Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages

KANAI Takanori

JCI Insight (JCI insight) 3 ( 12 ) 2018

The gut-liver axis is of clinical importance as a potential therapeutic target in a wide range of liver diseases; however, the mechanisms underlying interactions between microbial products and immune responses in the liver remain unknown. In this study, we demonstrated that IL-10-producing macrophages contribute to immune tolerance in the inflamed liver under intestinal barrier disruption in a murine tandem model of dextran sulfate sodium (DSS) colitis and concanavalin A (Con A) hepatitis. Intestinal barrier disruption protected mice from subsequent liver injury, and the severity of colitis directly affected susceptibility to such injury. The protective effect of DSS-Con A was canceled in gut-sterilized mice, suggesting that gut microbiota play a substantial role in this process. Altered gut microbiota and their metabolites, along with a disrupted intestinal barrier, directly gave rise to immunological permissiveness in the inflamed liver. We identified 1-methylnicotinamide (1-MNA) as a candidate metabolite capable of suppressing liver injury with the potential to induce IL-10-producing macrophages. Consistently, expression of nicotinamide N-methyltransferase, which converts nicotinamide to 1-MNA, was upregulated in the liver of DSS-Con A mice, and this effect was abrogated by gut sterilization. Collectively, our results provide a mechanistic insight into the regulation of immunological balance in the liver via the gut-liver axis.

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Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells

KANAI Takanori

BMC Cancer (BMC Cancer) 18 ( 1 ) 2018

© 2018 The Author(s). Background: We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. In this study, whether brusatol, an Nrf2 inhibitor, has dual anti-HCV and anticancer effects was explored. Methods: The anti-HCV effect of brusatol was investigated by analyzing HCV RNA and proteins in a hepatic cell line persistently-infected with HCV, HPI cells, and by analyzing HCV replication in a replicon-replicating hepatic cell line, OR6 cells. Then, dual anti-HCV and anticancer effects of brusatol and enhancement of the effects by the combination of brusatol with anticancer drugs including sorafenib, which has been reported to have the dual effects, were then investigated. Results: Brusatol suppressed the persistent HCV infection at both the RNA and protein levels in association with a reduction in Nrf2 protein in the HPI cells. Analysis of the OR6 cells treated with brusatol indicated that brusatol inhibited HCV persistence by inhibiting HCV replication. Combination of brusatol with an anticancer drug not only enhanced the anticancer effect but also, in the case of the combination with sorafenib, strongly suppressed HCV infection. Conclusions: Brusatol has dual anti-HCV and anticancer effects and can enhance the comparable effects of sorafenib. There is therefore the potential for combination therapy of brusatol and sorafenib for HCV-related hepatocellular carcinoma.

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Idiopathic Thrombocytopenic Purpura Responsive to Surgery for Crohn's Disease.

KANAI Takanori

Inflamm Bowel Dis (Inflammatory bowel diseases) 25 ( 3 ) 2018

ISSN 10780998

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Review of the small intestinal mucosal lesion

KANAI Takanori

Nihon Shokakibyo Gakkai Zasshi (Journal of Japanese Society of Gastroenterology) 115 ( 7 ) 605 - 611 2018

ISSN 04466586

Pancreatic Fat Content Detected by Computed Tomography and Its Significant Relationship With Intraductal Papillary Mucinous Neoplasm.

KANAI Takanori

Pancreas (Pancreas) 47 ( 9 ) 1087 - 1092 2018

ISSN 08853177

© Wolters Kluwer Health, Inc. All rights reserved. Objectives Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic ductal adenocarcinomas (PDACs). Fat accumulation in the pancreas is increasingly recognized as a cause of PDAC. We aimed to identify factors that are relevant between IPMN and metabolic-related factors, including pancreatic fat. Methods The database for 781 subjects who underwent a health checkup and upper abdominal magnetic resonance imaging was searched and computed tomography attenuation indexes (pancreatic and spleen attenuation, pancreas-to-spleen attenuation ratio) were decided by measuring the regions of interest in the pancreas and spleen on nonenhanced images, using Hounsfield units. Eighty-five subjects from each of the IPMN and noncyst groups were matched for age, sex, and glycemic status and statistically compared in clinical characteristics. Results There was no difference in metabolic-related factors except for apolipoprotein A1 and high-density lipoprotein cholesterol between the 2 groups in univariate analysis. Multivariate logistic regression analysis showed that both indexes were significantly associated with IPMN (odds ratio, 0.905 [95% confidence intervals, 0.851-0.963; P = 0.002]; odds ratio, 0.006 [95% confidence intervals, 0.000-0.152; P = 0.002]). Conclusions Pancreatic fat content measured by computed tomography was significantly associated with IPMN. These results suggest that IPMN may develop secondary to pancreatic steatosis that could be an overlapping risk factor for PDAC and IPMN.

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Immune Checkpoint Induced Colitis

KANAI Takanori

Gan To Kagaku Ryoho (Japanese Journal of Cancer and Chemotherapy) 45 ( 7 ) 1027 - 1030 2018

ISSN 03850684

© 2018 Japanese Journal of Cancer and Chemotherapy Publishers Inc. All Rights Reserved. Colitis is one of major adverse event induced by immune checkpoint inhibitor (ICPi), especially in the treatment with anti-CTLA-4 antibody. Colitis can occur anytime duringICPi therapy. The most common symptom is diarrhea. Other symptoms are abdominal pain, hematochezia, weight loss, fever and vomiting. To diagnoseICPi-induced colitis, it is important to deny infectious enterocolitis and tumor-related symptoms. Sigmoidoscopy or colonoscopy with biopsy are useful for proper diagnosis and evaluation of the severity. Patients with ulcer lesion tend to show resistance to steroid therapy. Diarrhea is an important symptom to evaluate the severity of colitis. American Society of Clinical Oncology and European Society for Medical Oncology published clinical guidelines for immune related adverse events including colitis. If patient has CTCAE Grade 2 or more severe diarrhea, both guidelines recommend stop ICPi and start corticosteroid therapy. As colitis can progress rapidly and induce perforation, the initiation of steroid therapy should not be hesitated. Some patients are resistant to steroid therapy, in which case infliximab, anti-TNF-a antibody, is recommended. ICPi-induced colitis is different from conventional adverse event induced by cytotoxic agents in terms of management with coticosteroid. Therefore, consultation to gastroenterologist is essential for proper diagnosis and corticosteroid initiation without delay.

Clinical impact of closure of the mucosal defect after duodenal endoscopic submucosal dissection

KANAI Takanori

Gastrointest Endosc (Gastrointestinal Endoscopy) 89 ( 1 ) 87 - 93 2018

ISSN 00165107

© 2019 American Society for Gastrointestinal Endoscopy Background and Aims: Delayed adverse events (bleeding or perforation) are major concerns associated with duodenal endoscopic submucosal dissection (ESD). The aim of this study was to assess the efficacy of prophylactic closure of the mucosal defect after duodenal ESD. Methods: This is a retrospective study from a university hospital. One hundred sixty-eight patients (173 lesions) who underwent duodenal ESD between July 2010 and June 2017 were included in this study. The study participants were divided into 3 subgroups according to the degree of closure: complete group, incomplete group, and unclosed group. The proportion of delayed adverse events, maximum serum level of C-reactive protein (CRP), and total length of hospital stay were compared among these subgroups. Moreover, a multivariate logistic regression model was constructed to identify the risk factors for delayed adverse events. Results: The proportion of delayed adverse events in the complete group, incomplete group, and unclosed group were 1.7%, 25%, and 15.6%, respectively. The difference between the complete group and the other groups was significant (P <.01). The maximum serum CRP level was much lower (1.51 ± 2.18 mg/dL vs 6.28 ± 10.0 mg/dL, P <.01), and the length of hospital stay was significantly shorter in the complete group than in the incomplete/unclosed group (median [range] 5 [5-14] days vs 8 [4-59] days, P <.01). Multivariate analysis revealed that complete closure had a significant decrease in delayed adverse events (odds ratio [OR], 0.055; 95% confidence interval [CI], 0.01-0.29; P <.01), and a lesion located distal from the descending part showed a statistical tendency to an increase in delayed adverse events (OR, 4.48; 95% CI, 0.85-23.6; P =.08). Conclusion: The present study revealed that complete closure of the mucosal defect after duodenal ESD significantly decreased the number of delayed adverse events and improved other outcomes.

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KANAI Takanori

Gastroenterology 2018

Clinical utility of novel ultrathin single-balloon enteroscopy: a feasibility study

KANAI Takanori

Endoscopy (Endoscopy) 51 ( 5 ) 468 - 471 2018

ISSN 0013726X

© Georg Thieme Verlag KG Stuttgart . New York. Background The advent of balloon-assisted enteroscopy (BAE) has facilitated the examination of the entire digestive tract. However, using a rigid sliding tube during the procedure reduces patient acceptance. This study evaluated the clinical application of a newly developed ultrathin single-balloon enteroscope for BAE. Methods 28 outpatients underwent enteroscopy with a novel ultrathin single-balloon enteroscope. None of the subjects required therapeutic procedures, such as balloon dilation or hemostasis. The insertability, efficacy, and safety of the ultrathin single-balloon endoscope were evaluated retrospectively. Results 7 patients underwent transoral enteroscopy and 21 patients underwent transanal enteroscopy under conscious sedation. No adverse events related to the procedure were reported in any patients. Targeted observation and/or targeted biopsy were achieved in all procedures. All transoral procedures allowed evaluation of the jejunum beyond the ligament of Treitz. All transanal procedures allowed intubation of the terminal ileum, despite several patients having severe stenosis of the colon and ileum. Conclusion A novel ultrathin single-balloon enteroscope showed adequate insertability and safety for outpatient surveillance enteroscopy under conscious sedation.

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Absence of high-risk stigmata predicts good prognosis even in severely anemic patients with suspected acute upper gastrointestinal bleeding

KANAI Takanori

United European Gastroenterol J. (United European Gastroenterology Journal) 6 ( 5 ) 684 - 690 2018

ISSN 20506406

© 2018, Author(s) 2018. Background: The need for a blood transfusion, defined as hemoglobin < 70 g/L, is the measure for assessing the risk levels in patients with upper gastrointestinal bleeding (UGIB). However, not all patients with a low hemoglobin level have a poor prognosis. Objective: We assessed the clinical predictive factors associated with poor short-term prognosis in patients with a low hemoglobin level. Methods: In this prospective cohort study, all consecutive patients with suspected acute UGIB at Tokyo Metropolitan Tama Medical Center were enrolled between 2008 and 2015. Then, we extracted those who needed a blood transfusion (hemoglobin < 70 g/L) and explored the variables associated with all-cause mortality within 28 days after presentation. Results: Among 1307 patients, 311 needed a blood transfusion and 13 (4.2%) died from all causes. The presence of high-risk stigmata requiring endoscopic treatment (peptic ulcers; Forrest scores Ia, Ib and IIa; varices with current bleeding or signs of recent bleeding; and spurting or gushing bleeding or visible vessel in other diseases), diagnosed by emergency endoscopy, was a unique factor affecting mortality (odds ratio: 8.47, 95% confidence interval: 1.45–160, P = 0.01). Patients without high-risk stigmata neither died from UGIB nor had rebleeding, irrespective of the hemoglobin levels. Conclusions: Patients without high-risk stigmata showed a good prognosis even if they needed a blood transfusion. This result could facilitate triage of patients with suspected acute UGIB who only need a blood transfusion.

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β-(1,3)-Glucan derived from Candida albicans induces inflammatory cytokines from macrophages and lamina propria mononuclear cells derived from patients with Crohn's disease.

KANAI Takanori

Intest Res 2018

Effect of elemental diet combined with infliximab dose escalation in patients with Crohn's disease with loss of response to infliximab: CERISIER trial.

KANAI Takanori

Intest Res (Intestinal Research) 16 ( 3 ) 494 - 498 2018

ISSN 15989100

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Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis.

KANAI Takanori

Cell (Cell) 174 ( 4 ) 856 - 869.e17 2018

ISSN 00928674

© 2018 Elsevier Inc. Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers. Generation and analysis of a human gastric cancer organoid bank reveal insights into molecular features underlying diverse histopathological subtypes and tumor independence from Wnt signals.

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Innate lymphoid cells in organ fibrosis. Cytokine Growth Factor Rev

KANAI Takanori

Cytokine Growth Factor Rev 2018

Correction: Clinical utility of novel ultrathin single-balloon enteroscopy: a feasibility study

KANAI Takanori

Endoscopy 2018

Management of challenging immune-related gastrointestinal adverse events associated with immune checkpoint inhibitors.

KANAI Takanori

Future Oncol (Future Oncology) 14 ( 30 ) 3187 - 3198 2018

ISSN 14796694

© 2018 Future Medicine Ltd. Immune-related gastrointestinal toxicities (irGI) are well-known adverse events (AEs) with immune checkpoint inhibitors. The aim of this review was to present clinical data from 82 cases to provide information to clinicians who face real-world challenges among their patients with irGI AEs. The findings of this review support the use of the current management guidelines. By analyzing the treatment courses and outcomes of all cases identified, our review recommends that recurrent cases be treated carefully regardless of the grade of diarrhea at the onset of events. Earlier gastroenterology consultation and computed tomography/endoscopy diagnosis are essential, especially when an irGI AE recurs or worsens during steroid tapering. We would also suggest earlier decision to add immunosuppressant agents, particularly for recurrent cases.

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Efficacy of Therapeutic Intervention for Patients With an Ulcerative Colitis Mayo Endoscopic Score of 1.

KANAI Takanori

Inflamm Bowel Dis (Inflammatory Bowel Diseases) 25 ( 4 ) 782 - 788 2018

ISSN 10780998

© 2018 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions. Background Mucosal healing (MH) is proposed as a therapeutic target for ulcerative colitis (UC). Recent studies have indicated that the rate of clinical relapse in patients with a Mayo endoscopic score (MES) of 1 is higher than that of patients with an MES of 0. However, no study has yet investigated whether therapeutic intervention prevents clinical relapse in patients with an MES of 1. Methods Patients with UC with an MES of 1 and partial Mayo score ≤2 were included in this study. All patients were followed from first colonoscopy (CS) until follow-up CS. Differences in the rate of clinical relapse (requiring additional treatment for UC) or endoscopic exacerbation (MES ≥2 and proximal extension) were compared between the therapeutic intervention (immediately after first CS) group and the nontherapeutic intervention group; risk factors for relapse were also assessed. Results Among 1523 patients with UC who underwent CS between 2013 and 2016, 220 patients were included in this study. The rate of clinical relapse (P = 0.005) and endoscopic exacerbation (P = 0.11) in patients with therapeutic intervention was lower than that in patients without therapeutic intervention. Multivariable analysis indicated that absence of therapeutic intervention (P = 0.001 for clinical relapse, P = 0.050 for endoscopic exacerbation) and a higher Ulcerative Colitis Endoscopic Index of Severity vascular pattern score immediately after first CS (P = 0.021 for clinical relapse, P = 0.019 for endoscopic exacerbation) were risk factors for both clinical relapse and endoscopic exacerbation. Conclusions Therapeutic intervention for patients with UC with an MES of 1 might prevent disease relapse.

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Large Volume Fluid Resuscitation for Severe Acute Pancreatitis is Associated With Reduced Mortality: A Multicenter Retrospective Study

KANAI Takanori

J Clin Gastroenterol (Journal of Clinical Gastroenterology) 53 ( 5 ) 385 - 391 2018

ISSN 01920790

Copyright © 2019 World Gastroenterology Organisation. All rights reserved. Background and Aims: Although fluid resuscitation is critical in acute pancreatitis, the optimal fluid volume is unknown. The aim of this study is to evaluate the association between the volume of fluid administered and clinical outcomes in patients with severe acute pancreatitis (SAP). Methods: We conducted a multicenter retrospective study at 44 institutions in Japan. Inclusion criteria were age 18 years or older, and diagnosed with SAP from 2009 to 2013. Patients were stratified into 2 groups: administered fluid volume <6000 and ≥ 6000 mL in the first 24 hours. We evaluated the association between the 2 groups and clinical outcomes using multivariable logistic regression analysis. The primary outcome was in-hospital mortality. Secondary outcomes included the incidence of pancreatic infection and the need for surgical intervention. Results: We analyzed 1097 patients, and the mean fluid volume administered was 5618±3018 mL (mean±SD), with 708 and 389 patients stratified into the fluid <6000 mL and fluid ≥6000 mL groups, respectively. Overall in-hospital mortality was 12.3%. The fluid ≥ 6000 mL group had significantly higher mortality than the fluid <6000 mL group (univariable analysis, 15.9% vs. 10.3%; P<0.05). In multivariable logistic regression analysis, administration of ≥6000 mL of fluid within the first 24 hours was significantly associated with reduced mortality (odds ratio, 0.58; P<0.05). No significant association was found between the administered fluid volume and pancreatic infection, or between the volume administered and the need for surgical intervention. Conclusions: In patients with SAP, administration of a large fluid volume within the first 24 hours is associated with decreased mortality.

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Reconstruction of the Human Colon Epithelium In Vivo.

KANAI Takanori

Cell Stem Cell (Cell Stem Cell) 22 ( 2 ) 171 - 176.e5 2018

ISSN 19345909

© 2017 Elsevier Inc. Genetic lineage tracing has revealed that Lgr5 + murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium. Xenografted organoids formed crypt structures distinctively different from surrounding mouse crypts, reflecting their human origin. Lineage tracing using CRISPR-Cas9 to engineer an LGR5-CreER knockin allele demonstrated self-renewal and multipotency of LGR5 + CoSCs. In contrast to the rapidly cycling properties of mouse Lgr5 + CoSCs, human LGR5 + CoSCs were slow-cycling in vivo. This organoid-based orthotopic xenograft model enables investigation of the functional behaviors of human CoSCs in vivo, with potential therapeutic applications in regenerative medicine. Sugimoto et al. established an orthotopic xenotransplantation system for human normal colon organoids. Using LGR5-CreER knockin organoids for genetic lineage tracing, they demonstrated the self-renewal and multipotency of LGR5 + colon stem cells in mouse colon. Interestingly, human LGR5 + colon stem cells showed slower cycling than those of mice in vivo.

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Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.

KANAI Takanori

Cell Stem Cell (Cell Stem Cell) 22 ( 3 ) 454 - 467.e6 2018

ISSN 19345909

© 2017 Elsevier Inc. Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression. Sato and colleagues established a library of patient-derived pancreas cancer organoids and identified heterogeneous patterns of dependency on Wnt ligands among pancreas cancers. Biological and genetic analyses highlighted GATA6 as a mediator of the Wnt niche requirement, which links pancreatic tumor progression to independence from the stem cell niche.

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