論文 - 金井　隆典

The entire intestinal tract surveillance using capsule endoscopy after immune checkpoint inhibitor administration: A prospective observational study

Shimozaki K., Hirata K., Horie S., Chida A., Tsugaru K., Hayashi Y., Kawasaki K., Miyanaga R., Hayashi H., Mizuno R., Funakoshi T., Hosoe N., Hamamoto Y., Kanai T.

Diagnostics （Diagnostics）  11 （ 3 ）  2021年03月

　概要を見る

Background: Despite the proven efficacy of immune checkpoint inhibitors (ICIs) against various types of malignancies, they have been found to induce immune-related adverse events, such as enterocolitis; however, the clinical features of ICI-induced enterocolitis remain to be sufficiently elucidated, which is significant, considering the importance of early detection in the appropriate management and treatment of ICI-induced enterocolitis. Therefore, the current study aimed to determine the utility of capsule endoscopy as a screening tool for ICI-induced enterocolitis. Methods: This single-center, prospective, observational study was conducted on patients with malignancy who received any ICI between April 2016 and July 2020 at Keio University Hospital. Next, second-generation capsule endoscopy (CCE-2) was performed on day 60 after ICI initiation to explore the entire gastrointestinal tract. Results: Among the 30 patients enrolled herein, 23 underwent CCE-2. Accordingly, a total of 23 findings were observed in 14 (60.8%) patients at any portion of the gastrointestinal tract (7 patients in the colon, 4 patients in the small intestine, 2 patients in both the colon and the small intestine, and 1 patient in the stomach). After capsule endoscopy, 2 patients (8.7%) developed ICI-induced enterocolitis: both had significantly higher Capsule Scoring of Ulcerative Colitis than those who had not developed ICI-induced enterocolitis (p = 0.0455). No adverse events related to CCE-2 were observed. Conclusions: CCE-2 might be a safe and useful entire intestinal tract screening method for the early detection of ICI-induced enterocolitis in patients with malignancies.

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Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial

Kita T., Ashizuka S., Ohmiya N., Yamamoto T., Kanai T., Motoya S., Hirai F., Nakase H., Moriyama T., Nakamura M., Suzuki Y., Kanmura S., Kobayashi T., Ohi H., Nozaki R., Mitsuyama K., Yamamoto S., Inatsu H., Watanabe K., Hibi T., Kitamura K.

Journal of Gastroenterology （Journal of Gastroenterology）  56 （ 2 ） 147 - 157 2021年02月

ISSN  09441174

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Background: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC. Methods: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0. Results: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (− 9.3 ± 1.2 vs. − 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM. Conclusions: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM. Clinical trial registry: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp.

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Ulcerative colitis exacerbation after the onset of immune checkpoint inhibitor related colitis

Kayashima A., Shimozaki K., Hirata K., Mutaguchi M., Takabayashi K., Hayashi Y., Hosoe N., Ogata H., Sujino T., Kanai T.

Clinical Journal of Gastroenterology （Clinical Journal of Gastroenterology）  14 （ 1 ） 152 - 158 2021年02月

ISSN  18657257

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Immune checkpoint inhibitors (ICPI) have been reported to be effective in various carcinomas. They excessively activate the immune system, resulting in frequent immune-related adverse events (irAEs). Colitis induced by ICPI is one of the most common and is known as immune-mediated colitis (IMC). Although IMC and inflammatory bowel disease (IBD) are similar in many respects, there are very few reports of IMC in patients with preexisting IBD such as ulcerative colitis (UC) and Crohn's disease (CD). Whether preexisting IBD is concerned with the development of the colitis is not well known. Here, we reported the case who developed severe ulcerative colitis which started from IMC. It is an important case to follow the time course of the colitis developed. Our conclusion indicated that frequent colonoscopy was important for the management of IMC in a patient who has suffered chronic inflammatory disease, such as UC.

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Wnt Signaling Shapes the Histologic Variation in Diffuse Gastric Cancer

Togasaki K., Sugimoto S., Ohta Y., Nanki K., Matano M., Takahashi S., Fujii M., Kanai T., Sato T.

Gastroenterology （Gastroenterology）  160 （ 3 ） 823 - 830 2021年02月

ISSN  00165085

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Background and Aims: Diffuse-type gastric cancer (GC) is currently subdivided into signet-ring cell carcinoma (SRCC) and non-SRCC, referred to as poorly cohesive carcinoma not otherwise specified (PCC-NOS). Although these subtypes are considered to be independent, they often coexist in the same tumors, raising a question of whether they clonally differ or not. To tackle this question, we established an experimental platform for human diffuse GC that enables accurate modeling of histologic subtypes. Methods: Seven patient-derived diffuse GC organoid lines were established, characterized by histopathologic analysis, in situ hybridization, and gene expression analysis. For genetic modeling of diffuse GC, we knocked out CDH1 and/or TP53 in human normal gastric organoids. Green fluorescent protein–labeled GC organoids were xenotransplanted into immune-deficient mice for in vivo assessment. Results: PCC-NOS organoids transformed into SRCC-like structures on removal of Wnt and R-spondin from the culture medium. This morphologic change paralleled downregulation of Wnt-target and gastric stem cell genes, including LGR5, and elevation of differentiation markers, such as KRT20 and MUCs. The association between Wnt target gene expression and histologic subtypes was confirmed in 3 patient-derived GC tissues. In vivo, single clone-derived organoids formed tumors that comprised 2 distinct histologic compartments, each corresponding to SRCC and PCC-NOS. The transition from PCC-NOS to SRCC histology reflected the abundance of surrounding R-spondin–expressing fibroblasts. Conclusions: SRCC and PCC-NOS were clonally identical, and their morphology was regulated by extracellular Wnt and R-spondin expression. Our results decoded how genetic mutations and the tumor environment shape pathohistologic and biologic phenotypes in human diffuse GCs.

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Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn’s disease in clinical remission

Takabayashi K., Hosoe N., Kato M., Hayashi Y., Nanki K., Fukuhara K., Mikami Y., Mizuno S., Sujino T., Mutaguchi M., Naganuma M., Yahagi N., Ogata H., Kanai T.

Journal of Gastroenterology （Journal of Gastroenterology）  56 （ 1 ） 25 - 33 2021年01月

ISSN  09441174

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Background: Small bowel lesions of Crohn’s disease (CD) are known to be associated with a poor prognosis; however, endoscopic healing leads to favorable patients’ outcome. The aim of this study was to clarify the clinical impact of assessing deep small bowel lesions (DSB) using balloon-assisted enteroscopy (BAE) on CD patients in clinical remission. Methods: From January 2012 to July 2018, a total of 100 CD patients in clinical remission were enrolled to undergo trans-anal enteroscopy using single-balloon enteroscope. Endoscopic evaluations at the terminal ileum (TI) were performed using a partial Simple Endoscopic Score for CD (pSES-CD). Endoscopic evaluations at the DSB used a modified partial SES-CD (mpSES-CD). We evaluated the factors associated with relapse, and the correlation of endoscopic score between the TI and DSB. For this study, relapse was defined as hospitalization within a year from enteroscopy. Results: 30 patients (30.0%) relapsed within a year from enteroscopy. Multivariate logistic regression analysis revealed that the Harvey–Bradshaw Index (OR 1.77, 95% CI 1.18–2.65; p = 0.003) and an mpSES-CD at DSB (OR 3.10, 95% CI 1.86–5.15; p = 0.001) were independent predictors for relapse, whereas a SES-CD at the TI did not exhibit independence. There was a significant correlation trend between the relapse rate and greater than 5 points of an mpSES-CD at DSB; however, there was no correlation between the relapse rate and pSES-CD at the TI. Conclusion: Even when Crohn's disease is in remission, it is important to evaluate DSB using BAE to assess endoscopic mucosal healing.

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Various Endoscopic Features in Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma

Aoki Y., Sujino T., Takabayashi K., Mutakuchi M., Emoto K., Hosoe N., Ogata H., Kanai T.

Case Reports in Gastroenterology （Case Reports in Gastroenterology）  15 （ 1 ） 312 - 322 2021年01月

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A 77-year-old female who had an acute severe abdominal pain was taken to the emergency room in the previous hospital. CT scans showed jejunum and ileum wall thickening and fatty deposits around the small intestinal tract, and gastrointestinal perforation could not be ruled out. By using single anal and oral balloon endoscopy, we observed mild edema with petechial erythema, shallow erosions with edematous mucosa and ulcers with surrounded disrupted villous structures at the jejunum and ileum. Histological analysis revealed atypical lymphocytes infiltrating the small intestinal mucosa demonstrating intraepithelial lymphocytosis. Immunohistochemical staining revealed that CD3, CD7, and CD56 staining was positive, and CD4, CD5, and CD8 staining was negative in infiltrated lymphocytes. We made the diagnosis of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) with the combination of HE staining and IHC. PET-CT showed abnormal uptake in irregular wall thickening of the small intestine, lymph nodes, ribs, spine and pelvic bone. She was treated with chemotherapy (etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin) and is still alive 1 year after the diagnosis. We reported the various endoscopic findings in the same MEITL patient by using single balloon endoscopy. We also summarized endoscopic characteristics of MEITL patients.

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Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease

Matsuoka K., Naganuma M., Hibi T., Tsubouchi H., Oketani K., Katsurabara T., Hojo S., Takenaka O., Kawano T., Imai T., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) （Journal of Gastroenterology and Hepatology (Australia)）  2021年

ISSN  08159319

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Background and Aim: E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments. Methods: This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase. Results: Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4–6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively. Conclusion: E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.

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Underwater endoscopic mucosal resection for a sporadic adenoma located at severe longitudinal ulcer scars in ulcerative colitis

Takabayashi K., Kato M., Sasaki M., Iwao Y., Ogata H., Kanai T., Yahagi N.

Endoscopy （Endoscopy）  2021年

ISSN  0013726X

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Week 2 Symptomatic Response with Vedolizumab as a Predictive Factor in Japanese Anti-TNFα-Naive Patients with Ulcerative Colitis: A post hoc Analysis of a Randomized, Placebo-Controlled Phase 3 Trial

Nagahori M., Watanabe K., Motoya S., Ogata H., Kanai T., Matsui T., Suzuki Y., Pinton P., Ursos L., Sakamoto S., Shikamura M., Hori T., Fernandez J., Hibi T., Watanabe M.

Digestion （Digestion）  2021年

ISSN  00122823

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Background and Aim: To evaluate the onset of symptomatic response with vedolizumab in patients with moderate-to-severe ulcerative colitis in Japan. Methods: Patients were randomized to receive vedolizumab 300 mg or placebo at Weeks 0, 2, and 6. Mayo subscores were analyzed in patients with baseline stool frequency (SF) ≥1 and rectal bleeding (RB) ≥1. In patients with baseline SF ≥2 and RB ≥1, the proportion who achieved SF ≤1 and RB = 0 was determined. Results: Patients were randomized to vedolizumab (n = 164) or placebo (n = 82). Decrease from baseline in mean SF subscore was greater with vedolizumab versus placebo from Week 2 (-6.6%; 95% confidence interval [CI], -16.2, 3.0), with a greater difference in anti-tumor necrosis factor (TNF)α-naive patients (vedolizumab vs. placebo, -13.2%; 95% CI, -29.7, 3.3). Mean percentage decrease from baseline RB subscore was numerically greater with vedolizumab versus placebo from Week 6 in anti-TNFα-naive patients (-10.7%; 95% CI, -33.0, 11.5). More patients in the anti-TNFα-naive subgroup achieved SF ≤1 and RB = 0 with vedolizumab versus placebo at Week 2 (14.8%; 95% CI, 2.5, 27.0) and Week 6 (20.3%; 95% CI, 4.4, 36.2). Patients with SF ≤1 and RB = 0 at Week 2 had higher clinical response, clinical remission, and mucosal healing rates at Week 10 than those without. Conclusions: Our results indicate that vedolizumab induces a rapid symptomatic response, particularly in anti-TNFα-naive patients, and suggest that early symptomatic improvement predicts treatment response at Week 10 (NCT02039505).

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Effect of physician-prescribed nalmefene on alcohol intake reduction in patients with alcohol-related liver disease

Hone Y., Taniki N., Chu P.S., Nakamoto N., Kanai T.

Acta Hepatologica Japonica （Acta Hepatologica Japonica）  62 （ 10 ） 620 - 629 2021年

ISSN  04514203

　概要を見る

A brief intervention is often effective for patients with mild alcohol use disorder (AUD), but it is not effective for most patients with severe AUD or alcohol dependence to reduce alcohol intake. Nalmefene (Selincro®), an opioid receptor modulator, was approved in Japan in 2019. Nalmefene was administered to 18 outpatients with alcohol-related liver diseases. Five patients stopped coming to the hospital without notice, and two patients stopped taking medicine due to dizziness. Thus, 11 patients were noted to have reduced amount of alcohol intake at 24 weeks of using nalmefene. However, one of these patients was referred to a hospital specializing in alcohol dependence thereafter. Thus, the use of nalmefene provides a new concept for AUD treatment (i. e., alcohol intake reduction). However, some adverse events are noted, such as nausea and dizziness. Therefore, physicians with more experience with AUD treatment should use the drugma.

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Predictors of necessity for endoscopic balloon dilatation in patients with Crohn’s disease-related small bowel stenosis

Hayashi Y., Takabayashi K., Hosoe N., Kiyohara H., Kinoshita S., Nanki K., Fukuhara K., Mikami Y., Sujino T., Mutaguchi M., Kawaguchi T., Kato M., Ogata H., Kanai T.

Annals of Medicine （Annals of Medicine）  53 （ 1 ） 2025 - 2033 2021年

ISSN  07853890

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Background and Aim: In patients with Crohn’s disease (CD) and small bowel stenosis, endoscopic balloon dilation (EBD) is considered to be useful in improving stenotic symptoms and avoiding surgery. However, it carries risks such as bleeding and perforation. The aim of this study was to identify the indications for endoscopic intervention in patients with CD and small bowel stenosis. Methods: From November 2007 to March 2020, 143 CD patients with small bowel stenosis were enrolled in this study. We identified the factors associated with not requiring endoscopic intervention during long-term follow-up of these patients. Results: Forty of the 143 patients had abdominal symptoms of stenosis and had undergone EBD, whereas the remaining 103 were asymptomatic and had not undergone endoscopic intervention. During long-term follow-up, 95 of those 103 patients never required endoscopic or surgical intervention. Multivariate logistic regression analysis revealed that not consuming an elemental diet (OR 3.18, 95% CI 1.48–6.82; p <.01) and ileocecal valve (ICV) stenosis (OR 0.30, 95% CI 0.11–0.83; p =.02) were independently associated with not requiring EBD. The cumulative emergency hospitalisation-free rate also tended to be higher in patients not consuming an elemental diet or with ICV stenosis. Conclusions: Two factors, namely not consuming an elemental diet and ICV stenosis, predict a long-term intervention-free prognosis in CD patients with small bowel stenosis.Key messages When an endoscopically impassable small bowel stenosis is found in a CD patient, long-term follow-up without endoscopic intervention may be possible if the patient is asymptomatic, is not using an elemental diet, and the stenosis is ICV.

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Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis

Inuki S., Hirata N., Kashiwabara E., Kishi J., Aiba T., Teratani T., Nakamura W., Kojima Y., Maruyama T., Kanai T., Fujimoto Y.

Scientific Reports （Scientific Reports）  10 （ 1 ）  2020年12月

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The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as α-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure–activity relationship studies of α-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been identified as potent CD1d ligands displaying higher cytokine induction levels and/or unique cytokine polarization. The studies also indicated that flexibility of the lipid moiety can affect the binding affinity, the total cytokine production level and/or cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz amide-containing derivatives 2 and 3, and evaluated their in vivo efficacy in a DSS-induced model of ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal inflammation in the DSS-induced model, after a single intraperitoneal injection.

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Late-onset acute liver failure due to Wilson’s disease managed by plasmapheresis and hemodiafiltration successfully serving as a bridge for deceased donor liver transplantation: a case report and literature review

Sukezaki A., Chu P.s., Shinoda M., Hibi T., Taniki N., Yoshida A., Kawaida M., Hori S., Morikawa R., Kurokouchi A., Wakino S., Kameyama K., Obara H., Kitagawa Y., Saito H., Kanai T., Nakamoto N.

Clinical Journal of Gastroenterology （Clinical Journal of Gastroenterology）  13 （ 6 ） 1239 - 1246 2020年12月

ISSN  18657257

　概要を見る

Late-onset acute liver failure due to Wilson’s disease (WD-ALF) is rare. A 44-year-old female patient presenting acute hepatic decompensation with extreme coagulopathy was transferred to our hospital for evaluation for liver transplantation (LT). Alveolar hemorrhage and Coombs-negative acute hemolysis occurred during workup. Mechanical ventilation, plasmapheresis, and hemodiafiltration with zinc and chelation were started immediately before placing the patient on the waitlist for deceased donor LT (DDLT), with a tentative diagnosis of WD-ALF using the Leipzig score and quick diagnostic criteria suggested by the Acute Liver Failure Study Group Registry. The peak MELD score was 40, and the revised version of King’s score for WD was 13. Serum free copper levels and the patient’s overall general condition were stabilized with artificial support systems, although triphasic wave on electroencephalogram and liver atrophy were noted. She successfully underwent emergent DDLT approximately 2 weeks after suffering from acute hemolysis and survived. The genetic tests confirmed mutations at 2 loci in the ATP7B gene and, therefore, the diagnosis of WD. This is the first and oldest patient reported in Japan to present late-onset WD-ALF that was successfully treated with emergent DDLT.

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Moderate alcohol consumption is not associated with subclinical cardiovascular damage but with hepatic fibrosis in non-alcoholic fatty liver disease

Kashiwagi K., Yamaguchi A., Shiba S., Taniki N., Inoue N., Takaishi H., Iwao Y., Kanai T.

Alcohol （Alcohol）  89   1 - 7 2020年12月

ISSN  07418329

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Background: Moderate alcohol consumption is believed to be associated with reduced mortality from cardiovascular disease (CVD) in the general population. This cross-sectional study aimed to comprehensively examine the association between alcohol consumption and subclinical cardiovascular damage or hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Methods: Subjects with NAFLD without a history of heart disease were extracted from 977 consecutive examinees who completed health checkups and optional cardiovascular examinations. Subclinical cardiovascular damage was assessed by coronary artery calcification (CAC), carotid artery ultrasound, and brachial-ankle pulse wave velocity (ba-PWV). CAC scores were classified into three grades (0, ≤100, and >100) by Agatston's method. Alcohol consumption was divided into three groups [Non-drinking (G0); Light (G1), 0.1–6.9 drinks/week; Moderate (G2), 7–20.9 drinks/week for men and 7–13.9 drinks/week for women]. Noninvasive markers (FIB-4, Fibrosis-4; NFS, NAFLD fibrosis score) were calculated for assessment of hepatic fibrosis and classified into low and intermediate-high grade. Results: The overall mean age was 60.2 years and males were 200 (74.6%) among 268 subjects with NAFLD. Number (%) of G0, G1, and G2 were 102 (38.1%), 103 (38.4%), and 63 (23.5%). Binary logistic regression analysis showed no significant difference between G0 and G1, or G0 and G2 in any of the above subclinical cardiovascular damages (CAC score >0, or CAC score >100, carotid plaque +, intima-media thickness ≥1.1 mm, and ba-PWV >1400 cm/s). However, only G2 had a significant association with intermediate-high grade of FIB-4 or NFS [odds ratio (95% confidence intervals), p value: 1.871 (1.209–2.893), p = 0.005; 2.910 (1.715–4.939), p = 0.000], compared to G0. Conclusions: Non-heavy drinking might not reduce the risk of CVD in NAFLD subjects. On the contrary, even moderate drinking could promote hepatic fibrosis. Thus, NAFLD drinkers should not be recommended for even a moderate amount of alcohol.

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An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping

Kawasaki K., Toshimitsu K., Matano M., Fujita M., Fujii M., Togasaki K., Ebisudani T., Shimokawa M., Takano A., Takahashi S., Ohta Y., Nanki K., Igarashi R., Ishimaru K., Ishida H., Sukawa Y., Sugimoto S., Saito Y., Maejima K., Sasagawa S., Lee H., Kim H.G., Ha K., Hamamoto J., Fukunaga K., Maekawa A., Tanabe M., Ishihara S., Hamamoto Y., Yasuda H., Sekine S., Kudo A., Kitagawa Y., Kanai T., Nakagawa H., Sato T.

Cell （Cell）  183 （ 5 ） 1420 - 1435.e21 2020年11月

ISSN  00928674

　概要を見る

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes. Gastroenteropancreatic neuroendocrine neoplasms are a rare but lethal cancer with a scarcity of clinically relevant models. Kawasaki et al. establish and characterize 25 organoid lines to identify molecular subtypes with genotype-phenotype mapping.

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Mucosal concentrations of N-acetyl-5-aminosalicylic acid related to endoscopic activity in ulcerative colitis patients with mesalamine

Fukuda T., Naganuma M., Takabayashi K., Hagihara Y., Tanemoto S., Nomura E., Yoshimatsu Y., Sugimoto S., Nanki K., Mizuno S., Mikami Y., Fukuhara K., Sujino T., Mutaguchi M., Inoue N., Ogata H., Iwao Y., Abe T., Kanai T.

Journal of Gastroenterology and Hepatology (Australia) （Journal of Gastroenterology and Hepatology (Australia)）  35 （ 11 ） 1878 - 1885 2020年11月

ISSN  08159319

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Background and Aim: 5-Aminosalicylic acid (5-ASA) is a fundamental treatment for mild-to-moderate ulcerative colitis (UC). 5-ASA is taken up into the colonic mucosa and metabolized to N-acetyl-5-ASA (Ac-5-ASA). Few studies have assessed whether mucosal 5-ASA and Ac-5-ASA concentrations are associated with endoscopic remission. This study aimed to investigate differences in 5-ASA and Ac-5-ASA concentrations according to endoscopic activity. Methods: This single-center, prospective, cross-sectional study was conducted between March 2018 and February 2019. UC patients who were administered with 5-ASA medication for at least 8 weeks before sigmoidoscopy were enrolled. Mucosal 5-ASA and Ac-5-ASA concentrations were measured using liquid chromatography with tandem mass spectrometry. The primary endpoint was defined as the difference in mucosal concentrations of 5-ASA and Ac-5-ASA, according to the Mayo endoscopic subscore (MES). Results: Mucosal concentrations were analyzed in 50 patients. In the sigmoid colon, the median 5-ASA concentration in patients with MES of 0 (17.3 ng/mg) was significantly higher than MES ≥ 1 (6.4 ng/mg) (P = 0.019). The median 5-ASA concentrations in patients with Ulcerative Colitis Endoscopic Index of Severity ≤ 1 (16.4 ng/mg) were also significantly higher than in patients with Ulcerative Colitis Endoscopic Index of Severity ≥ 2 (4.63 ng/mg) (P = 0.047). In the sigmoid colon, the concentration of Ac-5-ASA was higher in patients with MES of 0 (21.2 ng/mg) than in patients with MES ≥ 1 (5.81 ng/mg) (P = 0.022). Conclusions: The present study showed that mucosal Ac-5-ASA concentrations, as well as 5-ASA concentrations, are higher in UC patients with endoscopic remission. Ac-5-ASA may be useful for a biomarker of 5-ASA efficacy.

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The liver–brain–gut neural arc maintains the T<inf>reg</inf> cell niche in the gut

Teratani T., Mikami Y., Nakamoto N., Suzuki T., Harada Y., Okabayashi K., Hagihara Y., Taniki N., Kohno K., Shibata S., Miyamoto K., Ishigame H., Chu P.S., Sujino T., Suda W., Hattori M., Matsui M., Okada T., Okano H., Inoue M., Yada T., Kitagawa Y., Yoshimura A., Tanida M., Tsuda M., Iwasaki Y., Kanai T.

Nature （Nature）  585 （ 7826 ） 591 - 596 2020年09月

ISSN  00280836

　概要を見る

Recent clinical and experimental evidence has evoked the concept of the gut–brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders1–4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver–brain–gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut.

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Clinical features of cardiac nodularity-like appearance induced by Helicobacter pylori infection

Nishizawa T., Sakitani K., Yoshida S., Kataoka Y., Toyoshima O., Ebinuma H., Suzuki H., Nakai Y., Koike K., Kanai T.

World Journal of Gastroenterology （World Journal of Gastroenterology）  26 （ 35 ） 5354 - 5361 2020年09月

ISSN  10079327

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Background: We have previously reported that Helicobacter pylori (H. pylori)-associated nodular gastritis could occur in both the antrum and the cardia. Cardiac nodularity-like appearance (hereafter, called as cardiac nodularity) had a high predictive accuracy for the diagnosis of H. pylori infection. In the previous study, we included only the patients who were evaluated for H. pylori infection for the first time, and excluded patients with a history of eradication. Therefore, the prevalence and clinical features of cardiac nodularity remains unknown. Aim: To perform this cross-sectional study to explore the characteristics of cardiac nodularity. Methods: Consecutive patients who underwent esophagogastroduodenoscopy between May, 2017 and August, 2019 in the Toyoshima Endoscopy Clinic were enrolled in this study. We included H. pylori-negative, H. pylori-positive, and H. pylorieradicated patients, and excluded patients with unclear H. pylori status and eradication failure. H. pylori infection was diagnosed according to serum anti-H. pylori antibody and the urea breath test or histology. Cardiac nodularity was defined as a miliary nodular appearance or the presence of scattered whitish circular small colorations within 2 cm of the esophagogastric junction. Nodularity was visualized as whitish in the narrow-band imaging mode. We collected data on the patients' baseline characteristics. Results: A total of 1078 patients were finally included. Among H. pylori-negative patients, cardiac nodularity and antral nodularity were recognized in 0.14% each. Among H. pylori-positive patients, cardiac nodularity and antral nodularity were recognized in 54.5% and 29.5%, respectively. Among H. pylori-eradicated patients, cardiac nodularity and antral nodularity were recognized in 4.5% and 0.6%, respectively. The frequency of cardiac nodularity was significantly higher than that of antral nodularity in H. pylori-positive and -eradicated patients. The frequencies of cardiac nodularity and antral nodularity in H. pylori-eradicated patients were significantly lower than those in H. pylori-positive patients (P < 0.001). The patients with cardiac nodularity were significantly younger than those without cardiac nodularity (P = 0.0013). Intestinal metaplasia score of the patients with cardiac nodularity were significantly lower than those without cardiac nodularity (P = 0.0216). Among H. pylori-eradicated patients, the patients with cardiac nodularity underwent eradication significantly more recently compared with those without cardiac nodularity (P < 0.0001). Conclusion: This report outlines the prevalence and clinical features of cardiac nodularity, and confirm its close association with active H. pylori infection.

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Horibe GI bleeding prediction score: a simple score for triage decision-making in patients with suspected upper GI bleeding

Horibe M., Iwasaki E., Bazerbachi F., Kaneko T., Matsuzaki J., Minami K., Masaoka T., Hosoe N., Ogura Y., Namiki S., Hosoda Y., Ogata H., Chan A.T., Kanai T.

Gastrointestinal Endoscopy （Gastrointestinal Endoscopy）  92 （ 3 ） 578 - 588.e4 2020年09月

ISSN  00165107

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Background and Aims: Although upper GI bleeding (UGIB) is a significant cause of inpatient admissions, no scoring method has proven to be accurate and simple as a standard for triage purposes. Therefore, we compared a previously described 3-variable score (1 point each for absence of daily proton pump inhibitor use in the week before the index presentation, shock index [heart rate/systolic blood pressure] ≥1, and blood urea nitrogen/creatinine ≥30 [urea/creatinine≥140]), the Horibe gAstRointestinal BleedING scoRe (HARBINGER), with the 8-variable Glasgow-Blatchford Score (GBS) and 5-variable AIMS65 to evaluate and validate the accuracy in predicting high-risk features that warrant admission and urgent endoscopy. Methods: Consecutive patients presenting with suspected UGIB between 2012 and 2015 were prospectively enrolled in 3 acute care Japanese hospitals. On presentation to the emergency setting, an endoscopy was performed in a timely fashion. The primary outcome was the prediction of high-risk endoscopic stigmata. Results: Of 1486 enrolled patients, 637 (43%) harbored high-risk endoscopic stigmata according to international consensus statements. The area under the receiver operating characteristic curve (AUC) for the HARBINGER was.76 (95% confidence interval [CI],.72-.79), which was significantly superior to both the GBS (AUC,.68; 95% CI,.64-.71; P <.001) and the AIMS65 (AUC,.54; 95% CI,.50-.58; P <.001). When the HARBINGER cutoff value was set at 1 to rule out patients who needed admission and urgent endoscopy, its sensitivity and specificity was 98.8% (95% CI, 97.9-99.6) and 15.5% (95% CI, 13.1-18.0), respectively. Conclusions: The HARBINGER, a simple 3-variable score, provides a more accurate method for triage of patients with suspected UGIB than both the GBS and AIMS65.

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Efficacy of novel ultrathin single-balloon enteroscopy for Crohn's disease: A propensity score-matched study

Takabayashi K., Hosoe N., Kato M., Hayashi Y., Miyanaga R., Nanki K., Fukuhara K., Mikami Y., Mizuno S., Sujino T., Mutaguchi M., Naganuma M., Yahagi N., Ogata H., Kanai T.

Gut and Liver （Gut and Liver）  14 （ 5 ） 619 - 625 2020年09月

ISSN  19762283

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Background/Aims: The evaluation of small bowel lesions of Crohn's disease (CD) using balloon-assisted enteroscopy (BAE) is crucial because mucosal healing is associated with a good prognosis. However, BAE procedures are invasive, requiring sedation or analgesia to reduce the patient's pain. This study evaluated the clinical usefulness of a novel ultrathin single-balloon enteroscopy (SBE) procedure for CD. Methods: This single-center retrospective study included 102 CD patients who underwent trans-anal SBE between January 2012 and May 2018. Of these patients, 82 underwent enteroscopy using conventional SBE, while 20 underwent ultrathin SBE. Patients were analyzed using propensity score matching, with 20 patients per group. The median duration of the examination, terminal ileum intubation rate, median cecum intubation time, median insertion depth, adverse events, and sedated dose in each group were compared. Results: Before propensity score matching, the conventional SBE group had a larger number of surgical history patients than the ultrathin SBE group (p=0.05). After matching, the two groups did not significantly differ clinically. There were no significant differences in the mean duration of the examination, cecum intubation time, or terminal ileal intubation rate between ultrathin SBE and conventional SBE. The mean insertion depth of ultrathin SBE tended to be deeper than that of conventional SBE (p=0.09). The use of ultrathin SBE also reduced the sedative dose during needed for enteroscopy compared with conventional SBE (p=0.005). Conclusions: Novel ultrathin SBE may be less painful for CD patients than conventional SBE.

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