Aim: Changes in body composition parameters are important prognostic factors in hepatocellular carcinoma (HCC) treatment. This study aimed to assess the clinical impact of early changes in body composition during lenvatinib (LEN) treatment on its time to treatment failure (TTF) for patients with advanced HCC. Methods: In this retrospective study, we enrolled 65 patients who were administered LEN as the first-line treatment for unresectable HCC and evaluated the body composition change using computed tomography. We focused on the body composition change after 2 weeks of LEN treatment and assessed its impact on TTF and prognosis. Results: Significant changes in body composition were observed during 14 weeks of LEN treatment. Among these changes, mean-skeletal muscle attenuation (SMA) decreased significantly within 2 weeks (P = 0.004) without symptoms or changes in the other parameters. In multivariate analysis, this early change in mean-SMA after LEN treatment was a significant predictor of time to treatment failure (HR: 2.67, 95%CI: 1.338–5.081, P = 0.005) in patients with HCC. Conclusions: This study revealed that LEN treatment induces a change in the skeletal muscle asymptomatically for a short period, and evaluation of this change may help to predict the TTF of LEN treatment in patients with HCC. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2049322.

DOI： 10.1080/01635581.2022.2049322

先天性フィブリノゲン異常症患者に合併した多発動脈血栓の一例

服部真代, 笹木優賢, 鈴木伸明, 石津洋二, 荒木芳生, 岩﨑純子, 新島萌, 山本健太, 伊藤隆徳, 川嶋啓揮, 古澤健司, 松下正

超音波検査技術抄録集 Vol. 47 ( 0 ) page： S137 - S137 2022

Changes in the gut microbiota after hepatitis C virus eradication. Open Access

Honda T, Ishigami M, Yamamoto K, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Kawashima H, Miyahara R, Ishikawa T, Hirooka Y, Fujishiro M

Scientific reports Vol. 11 ( 1 ) page： 23568 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

DOI： 10.1038/s41598-021-03009-0

Impact of switching to tenofovir alafenamide fumarate in patients with entecavir-treated chronic hepatitis B.

Kumada T, Toyoda H, Yasuda S, Ito T, Tanaka J

European journal of gastroenterology & hepatology Vol. 33 ( 1S Suppl 1 ) page： e898 - e904 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Gastroenterology and Hepatology

Background and aims Tenofovir alafenamide (TAF), a new tenofovir prodrug, has been developed to circumvent the less favorable safety profile of tenofovir disoproxil fumarate (TDF). We investigated reductions in hepatitis B surface antigen (HBsAg) levels in patients with HBV infection who received continuous entecavir (ETV) monotherapy or sequential therapy with ETV and TAF. Methods: This retrospective cohort study included 286 patients who were divided into two groups: continuous ETV monotherapy (ETV group, n = 168) and sequential therapy with ETV and TAF (ETV-TAF group, n = 108). Factors associated with a 90% reduction in HBsAg levels were analyzed by a Cox proportional hazards model using a time-dependent covariate in both groups. Results In the multivariate Cox proportional hazards model, the ETV-TAF group [adjusted hazard ratio (aHR) 2.750; 95% confidence interval (CI), 1.265-3.405; P = 0.0038] and BMI ≤ 25.0 kg/m<sup>2</sup>(aHR 0.520, 95% CI, 0.308-0.875; P = 0.0139) demonstrated a 90% reduction in HBsAg levels. HBsAg levels of patients in the TAF phase in the ETV-TAF group showed greater yearly percent reductions than those in the ETV group and those in the ETV phase in the ETV-TAF group (P = 0.0361 and P = 0.0022, respectively, Steel-Dwass test). Conclusion HBsAg levels decreased more rapidly after patients switched from ETV to TAF. Switching to TAF may be an effective treatment option to reduce HBsAg levels.

DOI： 10.1097/MEG.0000000000002292

Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis. Open Access

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

European journal of gastroenterology & hepatology Vol. 33 ( 1S Suppl 1 ) page： e916 - e921 2021.12

Obesity and myosteatosis: The two characteristics of dynapenia in patients with cirrhosis Open Access

Sugiyama Y., Ishizu Y., Ando Y., Yokoyama S., Yamamoto K., Ito T., Imai N., Nakamura M., Honda T., Kawashima H., Ishikawa T., Ishigami M.

European Journal of Gastroenterology and Hepatology Vol. 33 ( 1 ) page： E916 - E921 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：European Journal of Gastroenterology and Hepatology

Objective In patients with liver cirrhosis, the clinical characteristics of dynapenia, a condition in which skeletal muscle mass is maintained but muscle strength is reduced, are not yet known. This study aimed to clarify the characteristics of dynapenia and its impact on quality of life (QOL) in patients with liver cirrhosis. Methods We retrospectively analyzed 116 patients with cirrhosis. Based on grip strength and skeletal muscle mass measured by the bioelectrical impedance analysis method, patients were divided into four groups: normal muscle status, dynapenia, pre-sarcopenia (a condition involving only low muscle mass), and sarcopenia. The characteristics of dynapenia and its influence on QOL were examined. Results Fourteen patients had dynapenia. Liver function did not differ among the four groups. In patients with dynapenia, BMI was highest and computed tomography attenuation of skeletal muscle at the third lumbar spine vertebra was lowest among the four groups. The percentage of patients with both BMI ≥25 kg/m<sup>2</sup>and myosteatosis was significantly higher in patients with dynapenia [9/14 (64.3%)] than in those with sarcopenia [2/23 (8.7%), P = 0.004] and pre-sarcopenia [0/18 (0%), P < 0.001] and tended to be higher than those with normal muscle status [16/61 (26.2%), P = 0.065]. The physical QOL in patients with dynapenia was as low as that in those with sarcopenia and significantly lower than that in those with normal muscle status. Conclusion Cirrhotic patients with dynapenia had high BMI and myosteatosis, and impaired physical QOL.

DOI： 10.1097/MEG.0000000000002303

Cationic surface charge effect on proliferation and protein production of human dental pulp stem cells cultured on diethylaminoethyl-modified cellulose porous beads Reviewed

Oki Yuichiro, Harano Kodai, Hara Yuichi, Sasajima Yoshiyuki, Sasaki Ryo, Ito Takanori, Fujishiro Mitsuhiro, Ito Taichi

BIOCHEMICAL ENGINEERING JOURNAL Vol. 176 2021.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical Engineering Journal

Human adult dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells (MSCs). Recently, DPSCs have been proposed as a new MSC source for treating immune-mediated, inflammatory, and degenerative diseases via cell-based therapy. Hence, large-scale industrial production of the required cell number will be necessary. In this study, to investigate the cationic surface charge effect on DPSC proliferation, we fabricated two types of 2-diethylaminoethyl -modified cellulose porous beads (CPB-DEAE) with different ion exchange capacities. The cationic surface charge effect increased with increase in DPSC proliferation rate for the ion exchange capacity of 0.55–1.82 meq/g. However, the DPSC proliferation rate decreased at 2.50 meq/g. Thus, the optimal ion exchange capacity was determined to be 1.82 meq/g for DPSC proliferation. Additionally, the total amount of protein produced from the DPSCs on the CPB-DEAE microcarriers was higher than that produced under the conventional monolayer culture conditions. Furthermore, the hepatocyte growth factor, which is one of the anti-inflammatory growth factors, was produced from the DPSCs on the CPB-DEAE microcarriers. Finally, the DPSCs were confirmed to maintain their proliferative and multidifferentiation ability after culture on the CPB-DEAE microcarriers. CPB-DEAE microcarriers have the potential to be used for large-scale MSC expansion and protein production.

DOI： 10.1016/j.bej.2021.108217

Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis Open Access

Sugiyama Yoshiaki, Ishizu Yoji, Ando Yusuke, Yokoyama Shinya, Yamamoto Kenta, Ito Takanori, Imai Norihiro, Nakamura Masanao, Honda Takashi, Kawashima Hiroki, Ishikawa Tetsuya, Ishigami Masatoshi

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY Vol. 33 ( 1S ) page： E916 - E921 2021.12

Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis Open Access

Sugiyama, Y; Ishizu, Y; Ando, Y; Yokoyama, S; Yamamoto, K; Ito, T; Imai, N; Nakamura, M; Honda, T; Kawashima, H; Ishikawa, T; Ishigami, M

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY Vol. 33 page： E916 - E921 2021.12

Microbiome, fibrosis and tumor networks in a non-alcoholic steatohepatitis model of a choline-deficient high-fat diet using diethylnitrosamine.

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

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver Vol. 53 ( 11 ) page： 1443 - 1450 2021.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Digestive and Liver Disease

Background & aims: Hepatocellular carcinoma in nonalcoholic steatohepatitis is caused by the complex factors of inflammation, fibrosis and microbiomes. We used network analysis to examine the interrelationships of these factors. Methods: C57Bl/6 mice were categorized into groups: choline-sufficient high-fat (CSHF, n = 8), choline-deficient high-fat (CDHF, n = 9), and CDHF+ diethylnitrosamine (DEN, n = 8). All mice were fed CSHF or CDHF for 20 weeks starting at week 8, and mice in the CDHF + DEN group received one injection of DEN at 3 weeks of age. Bacterial gene was isolated from feces and analyzed using Miseq. Results: The CSHF group had less fibrosis than the other groups. Tumors were found in 22.2% and 87.5% of the CDHF group and CDHF + DEN groups, respectively. Gene expression in the liver of Cdkn1a (p21: tumor-suppressor) and c-jun was highest in the CDHF group. Bacteroides, Roseburia, Odoribacter, and Clostridium correlated with fibrosis. Streptococcus and Dorea correlated with inflammation and tumors. Akkermansia and Bilophila were inversely correlated with fibrosis and Bifidobacterium was inversely correlated with tumors. Conclusions: DEN suppressed the overexpression of p21 caused by CDHF. Some bacteria formed a relationship networking associated with their progression and inhibition for tumors and fibrosis.

DOI： 10.1016/j.dld.2021.02.013

Safety and Efficacy of Glass Membrane Pumping Emulsification Device in Transarterial Chemoembolization for Hepatocellular Carcinoma: First Clinical Outcomes. Open Access

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

Anticancer research Vol. 41 ( 11 ) page： 5817 - 5820 2021.11

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

Aim: Novel glass membrane pumping emulsification devices (GMDs) enable the formation of a high-percentage water-in-oil emulsion with homogeneous and stable droplets. Although GMDs are expected to improve therapeutic effects in transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), clinical outcomes are not yet available. Patients and Methods: A total of 26 patients with unresectable HCC who underwent TACE using a GMD were analyzed retrospectively. Ethiodized oil was mixed with epirubicin solution using a GMD. The emulsion was injected into the tumor-feeding artery, followed by embolization. Results: The median size of HCCs was 28 (range=15-60) mm, and 15 nodules were solitary. Overall treatment effects were complete response in 18 cases (90%) and partial response in two (10%). The local recurrence rate at 6 months was 24.2%. No major complication was observed except for grade 4 elevations of liver enzymes in one case. Conclusion: TACE using a GMD is effective and safe in clinical practice.

DOI： 10.21873/anticanres.15399

Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis. Open Access

Ryuge A, Kosugi T, Maeda K, Banno R, Gou Y, Zaitsu K, Ito T, Sato Y, Hirayama A, Tsubota S, Honda T, Nakajima K, Ozaki T, Kondoh K, Takahashi K, Kato N, Ishimoto T, Soga T, Nakagawa T, Koike T, Arima H, Yuzawa Y, Minokoshi Y, Maruyama S, Kadomatsu K

JCI insight Vol. 6 ( 20 ) 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Jci Insight

Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane–selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

DOI： 10.1172/jci.insight.142464

Factors associated with bleeding after endoscopic variceal ligation in children. Open Access

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

Pediatrics international : official journal of the Japan Pediatric Society Vol. 63 ( 10 ) page： 1223 - 1229 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatrics International

Background: Endoscopic variceal ligation (EVL) is a widely accepted treatment for esophagogastric varices in patients with portal hypertension (PHT). It is used for urgent treatment and prophylactic treatment of esophagogastric varices in pediatric as well as adult patients. However, major life-threatening adverse events such as early rebleeding can occur. Although early rebleeding after EVL among children and adolescents has been reported, the risk factors remain obscure. This study evaluated the risk factors for early rebleeding after EVL in children and adolescents. Methods: The subjects were children and adolescents (<18 years) with PHT who underwent EVL for esophagogastric varices. Early rebleeding was defined as hematemesis, active bleeding, or blood retention in the stomach, confirmed by esophagogastroduodenoscopy from 2 h to 5 days after EVL. Results: A total of 50 EVL sessions on 22 patients were eligible for this study. There were four episodes of early rebleeding. No other major adverse event has occurred. Multivariate analysis showed that EVL implemented at cardiac varices just below the esophagogastric junction (EGJ), within 5 mm from the EGJ, is the independent factor for a higher risk of early rebleeding: odds ratio 18.2 (95% confidence interval: 1.40–237.0), P = 0.02. Conclusions: Children and adolescents who undergo EVL for cardiac varices just below the EGJ have a higher risk of early rebleeding than those who do not.

DOI： 10.1111/ped.14614

Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies. Open Access

Ito T, Ishigami M, Yamamoto T, Mizuno K, Yamamoto K, Imai N, Ishizu Y, Honda T, Kawashima H, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Kato M, Hashimoto N, Hibi H, Kodera Y, Sone M, Ando Y, Akiyama M, Shimoyama Y, Fujishiro M

Hepatology international Vol. 15 ( 5 ) page： 1278 - 1287 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Hepatology International

Background: The clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury. Methods: We evaluated the characteristics and clinical course of immune-related liver injury in 1214 patients treated with ICIs for advanced malignancies except for hepatocellular carcinoma between August 2014 and May 2021. Results: During the follow-up period (median, 252 days), 58 patients (4.8%) had an immune-related liver injury (≥ Grade 3). The liver-injury patterns were hepatocellular (n = 26, 44.8%), mixed (n = 11, 19.0%), or cholestatic (n = 21, 36.2%), and the median time to onset of liver injury was 39, 81, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (p = 0.047). Corticosteroids were administered to 30 (51.7%) patients; while liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns, and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20. Conclusion: The incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differ according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed.

DOI： 10.1007/s12072-021-10238-y

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