Papers - Kanai, Takanori

Treatment strategy for inflammatory bowel disease with a focus on biologicals].

KANAI Takanori

Nihon Shokakibyo Gakkai Zasshi  2018

Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis.

KANAI Takanori

J Clin Invest (Journal of Clinical Investigation)  128 ( 4 ) 1581 - 1596 2018

ISSN  00219738

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© 2018 American Society for Clinical Investigation. All rights reserved. Incidence of nonalcoholic steatohepatitis (NASH), which is considered a hepatic manifestation of metabolic syndrome, has been increasing worldwide with the rise in obesity; however, its pathological mechanism is poorly understood. Here, we demonstrate that the hepatic expression of aortic carboxypeptidase-like protein (ACLP), a glycosylated, secreted protein, increases in NASH in humans and mice. Furthermore, we elucidate that ACLP is a ligand, unrelated to WNT proteins, that activates the canonical WNT pathway and exacerbates NASH pathology. In the liver, ACLP is specifically expressed in hepatic stellate cells (HSCs). As fatty liver disease progresses, ACLP expression is enhanced via activation of STAT3 signaling by obesity-related factors in serum. ACLP specifically binds to frizzled-8 and low-density lipoprotein-related receptor 6 to form a ternary complex that activates canonical WNT signaling. Consequently, ACLP activates HSCs by inhibiting PPARγ signals. HSC-specific ACLP deficiency inhibits fibrosis progression in NASH by inhibiting canonical WNT signaling in HSCs. The present study elucidates the role of canonical WNT pathway activation by ACLP in NASH pathology, indicating that NASH can be treated by targeting ACLP-induced canonical WNT pathway activation in HSCs.

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Post-progression survival following second-line chemotherapy in patients with advanced pancreatic cancer previously treated with gemcitabine : a meta-analysis.

KANAI Takanori

Invest New Drugs (Investigational New Drugs)  36 ( 5 ) 939 - 948 2018

ISSN  01676997

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© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Background Post-progression survival (PPS) could be a confounding element in interpreting data from clinical trials of second-line chemotherapy in patients with advanced pancreatic cancer (PC) previously treated with gemcitabine (GEM) because a recent meta-analysis of oxaliplatin combination therapy showed statistical heterogeneity for overall survival (OS) but not for progression-free survival (PFS). This study aimed to improve the understanding of the impact of PPS on OS in this setting. Methods Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. We evaluated relationships between OS and PFS, PPS, and other variables. Results Totally, 17 RCTs with 3253 patients were identified. Median OS was strongly and moderately associated with median PPS and PFS, respectively (r = 0.913; p < 0.001 and 0.780; p < 0.001, respectively). The proportion of patients with good performance status was significantly associated with both PPS and PFS (r = 0.574, p < 0.001 and 0.492, p < 0.001, respectively). The induction rate of subsequent chemotherapy was related to the duration of PPS and OS (r = 0.640, p < 0.001 and 0.647, p < 0.001, respectively). Median PPS and OS were significantly longer in recent trials than those in older trials (3.55 versus 2.78 months, p < 0.001 and 6.29 versus 5.02 months, p < 0.001). Conclusions Median PPS was strongly correlated with median OS. Given the recently increased opportunity for subsequent chemotherapy and supportive care, PPS may serve as an important element to clarify problems in this setting.

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Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia.

KANAI Takanori

PLoS Pathog  2018

Initial Management of Colonic Diverticular Bleeding: Observational Study

KANAI Takanori

Digestion (Digestion)  98 ( 1 ) 41 - 47 2018

ISSN  00122823

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© 2018 S. Karger AG, Basel. Background/Aims: Although colonic diverticular bleeding (CDB) often ceases spontaneously, re-bleeding occurs in about 30%. Bleeding diverticulum can be treated directly by endoscopic hemostasis; however, it is difficult to perform colonoscopy in all cases with limited medical resource and certain risks. The aim of this study was to clarify who should undergo colonoscopy as well as appropriate methods of initial management in CDB patients. Methods: A total of 285 patients who were diagnosed as CDB and underwent colonoscopy from March 2004 to October 2015 were retrospectively analyzed. First, the association between re-bleeding and various factors including patients' background and initial management were analyzed. Second, the examination conditions that influenced bleeding point identification were analyzed. Results: Of 285 patients, 187 were men and 98 were women. Median age was 75 years, and the median observation period was 17.5 months. Re-bleeding was observed in 79 patients (28%). A history of CDB (OR 2.1, p = 0.0090) and chronic kidney disease (CKD; OR 2.3, p = 0.035) were risk factors, and bleeding point identification (OR 0.20, p = 0.0037) was a preventive factor for re-bleeding. Bleeding point identification significantly reduced approximately 80% of re-bleeding. Furthermore, extravasation on CT (OR 3.7, p = 0.031) and urgent colonoscopy (OR 5.3, p < 0.001) were predictors for identification of bleeding point. Compared to bleeding point identification of 11% in all patients who underwent colonoscopy, identification rate in those who had extravasation on CT and underwent urgent colonoscopy was as high as 70%. Conclusions: Contrast-enhanced CT upon arrival is suggested, and patients with extravasation on CT would be good candidates for urgent colonoscopy, as well as patients who have a history of CDB and CKD.

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The effect of fecal microbiota transplantation on psychiatric symptoms among patients with irritable bowel syndrome, functional diarrhea and functional constipation: An open-label observational study

KANAI Takanori

J Affect Disord (Journal of Affective Disorders)  235   506 - 512 2018

ISSN  01650327

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© 2018 Elsevier B.V. Backgrounds: The intestinal microbiota is considered as a potential common underpinning pathophysiology of Functional Gastrointestinal Disorders (FGIDs) and psychiatric disorders such as depression and anxiety. Fecal Microbiota Transplantation (FMT) has been reported to have therapeutic effects on diseases related to dysbiosis, but few studies have evaluated its effect on psychiatric symptoms. Methods: We followed 17 patients with either Irritable Bowel Syndrome (IBS), Functional Diarrhea (FDr) or Functional Constipation (FC) who underwent FMT for the treatment of gastrointestinal symptoms and observation of psychiatric symptoms. Changes in Hamilton Rating Scale for Depression (HAM-D) and subscale of sleep-related items, Hamilton Rating Scale for Anxiety (HAM-A) and Quick Inventory for Depressive Symptoms (QIDS) between baseline and 4 weeks after FMT, and relationship with the intestinal microbiota were measured. Results: At baseline, 12 out of 17 patients were rated with HAM-D ≥ 8. Significant improvement in HAM-D total and sleep subscale score, HAM-A and QIDS were observed (p = 0.007, p = 0.007, p = 0.01, p = 0.007, respectively). Baseline Shannon index indicated that microbiota showed lower diversity in patients with HAM-D ≥ 8 compared to those of healthy donors and patients with HAM-D < 8. There was a significant correlation between baseline Shannon index and HAM-D score, and a correlation between Shannon index change and HAM-D improvement after FMT. Limitations: The small sample size with no control group. Conclusions: Our results suggest that depression and anxiety symptoms may be improved by FMT regardless of gastrointestinal symptom change in patients with IBS, FDr and FC, and the increase of microbiota diversity may help to improve patient's mood.

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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

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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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Future perspectives on fecal microbiota transplantation

KANAI Takanori

Nihon Shokakibyo Gakkai Zasshi (Journal of Japanese Society of Gastroenterology)  115 ( 5 ) 449 - 459 2018

ISSN  04466586

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Acquisition of double mutation in gyrA caused high resistance to sitafloxacin in Helicobacter pylori after unsuccessful eradication with sitafloxacin-containing regimens

KANAI Takanori

United European Gastroenterol J (United European Gastroenterology Journal)  6 ( 3 ) 391 - 397 2018

ISSN  20506406

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© 2017, © Author(s) 2017. Background and aim: Although sitafloxacin (STFX)-containing regimens are effective rescue treatments for Helicobacter pylori infection, prevalence of fluoroquinolone resistance in H. pylori has increased rapidly worldwide. The change in resistance levels and gyrA mutations, a major cause of fluoroquinolone resistance, after unsuccessful STFX-containing treatment has not been investigated. Methods: We conducted a retrospective, non-randomized study to compare the minimum inhibitory concentrations (MICs) of STFX and the location of gyrA mutations in H. pylori before and after unsuccessful eradication with STFX-containing regimens at Keio University Hospital between December 2011 and March 2015. Results: A total of 266 patients treated with STFX-containing regimens for third-line H. pylori eradication were evaluated. Double mutations in gyrA were acquired by 20.8% of strains that exhibited seven-fold increased STFX MICs, compared to pre-treatment MICs. The STFX MICs did not increase, however, when the location of the gyrA mutations did not change after treatment. Double mutations in gyrA developed in 60.0% of the strains in which eradication failed, which exhibited a baseline mutation at position D91, and in 11.1% of strains with baseline mutations at position N87. Conclusion: Acquisition of double mutations in gyrA evoked high-level resistance to STFX in H. pylori after unsuccessful eradication with STFX-containing regimens.

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Burden of impaired sleep quality on work productivity in functional dyspepsia

KANAI Takanori

United European Gastroenterol J (United European Gastroenterology Journal)  6 ( 3 ) 398 - 406 2018

ISSN  20506406

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© 2017, © Author(s) 2017. Background: Impaired sleep quality is common, and can reduce work productivity in patients with functional dyspepsia (FD). Objective: The objective of this article is to evaluate whether there is a direct association between the presence of FD and the severity of impaired sleep quality, and to calculate the economic loss due to the decreased work productivity associated with sleep quality. Methods: In Study 1, using a web-based survey completed by workers with and without FD, we evaluated impaired sleep quality, work and daily productivity, and the severity of reflux and bowel symptoms. In Study 2, the association between the presence of FD and the severity of impaired sleep quality was validated in a hospital-based cohort. Results: In both Study 1 and 2, although impaired sleep quality was more frequent in participants with FD than in those without FD, the independent association between the presence of FD and the severity of impaired sleep quality was not observed after adjustment for the severity of reflux and bowel symptoms. FD participants with impaired sleep quality reported additional economic loss of 53,500 Japanese yen/month. Conclusion: Although the association between impaired sleep quality and FD was indirect, concomitant impaired sleep quality could worsen economic loss.

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Establishment of a Novel Scoring System for Colon Capsule Endoscopy to Assess the Severity of Ulcerative Colitis-Capsule Scoring of Ulcerative Colitis

KANAI Takanori

Inflamm Bowel Dis (Inflammatory Bowel Diseases)  24 ( 12 ) 2641 - 2647 2018

ISSN  10780998

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© 2018 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved. Background: The usefulness of second-generation colon capsule endoscopy (CCE-2) for ulcerative colitis (UC) has not been fully demonstrated. This study aimed to develop an endoscopic severity score of UC for CCE-2. Methods: Patients diagnosed with UC were enrolled prospectively and underwent colonoscopy and CCE-2 on the same day. The collected CCE-2 videos were adopted for the development of the score. These videos were scored by 4 blinded inflammatory bowel disease experts. The items validated with the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were used as the candidate items, some of which were automatically assessed using the workstation. Each item was divided into proximal and distal parts at the splenic flexure and then individually assessed. The image readers simultaneously evaluated the inflammation severity using the visual analog scale (VAS). The descriptors that contribute to this scale were evaluated, and a model to predict the VAS was constructed. The UCEIS was scored by other endoscopists using colonoscopy videos. The correlation coefficients with fecal calprotectin, blood tests, and Lichtiger index were calculated. Results: The final scoring system was fixed as "vascular pattern sum (proximal + distal) + bleeding sum + erosions and ulcers sum (minimum- maximum, 0-14)" and was named Capsule Scoring of Ulcerative Colitis (CSUC). The correlation coefficient of CSUC with biomarkers and clinical score was similar to that of the UCEIS. Conclusions: We developed a new simple score using the 3 descriptors of CCE-2.

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Safety and efficacy of ultra-tapered mechanical dilator for EUS-guided hepaticogastrostomy and pancreatic duct drainage compared with electrocautery dilator (with video)

KANAI Takanori

Endosc Ultrasound (Endoscopic Ultrasound)  7 ( 6 ) 376 - 382 2018

ISSN  23039027

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© 2018 SPRING MEDIA PUBLISHING CO. LTD Background and Objectives: Successful tract dilation is one of the most important steps to accomplish EUS-guided drainage. Although mechanical dilation is safer than electrocautery dilation, no dedicated mechanical dilator (MD) is currently available. Thus, we developed a new ultra-tapered MD for EUS-guided drainage. This study aimed to evaluate the safety and usefulness of this novel MD. Patients and Methods: Consecutive patients who underwent EUS-guided hepaticogastrostomy (EUS-HGS) or EUS-guided pancreatic duct drainage (EUS-PD) at two centers were included in the study. Dilation of the needle tract was initially performed with a diathermic sheath or the ultra-tapered MD. Technical success and adverse events were assessed. Results: Sixty-four patients (mean age = 68.9 ± 13.8 years, 35 men) underwent EUS-HGS (49 patients) and EUS-PD (15 patients). Thirty-three patients were included in the cautery dilator (CD) group and 31 in the ultra-tapered MD group. Initial dilation of the puncture site was achieved in 95.3% (61/64): 97% (32/33) of the patients in the CD group and 93.3% (29/31) of the patients in the MD group (P > 0.05). Adverse events were observed in 14 patients: abdominal pain in 8 patients and bleeding in 6 patients at the puncture site. All bleedings occurred in the CD group and there was no patient in whom bleeding occurred after EUS intervention in the MD group (P = 0.04). Conclusion: The novel ultra-tapered MD designed for interventional EUS appears to be safe and useful as it reduced postprocedure bleeding with a high technical success rate compared with the conventional electrocautery dilator.

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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

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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

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© 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

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© 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

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© 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

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© 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