Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Small-Bowel Lesions in Patients Taking Direct Oral Anticoagulants Detected Using Capsule Endoscopy

Yamaoka M., Imaeda H., Hosoe N., Yoneno K., Kanno R., Mitsufuji T., Sasaki T., Akiyama Y., Ohgo H., Morohoshi Y., Kanai T., Yamamoto T., Mimura T., Ogata H., Araki N., Yamamoto K., Nakamoto H.

Gastroenterology Research and Practice (Gastroenterology Research and Practice) 2020 2020

ISSN 16876121

Background and Aim. Direct oral anticoagulant- (DOAC-) induced small-bowel lesions have not been described. We evaluated small-bowel lesions related to DOAC using video capsule endoscopy (VCE). Methods. This study was a prospective, open-label, nonblinded, multicenter, and observational study. From September 2013 to March 2017, patients taking DOACs were enrolled. Patients underwent VCE. The type and location of small-bowel lesions were registered. Also, (1) the proportion of lesions detected between types of DOAC was evaluated and (2) the hemoglobin (Hb) and serum ferritin levels were compared between patients with and without small-bowel lesions. Results. 33 patients were enrolled, but 4 patients withdrew their consent, and VCE was performed on 29 patients. Eight, 13, and 8 patients received dabigatran, rivaroxaban, and apixaban, respectively. Small-bowel transit was complete in 27 of 29 patients (93.1%). Small-bowel lesions were detected in 23 (79.3%), redness in 12 (41.4%), erosions in 14 (48.3%), and angioectasia in 3 (10.3%) patients, and 6 patients (20.7%) had no abnormalities. Redness and erosions were detected in the upper, middle, or lower portions, but erosions tended to be less frequent in the middle portion (p=0.25, 0.06). Angioectasia was not detected in the lower portion. No patients had active bleeding. The findings did not differ according to the drug. The relationships between the endoscopic findings and the Hb and serum ferritin levels were not significant. Conclusion. Many patients taking DOACs had small-bowel lesions; however, most lesions were relatively mild. Observing small-bowel lesions over longer periods may be necessary in patients taking DOACs. This trial is registered with UMIN000011527.

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Of infliximab with long-term administration in Japanese patients with Crohn's disease: Analysis using population pharmacokinetics

Matsuoka K., Hamada S., Shimizu M., Nanki K., Mizuno S., Kiyohara H., Arai M., Sugimoto S., Iwao Y., Ogata H., Hisamatsu T., Nagauma M., Kanai T., Mochizuki M., Hashiguchi M.

International Journal of Clinical Pharmacology and Therapeutics (International Journal of Clinical Pharmacology and Therapeutics) 58 ( 2 ) 89 - 102 2020

ISSN 09461965

Objective: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration. Materials and methods: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX. Results: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATInegative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group. Conclusion: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.

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Multiple immune-related adverse events and anti-tumor efficacy: Real-world data on various solid tumors

Shimozaki K., Sukawa Y., Beppu N., Kurihara I., Suzuki S., Mizuno R., Funakoshi T., Ikemura S., Tsugaru K., Togasaki K., Kawasaki K., Hirata K., Hayashi H., Hamamoto Y., Takaishi H., Kanai T.

Cancer Management and Research (Cancer Management and Research) 12 4585 - 4593 2020

Purpose: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice. Patients and Methods: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model. Results: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33–0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346–0.647; P < 0.0001). Conclusion: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.

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External drainage of bile and pancreatic juice after endoscopic submucosal dissection for duodenal neoplasm: Feasibility study (with video)

Fukuhara S., Kato M., Iwasaki E., Machida Y., Tamagawa H., Kawasaki S., Sasaki M., Kiguchi Y., Takatori Y., Matsuura N., Nakayama A., Ogata H., Kanai T., Yahagi N.

Digestive Endoscopy (Digestive Endoscopy) 2020

ISSN 09155635

Background and Aims: Endoscopic submucosal dissection (ESD) for superficial duodenal epithelial tumors (SDETs) is technically difficult and has a high risk of adverse events. Endoscopic nasobiliary and nasopancreatic duct drainage (ENBPD) may reduce the risk of delayed adverse events by preventing exposure of the post-ESD mucosal defect to bile and pancreatic juice. This study was performed to evaluate the safety and feasibility of ENBPD after duodenal ESD. Methods: Patients who underwent ESD for SDETs from July 2010 to March 2020 were included. We collected data on the success rate of ENBPD, adverse events due to insertion of a side-viewing endoscope, and pancreatitis after ENBPD. We also collected the clinical outcomes of duodenal ESD, including the incidence rate of delayed adverse events (defined as bleeding or perforation found after the endoscopic procedure). Results: Among 70 patients without complete closure of the post-ESD mucosal defect, ENBPD was successfully performed in all 25 patients including 21 cases inserted immediately after ESD and four cases inserted later. There were no adverse events associated with ENBPD procedure intraoperatively, while pancreatitis after ENBPD occurred in four patients (16.0%). No patients who underwent immediate ENBPD required intervention for an intra-abdominal abscess or delayed perforation, whereas 3 of 49 patients (6.1%) who did not undergo immediate ENBPD required surgery or drainage of an abscess. Conclusions: Endoscopic nasobiliary and nasopancreatic duct drainage is technically feasible and might provide effective prophylaxis for delayed adverse events, even if a large mucosal defect is present after ESD.

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Characteristics of the Mucosal Surface on Scanning Electron Microscopy in Patients with Remitting Ulcerative Colitis

Nomura E., Sujino T., Hosoe N., Yoshimatsu Y., Tanemoto S., Takabayashi K., Mutaguchi M., Shimoda M., Naganuma M., Ogata H., Kanai T.

Digestive Diseases and Sciences (Digestive Diseases and Sciences) 2020

ISSN 01632116

Background: Ulcerative colitis (UC) is characterized by chronic intestinal epithelial damage, and previous studies have evaluated the epithelial structure of patients with active UC using electron microscopy. Aims: This study aimed to assess the intestinal epithelial structure using scanning electron microscopy (SEM) and the features of patients with UC who are in remission. Methods: In total, eight healthy controls and 20 patients with UC were enrolled, and colonic tissue samples from the cecum and rectum were collected. Then, we compared the epithelial surface structure on SEM between patients with UC who are in clinical remission and healthy controls. Results: In healthy controls, the colonic surface comprises small lobes (termed units), with one crypt located in the middle of each unit. In patients with UC, we found irregular unit and crypt mouth size, double crypt sign (> 1 crypt per unit), and lower number of small vesicles in the intestinal epithelial cells. Compared with healthy controls, patients with UC often presented with irregular unit size, double crypt sign, and irregular crypt mouth size in the rectum. The small vesicles were observed less frequently in patients with UC than in healthy controls. Conclusions: SEM revealed a unique epithelial structure in patients with UC who are in remission.

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A case of intrahepatic cholangiocellular carcinoma due to thorotrast deposition, well-controlled by radiofrequency ablation therapy

Taniki N., Nakamoto N., Yoshida A., Chu P.S., Ikura A., Yamataka K., Morikawa R., Shiba S., Yamaguchi A., Usui S., Ojiro K., Ebinuma H., Saito H., Kubota N., Masugi Y., Sakamto M., Kanai T.

Acta Hepatologica Japonica (Acta Hepatologica Japonica) 61 ( 5 ) 262 - 269 2020

ISSN 04514203

An 87-year-old man with an enlarged hepatic tumor was referred to our institute by a medical examination center. He had been diagnosed with a malignant liver tumor through several contrast imaging studies. Because of the patient’s age, the underlying disease, and the absence of bile duct invasion on imaging, radiofrequency ablation (RFA) was selected as a treatment option. A histological examination during the RFA procedure revealed the tumor to be a cholangiocellular carcinoma. In addition, the deposition of Thorotrast, a contrast agent used in the 1930s to 1950s, was suspected in the background liver collected simultaneously. Radiofrequency ablation was performed twice for recurrent lesions, and the tumor was controlled for roughly 3 years following the initial treatment. A case of intrahepatic cholangiocellular carcinoma due to Thorotrast deposition was observed and successfully controlled by RFA. Since intrahepatic cholangiocellular carcinoma from Thorotrast deposition occurs multicentrically and intrahepatically, RFA and other local therapies may present effective options for older patients with cholangiocarcinoma who are at a higher risk of surgical resection intolerance.

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Erratum: Leucine-rich Alpha-2 Glycoprotein is a Serum Biomarker of Mucosal Healing in Ulcerative Colitis (Journal of Crohn's and Colitis DOI: 10.1093/ecco-jcc/jjw132)

Shinzaki S., Matsuoka K., Iijima H., Mizuno S., Serada S., Fujimoto M., Arai N., Koyama N., Morii E., Watanabe M., Hibi T., Kanai T., Takehara T., Naka T.

Journal of Crohn's and Colitis (Journal of Crohn's and Colitis) 13 ( 12 ) 2019.12

ISSN 18739946

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The relationship between gut microbiome, immune system, and cancer

Ichikawa M., Sujino T., Kanai T.

Japanese Journal of Cancer and Chemotherapy (Japanese Journal of Cancer and Chemotherapy) 46 ( 12 ) 1807 - 1813 2019.12

ISSN 03850684

Various microbes having been living in our intestine and forming the gut microbiome. When dysbiosis which is typically characterized by reduced microbial diversity occurs, many types of diseases are triggered in our bodies. Recently, relationship between gut microbiome and our immune function are discovered gradually. From this view point, the gut microbiome may have an influence on cancer medicine such as development, therapy (immune checkpoint blockade or chemotherapy), and therapeutic toxicity. In real clinical practice, this influence is reported in some cases such as colorectal cancer and other malignancies. In the near future, the approach from gut microbiome may be a clue to improve the existent cancer diagnosis and therapy. In addition, the modulation of gut microbiome in itself, for example fecal microbiota transplant (FMT), probiotics, and limited usage of antibiotics, is expected to be hints for cancer medicine, though this is not yet established and further studies are needed.

広範な潰瘍性病変を呈したアメーバ性大腸炎の一例

津軽開, 高林馨, 南木康作, 野田まりん, 林由紀恵, 下嵜啓太郎, 平田賢郎, 福原佳代子, 三上洋平, 水野慎大, 加藤元彦, 正岡建洋, 細江直樹, 長沼誠, 緒方晴彦, 金井隆典

Progress of Digestive Endoscopy ((一社)日本消化器内視鏡学会-関東支部) 95 ( 1 ) 126 - 128 2019.12

ISSN 1348-9844

症例は63歳男性で、2年前より自然軽快する水様性下痢を繰り返していたが、2週間前からの血性下痢が軽快せず発熱や食事摂取困難を伴ったため入院した。血液検査では炎症反応上昇、低栄養、低Ig血症を認め、下部消化管内視鏡(CS)では全大腸に渡り粘稠度の高い白苔が付着した不整形潰瘍を全周性に認め、遠位結腸は一部正常粘膜が介在し回腸末端は異常を認めなかった。入院第5病日に生検検体および便塗抹検査にてアメーバ原虫を検出し、アメーバ性大腸炎と診断した。メトロニダゾールを10日間、その後パロモマイシンを7日間投与し、入院第17病日に退院した。退院3ヵ月後のCSで潰瘍は消失したが脾彎曲に小潰瘍を伴った浮腫性狭窄が残存し、退院9ヵ月後のCSでは狭窄部以外の全大腸の治癒を確認した。狭窄箇所の生検からはアメーバ原虫は検出されなかった。

Intramucosal poorly differentiated and signet-ring cell components in patients with ulcerative colitis-associated high-grade dysplasia

Sugimoto S., Shimoda M., Iwao Y., Mutaguchi M., Nanki K., Mizuno S., Kameyama K., Ogata H., Naganuma M., Kanai T.

Digestive Endoscopy (Digestive Endoscopy) 31 ( 6 ) 706 - 711 2019.11

ISSN 09155635

© 2019 Japan Gastroenterological Endoscopy Society Despite the rarity of colorectal poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig), they are more frequent in patients with ulcerative colitis (UC). However, little is known about these components of early colitis-associated cancer due to the difficulty of detection at an early stage. Here, we reviewed colitis-associated high-grade dysplasia/cancer with Por/Sig components within the submucosa among 103 lesions of 79 UC patients who presented between 1997 and 2017. In total, one Sig in situ, three intramucosal and two submucosal carcinomas (8.7%) were identified among 69 lesions within the submucosa. Depressed appearance, loss of crypt architecture and amorphous surface pattern suggested the presence of Por/Sig, rather than submucosal infiltration. All lesions were located in the rectosigmoid colon and included high-grade dysplasia. While the surrounding noncancerous mucosa expressed E-cadherin and MUC5AC, the expression of E-cadherin was reduced and the expression of MUC5AC was negative in all of the carcinomas except for the Sig in situ. The gastric type metaplasia associated with altered MUC5AC profiles may be a sign of the stepwise accumulation of molecular alterations, including TP53 defects and a reduced expression level of E-cadherin.

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Pancreatic fat content may increase the risk of imaging progression in low-risk branch duct intraductal papillary mucinous neoplasm

Kashiwagi K., Minami K., Seino T., Hirata K., Iwasaki E., Inoue N., Iwao Y., Kanai T.

Journal of Digestive Diseases (Journal of Digestive Diseases) 20 ( 10 ) 557 - 562 2019.10

ISSN 17512972

© 2019 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd Objective: To identify risk factors of imaging progression (increase in cyst size or main pancreatic duct size, or a new mural nodule) in low-risk branch duct intraductal papillary mucinous neoplasm (BD-IPMN), including obesity-related factors such as pancreatic fat content. Methods: Our hospital databases were searched for patients who had completed health checkup, including upper abdominal magnetic resonance imaging (MRI) over 48 months (August 2012 to July 2016). Individuals with BD-IPMN without worrisome features and high-risk stigmata who underwent surveillance with at least one follow-up MRI, irrespective of the follow-up period, were included. Pancreatic computed tomography attenuation indexes were defined as the difference between the pancreas and spleen attenuation (P - S) and the pancreas to spleen attenuation ratio (P/S). Results: Among 75 patients diagnosed as having low-risk BD-IPMN, during a median follow-up of 36 months, 11 (15%) had imaging progression in cyst size, including two with worrisome features. A multivariate logistic analysis showed that the initial cyst size and both indexes (P - S, or P/S) were significantly associated with imaging progression in IPMN, respectively (Model 1: odds ratio [OR] 1.188, 95% confidence interval [CI] 1.060-1.331, P = 0.003; OR 0.871, 95% CI 0.776-0.977, P = 0.019; Model 2: OR 1.186, 95% CI 1.064-1.322, P = 0.002; OR 0.002, 95% CI 0.000-0.970, P = 0.049). Conclusions: Pancreatic fat content and initial cyst size were significantly associated with imaging progression in low-risk BD-IPMN. Revisions of international consensus Fukuoka guidelines might be customized based on initial cyst size and pancreatic fat content.

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Concerns and Side Effects of Azathioprine During Adalimumab Induction and Maintenance Therapy for Japanese Patients With Crohn's Disease: A Subanalysis of a Prospective Randomised Clinical Trial [DIAMOND Study

Hisamatsu T., Matsumoto T., Watanabe K., Nakase H., Motoya S., Yoshimura N., Ishida T., Kato S., Nakagawa T., Esaki M., Nagahori M., Matsui T., Naito Y., Kanai T., Suzuki Y., Nojima M., Watanabe M., Hibi T.

Journal of Crohn's & colitis (Journal of Crohn's & colitis) 13 ( 9 ) 1097 - 1104 2019.09

ISSN 18739946

Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. BACKGROUND: Combining a thiopurine with the human anti-tumour necrosis factor-α monoclonal antibody adalimumab for Crohn's disease [CD] treatment is controversial with regard to efficacy and safety. By conducting a subanalysis of a multicentre, randomised, prospective, open-label trial [the DIAMOND study, UMIN registration number 000005146], we studied the risk of discontinuation of thiopurine in combination with adalimumab. METHODS: In the preceding DIAMOND study, we analysed the: [i] timing and reasons for dropout in the monotherapy group and combination group; [ii] risk factors for dropout in the combination group. RESULTS: There was no significant difference in the dropout rate up to Week 52 between the monotherapy group and combination group [p = 0.325]. The main reason for study dropout was active CD in the monotherapy group, whereas it was adverse effects in the combination group [Fisher's exact test, p <0.001]. Kaplan-Meier analyses revealed significantly earlier dropout in the combination group [log-rank test, p = 0.001]. Multivariable analysis revealed low body weight to be a risk for dropout due to adverse effects in the combination group. CONCLUSIONS: Combination of azathioprine with adalimumab resulted in dropout in the early stage of the study due to side effects of azathioprine, in comparison with late dropout due to active CD in the adalimumab monotherapy group.

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Difference in the clinical characteristic and prognosis of colitis-associated cancer and sporadic neoplasia in ulcerative colitis patients

Mutaguchi M., Naganuma M., Sugimoto S., Fukuda T., Nanki K., Mizuno S., Hosoe N., Shimoda M., Ogata H., Iwao Y., Kanai T.

Digestive and Liver Disease (Digestive and Liver Disease) 51 ( 9 ) 1257 - 1264 2019.09

ISSN 15908658

© 2019 Editrice Gastroenterologica Italiana S.r.l. Background: Although various studies have been conducted on colitis-associated cancer (CAC), few have assessed the differences in the clinical and endoscopic features, treatment, and prognosis of CAC and sporadic neoplasia (SN) in the inflamed mucosa of ulcerative colitis (UC) patients. Aims: To compare the characteristics of CAC and SN within the previously or currently inflamed mucosa. Methods: Between 1997 and 2017, we retrospectively analyzed the endoscopic chart data of 348 colonic lesions from 266 UC patients. Non-dysplastic lesions and lesions located outside the inflamed mucosa were excluded. The diagnosis of CAC or SN was confirmed by conventional histopathological and immunohistochemical evaluation of p53 and Ki67. Results: In total, 74 patients with CAC (97 lesions) and 46 with SN (58) were enrolled. The proportions of patients with a younger age of onset of UC, with chronic persistent UC, and with severe inflamed mucosa were significantly higher in the CAC group. In the SN group, no flat lesions were found, whereas 26% of the lesions in the CAC group were flat. Sixteen patients died during a median follow-up of 6.1 years (interquartile range (IQR) 1.8–11.1)in the CAC group, whereas 1 patient died during a median follow-up 3.2 years(IQR 1.4–4.6) in the SN group. Mortality from colorectal cancer was significantly higher (P = 0.015) in the CAC group (12/68; 17.6%) than in the SN group (1/44; 2.3%). The 5-year survival rate was 100% in the SN group and 97% in the CAC group for lesions located in the mucosa or submucosa. Conclusion: Recognizing differences in the characteristics of CAC and SN within the inflamed mucosa is critical to avoid unnecessary total colectomy in patients with SN.

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Sustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: A systematic review and meta-analysis

Ji F., Yeo Y., Wei M., Ogawa E., Enomoto M., Lee D., Iio E., Lubel J., Wang W., Wei B., Ide T., Preda C., Conti F., Minami T., Bielen R., Sezaki H., Barone M., Kolly P., Chu P., Virlogeux V., Eurich D., Henry L., Bass M., Kanai T., Dang S., Li Z., Dufour J., Zoulim F., Andreone P., Cheung R., Tanaka Y., Furusyo N., Toyoda H., Tamori A., Nguyen M.

Journal of Hepatology (Journal of Hepatology) 71 ( 3 ) 473 - 485 2019.09

ISSN 01688278

© 2019 European Association for the Study of the Liver Background & Aims: The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) infection remains unclear. Using a systematic review and meta-analysis approach, we aimed to investigate the effect of DAA therapy on sustained virologic response (SVR) among patients with CHC and either active, inactive or no HCC. Methods: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from 1/1/2013 to 9/24/2018. The pooled SVR rates were computed using DerSimonian-Laird random-effects models. Results: We included 49 studies from 15 countries, comprised of 3,341 patients with HCC and 35,701 without HCC. Overall, the pooled SVR was lower in patients with HCC than in those without HCC (89.6%, 95% CI 86.8–92.1%, I2 = 79.1% vs. 93.3%, 95% CI 91.9–94.7%, I2 = 95.0%, p = 0.0012), translating to a 4.8% (95% CI 0.2–7.4%) SVR reduction by meta-regression analysis. The largest SVR reduction (18.8%) occurred in patients with active/residual HCC vs. inactive/ablated HCC (SVR 73.1% vs. 92.6%, p = 0.002). Meanwhile, patients with HCC who received a prior liver transplant had higher SVR rates than those who did not (p <0.001). Regarding specific DAA regimens, patients with HCC treated with ledipasvir/sofosbuvir had lower SVR rates than patients without HCC (92.6%, n = 884 vs. 97.8%, n = 13,141, p = 0.026), but heterogeneity was high (I2 = 84.7%, p <0.001). The SVR rate was similar in patients with/without HCC who were treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 101) (97.2% vs. 94.8%, p = 0.79), or daclatasvir/asunaprevir (91.7% vs. 89.8%, p = 0.66). Conclusion: Overall, SVR rates were lower in patients with HCC, especially with active HCC, compared to those without HCC, though heterogeneity was high. Continued efforts are needed to aggressively screen, diagnose, and treat HCC to ensure higher CHC cure rates. Lay summary: There are now medications (direct-acting antivirals or “DAAs”) that can “cure” hepatitis C virus, but patients with hepatitis C and liver cancer may be less likely to achieve cure than those without liver cancer. However, patients with liver cancer are also more likely to have advanced liver disease and risk factors that can decrease cure rates, so better controlled studies are needed to confirm these findings.

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Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

Koda Y., Nakamoto N., Chu P., Ugamura A., Mikami Y., Teratani T., Tsujikawa H., Shiba S., Taniki N., Sujino T., Miyamoto K., Suzuki T., Yamaguchi A., Morikawa R., Sato K., Sakamoto M., Yoshimoto T., Kanai T.

Journal of Clinical Investigation (Journal of Clinical Investigation) 129 ( 8 ) 3201 - 3213 2019.08

ISSN 00219738

© 2019, American Society for Clinical Investigation. Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A–induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35–dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35–deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.

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Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease

Igaki K., Nakamura Y., Tanaka M., Mizuno S., Yoshimatsu Y., Komoike Y., Uga K., Shibata A., Imaichi H., Takayuki S., Ishimura Y., Yamasaki M., Kanai T., Tsukimi Y., Tsuchimori N.

Inflammation Research (Inflammation Research) 68 ( 6 ) 493 - 509 2019.06

ISSN 10233830

© 2019, Springer Nature Switzerland AG. Objective and design: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. Methods and results: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ−/− mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. Conclusions: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.

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The association between environmental factors and the development of Crohn's disease with focusing on passive smoking: A multicenter case-control study in Japan

Kondo K., Ohfuji S., Watanabe K., Yamagami H., Fukushima W., Ito K., Suzuki Y., Hirota Y., Motoya S., Sakuraba H., Ishiguro Y., Sasaki I., Suzuki K., Fukuda K., Saruta M., Shinozaki M., Shimizu T., You A., Nagahori M., Watanabe M., Kanai T., Iizuka B., Watanabe T., Kobayashi K., Kunisaki R., Sugita A., Ishige T., Miura S., Hokari R., Hanai H., Goto H., Ando T., Tanida S., Joh T., Mizoshita T., Sasaki M., Kitamura K., Umegae S., Fujiyama Y., Ando A., Shimizu S., Yoshioka K., Kitano A., Aomatsu K., Naito Y., Yoshida M., Ooi M., Matsumoto T., Fukunaga K., Iimuro M., Ikeuchi H., Ishihara S., Tanaka S., Ueno Y., Matsui T., Yano Y., Yamasaki H., Mitsuyama K., Yamamoto S., Tsubouchi H., Sugimura K., Tenjin T.

PLoS ONE (PLoS ONE) 14 ( 6 ) 2019.06

© 2019 Kondo et al. Background The number of patients with Crohn's disease (CD) in Japan has recently been increasing. We examined the association between environmental factors and the development of CD in Japanese focusing on passive smoking. Methods We conducted a multicenter case-control study and compared the environmental factors of 93 cases who were newly diagnosed with CD to the environmental factors of 132 controls (hospital-, age-, and sex-matched patients with other diseases). The odds ratio (OR) of each factor for the development of CD and the 95% confidence interval (CI) were calculated using a logistic regression model. The association between the details of passive smoking history and the development of CD was examined for those who had an active smoking history "no". Odds ratios of number of passively smoked cigarettes (per day), time of passive smoking (per day) and period of passive smoking (year) were calculated using "passive smoking 'No'" as a reference. Results History of appendicitis, family history of inflammatory bowel disease, and active smoking history were not significantly associated with the development of CD. Drinking history showed a decreased OR for the development of CD (0.39, 0.19-0.77). "Passive smoking Yes" showed significantly increased OR (2.49, 1.09-5.73). Regarding the association between passive smoking and the development of CD, the OR increased as the number of cigarettes per day, smoking time per day, and smoking duration increased, and there was a dose-response relationship (trend P = 0.024, 0.032, 0.038). Conclusions The association between environmental factors and the development of CD among Japanese was examined by case-control study. It was suggested that the passive smoking history may be associated to the development of CD.

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How Can We Assess "Complete Healing" Beyond Endoscopic Remission?

Fukuda T., Naganuma M., Kanai T.

Inflammatory bowel diseases (Inflammatory bowel diseases) 25 ( 6 ) 2019.05

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Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study

Komatsu A., Yoshino T., Suzuki T., Nakamura T., Kanai T., Watanabe K.

Basic and Clinical Pharmacology and Toxicology (Basic and Clinical Pharmacology and Toxicology) 124 ( 5 ) 607 - 614 2019.05

ISSN 17427835

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.

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Recent topics in intestinal microbiota and fecal microbiota transplantation

Mizuno S., Kanai T.

Otolaryngology - Head and Neck Surgery (Japan) (Otolaryngology - Head and Neck Surgery (Japan)) 91 ( 6 ) 467 - 471 2019.05

ISSN 09143491

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