Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
UMENO JUNJI Last modified date:2022.05.02

Assistant Professor / Department of Medicine and Clinical Science, Graduate School of Medical Sciences / Department of Gastroenterology / Kyushu University Hospital

1. Esaki M, Matsumoto T, Hirakawa K, Nakamura S, Umeno J, Koga H, Yao T, Iida M, Risk factors for local recurrence of superficial esophageal cancer after treatment by endoscopic mucosal resection., Endoscopy, 10.1055/s-2006-945143, 39, 1, 41-45, 2007.01.
2. Umeno J, Matsumoto T, Nakamura S, Jo Y, Yada S, Hirakawa K, Yoshimura R, Yamagata H, Kudo T, Hirano A, Gushima M, Yao T, Nakashima Y, Iida M, Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis., Gastrointest Endosc, 10.1016/j.gie.2008.02.013, 67, 7, 1185-91, 2008.01, BACKGROUND: Although some cases of collagenous colitis have been induced by lansoprazole (LPZ), the clinicopathologic features of LPZ-associated collagenous colitis have not been elucidated. OBJECTIVE: To elucidate the clinical, endoscopic, and histopathologic features of LPZ-associated collagenous colitis. DESIGN: Retrospective case study. PATIENTS: The subjects were 13 patients with collagenous colitis diagnosed during a period from 2002 to 2007. MAIN OUTCOME MEASUREMENTS: The colonoscopic and histopathologic findings were compared retrospectively between 9 cases of LPZ use (LPZ group) and 4 cases without the use of LPZ (non-LPZ group). RESULTS: A colonoscopy revealed a linear mucosal defect more frequently in the LPZ group (7 of 9 cases [78%]) than in the non-LPZ group (0 of 4 cases [0%], P = .02). Friable mucosa was also noted in 4 patients (44%) in the LPZ group but none in the non-LPZ group. The colonoscopic finding in the non-LPZ group was either normal mucosa or nonspecific minimal abnormalities, whereas patients in the LPZ group had either a linear mucosal defect, mucosal bleeding, or both (P = .001). On histologic examination, the subepithelial collagen band was thicker in patients in the LPZ group than in those in the non-LPZ group (median 45 vs 26.3 mum). All patients in the LPZ group recovered from diarrhea after discontinuance of LPZ. LIMITATION: A small number of patients. CONCLUSIONS: Linear mucosal defects and friable mucosa may be characteristic colonoscopic findings in cases of LPZ-associated collagenous colitis..
3. Asano K, Matsushita T, Umeno J, Hosono N, Takahashi A, Kawaguchi T, Matsumoto T, Matsui T, Kakuta Y, Kinouchi Y, Shimosegawa T, Hosokawa M, Arimura Y, Shinomura Y, Kiyohara Y, Tsunoda T, Kamatani N, Iida M, Nakamura Y, Kubo M, A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population, Nat Genet, 10.1038/ng.482, 41, 12, 1325-9, 2009.12, Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 x 10(-12)), a locus on chromosome 13q12 (rs17085007, P = 6.64 x 10(-8)) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 x 10(-8)). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis..
4. Matsushita T, Umeno J, Hirakawa Y, Yonemoto K, Ashikawa K, Amitani H, Ninomiya T, Hata J, Doi Y, Kitazono T, Iida M, Nakamura Y, Kiyohara Y, Kubo M, Association study of the polymorphisms on chromosome 12p13 with atherothrombotic stroke in the Japanese population, J Hum Genet, 10.1038/jhg.2010.45, 55, 7, 473-6, 2010.07, Recent genome-wide association study using four prospective population-based cohorts identified two single-nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579, to be significantly associated with the incidence of atherothrombotic stroke. To examine the association of these SNPs with atherothrombotic stroke in the Japanese population, we carried out a case-control association study using a total of 3784 cases and 3102 controls. We also examined the effect of these SNPs on the subtypes of ischemic stroke. Association analysis was carried out using logistic regression model after adjustment of age, sex and cardiovascular risk factors. Rs12425791 was significantly associated with atherothrombotic stroke (P=0.0084, odds ratio (OR)=1.15). When we analyzed effects of rs12425791 on ischemic stroke subtypes, rs12425791 was significantly associated with both small-artery occlusion (P=0.015, OR=1.15) and large-artery atherosclerosis (P=0.024, OR=1.19). Rs11833579 showed no association with atherothrombotic stroke or its subtypes in our population. Our data suggest that rs12425791 on chromosome 12p13 is a genetic marker for atherothrombotic stroke in multiethnic population..
5. Umeno J, Matsumoto T, Esaki M, Kukita Y, Tahira T, Yanaru-Fujisawa R, Nakamura S, Arima H, Hirahashi M, Hayashi K, Iida M, Impact of group IVA cytosolic phospholipase A2 gene polymorphisms on phenotypic features of patients with familial adenomatous polyposis, Int J Colorectal Dis, 10.1007/s00384-009-0808-x, 25, 3, 293-301, 2010.10, OBJECTIVE: Group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) plays a key role in tumorigenesis via generating arachidonic acids as the substrate of cyclooxygenase. The aim of this study was to elucidate the possible associations between cPLA ( 2 )alpha gene polymorphisms and phenotypic features of patients with familial adenomatous polyposis (FAP). PATIENTS AND METHODS: A tag single nucleotide polymorphisms (SNPs)-based genotype-phenotype association study of the cPLA ( 2 )alpha gene was conducted in 73 Japanese patients from 59 families with FAP. Based on the HapMap database, seven tag SNPs of the cPLA ( 2 )alpha gene were selected and genotyped by direct sequencing analysis. The genotype-phenotype association in relation to the adenomatous polyposis coli (APC) gene mutation was also assessed. RESULTS: The single SNP analysis showed that rs3820185 C allele [odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2-4.9] and rs127446200 GG genotype (OR, 10.9; 95%CI, 1.6-69.8), were more frequent in patients with gastric fundic gland polyposis (FGP) than in those without. Rs12749354 C allele was more frequently found in patients with small intestinal adenoma (OR, 7.0; 95% CI, 1.5-30.4; p = 0.008). This association was also significant when adjusted for covariates (age, sex, and APC mutation) in a logistic regression analysis (adjusted OR, 7.4; 95% CI, 1.2-64.2; p = 0.027). CONCLUSIONS: The cPLA ( 2 )alpha gene may be a possible disease modifier gene in FAP..
6. Okada Y, Yamazaki K, Umeno J, Takahashi A, Kumasaka N, Ashikawa K, Aoi T, Takazoe M, Matsui T, Hirano A, Matsumoto T, Kamatani N, Nakamura Y, Yamamoto K, Kubo M, HLA-Cw*1202-B*5201-DRB1*1502 Haplotype Increases Risk for Ulcerative Colitis but Reduces Risk for Crohn's Disease, Gastroenterology, 10.1053/j.gastro.2011.05.048, 141, 3, 864-871, 2011.09, BACKGROUND & AIMS: There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohn's disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined. METHODS: We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD. RESULTS: The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 × 10⁻⁷⁰; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw*1202-B*5201-DRB1*1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 × 10⁻³³; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 × 10⁻²¹; OR = 2.65), but reduces risk for CD (P = 1.1 × 10⁻⁷; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 × 10⁻¹⁹ and P = 7.2 × 10⁻⁵, respectively). CONCLUSIONS: The HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population..
7. Umeno J, Asano K, Matsushita T, Matsumoto T, Kiyohara Y, Iida M, Nakamura Y, Kamatani N, Kubo M, Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn's disease and ulcerative colitis, Inflamm Bowel Dis, 10.1002/ibd.21651, 17, 12, 2407-15, 2011.12, BACKGROUND: Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies. METHODS: We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects. RESULTS: We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R. CONCLUSIONS: These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC..
8. Significance of Gastric Involvement in Gastrointestinal Polyposis Syndromes.
9. Hirano A, Yamazaki K, Umeno J, Ashikawa K, Aoki M, Matsumoto T, Nakamura S, Ninomiya T, Matsui T, Hirai F, Kawaguchi T, Takazoe M, Tanaka H, Motoya S, Kiyohara Y, Kitazono T, Nakamura Y, Kamatani N, Kubo M, Association study of 71 European Crohn's disease susceptibility loci in a Japanese population, Inflamm Bowel Dis, 10.1097/MIB.0b013e31828075e7, 19, 3, 526-533, 2013.03, BACKGROUND: A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohn's disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations. METHODS: We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran-Armitage trend test. In addition, genotype-phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification. RESULTS: Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype-phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes. CONCLUSIONS: Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations..
10. Yamazaki K, Umeno J, Takahashi A, Hirano A, Johnson TA, Kumasaka N, Morizono T, Hosono N, Kawaguchi T, Takazoe M, Yamada T, Suzuki Y, Tanaka H, Motoya S, Hosokawa M, Arimura Y, Shinomura Y, Matsui T, Matsumoto T, Iida M, Tsunoda T, Nakamura Y, Kamatani N, Kubo M, A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population., Gastroenterology, 10.1053/j.gastro.2012.12.021, 144, 4, 781-788, 2013.04, BACKGROUND & AIMS: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population. METHODS: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS: We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27). CONCLUSIONS: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease..
11. Daisuke Oryoji, Tadakazu Hisamatsu, Kiichiro Tsuchiya, Umeno Junji, Associations of HLA class I alleles in Japanese patients with Crohn's disease, 10.1038/gene.2014.61, 16, 1, 54-56, 2015.01.
12. Kouichi Asano, Junji Umeno, Yuji Maehata, Motohiro Esaki, Moriyama Tomohiko, Atsushi Hirano, Kitazono T, Contribution of susceptibility variants at FCGR2A and 13q12 to the risk of relapse among Japanese patients with ulcerative colitis., Journal of gastroenterology, 10.1007/s00535-015-1062-3, 50, 11, 1094-1102, 2015.11, BACKGROUND: Recent genome-wide association studies have identified nearly 100 susceptibility genes for ulcerative colitis (UC). However, the contribution of susceptibility variants for UC to clinical outcome has scarcely been reported. The aim of this study was to investigate whether UC-associated genetic variants confer a risk of clinical relapse. METHODS: One hundred and nine consecutive Japanese subjects with quiescent UC were recruited. Four genetic variants of HLA-DRB1*1502, rs6671847 at FCGR2A, rs17085007 at 13q12, and rs2108225 at SLC26A3 were genotyped by Invader assay. The clinical courses were followed after blood sampling, and the risk of relapse according to these genotypes was calculated by Cox proportional hazard model. RESULTS: During the mean follow-up period of 35 months (range 1-81 months), 49 of 109 subjects (45 %) relapsed. Carriers of the G allele of rs6671847 showed an increased risk of relapse compared with non-carriers [adjusted hazard ratio (HR), 2.27; 95 % confidence interval (CI), 1.20-4.32; p = 0.01]. Patients with the CT or TT genotypes of rs17085007 also had an increased risk of relapse compared to subjects with the CC genotype (for CT: adjusted HR, 2.16; 95 % CI, 1.10-4.23; p = 0.03; for TT: adjusted HR, 3.25; 95 % CI, 1.18-8.95; p = 0.02). These two risk variants multiplied the risk of relapse by 2.74 times (95 % CI, 1.10-4.23; p = 0.01) in patients with one risk genotype and 5.40 times (95 % CI, 2.06-14.13; p = 0.0006) in patients with both risk genotypes. CONCLUSIONS: Genetic variants of rs6671847 at FCGR2A and rs17085007 at 13q12 conferred a risk of relapse in patients with UC..
13. Yutaka Nagata, motohiro esaki, Junji Umeno, Kitazono T, Therapeutic strategy for Crohn's disease with a loss of response to infliximab: a single-center retrospective study., Digestion, 10.1159/000368815, 91, 1, 50-56, 2015.01, BACKGROUND/AIMS:

Infliximab (IFX) is an effective treatment for maintaining clinical remission in patients with initially moderate-to-severe Crohn's disease (CD). However, a certain number of patients become unresponsive to IFX, subsequently requiring i.
14. Umeno Junji, Pediatric-onset Chronic Nonspecific Multiple Ulcers of Small Intestine: A Nationwide Survey and Genetic Study in Japan, JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION, 10.1097/MPG.0000000000001321, 64, 4, 565-568, 2017.04, We performed a Japanese nationwide survey of pediatric-onset chronic nonspecific multiple ulcers of the small intestine between January 2000 and July 2013 in 176 institutions of pediatric surgery or pediatric gastroenterology and clarified the clinical features associated with genetic abnormalities in the Solute Carrier Organic Anion Transporter Family, Member 2A1 (SLCO2A1) gene. A total of 4 cases (3 girls and 1 boy) were diagnosed in this series, which had to be differentiated from Crohn disease, Behçet disease, tuberculosis, or drug-induced enteropathy. Clinical symptoms appeared in infants and accurate diagnosis required several years. Medical therapies for inflammatory bowel disease were administered in all patients; however, 2 of the 4 patients had mutation in the SLCO2A1 gene which are responsible for primary hypertrophic osteoarthopathy, and underwent strictureplasty or ileal resection after long-term follow-up. Pediatric gastroenterologists should include this new entity in the differential diagnosis of small intestinal ulcers and inflammatory bowel disease..
15. Distinction between Chronic Enteropathy Associated with the SLCO2A1 Gene and Crohn's Disease.
Background/Aims: We recently identified recessive mutations in the solute carrier organic anion transporter family member 2A1 gene (SLCO2A1) as causative variants of chronic nonspecific multiple ulcers of the small intestine (chronic enteropathy associated with SLCO2A1, CEAS). The aim of this study was to investigate the gastroduodenal expression of the SLCO2A1 protein in patients with CEAS and Crohn's disease (CD). Methods: Immunohistochemical staining for SLCO2A1 was performed with a polyclonal antibody, HPA013742, on gastroduodenal tissues obtained by endoscopic biopsy from four patients with CEAS and 29 patients with CD. Results: The expression of SLCO2A1 was observed in one of four patients (25%) with CEAS and in all 29 patients (100%) with CD (p<0.001). The three patients with CEAS without SLCO2A1 expression had a homozygous splice-site mutation in SLCO2A1, c.1461+1G>C (exon 7) or c.940+1G>A (exon 10). The remaining one CEAS patient with positive expression of SLCO2A1 had compound heterozygous c.664G>A and c.1807C>T mutations. Conclusions: Immunohistochemical staining for SLCO2A1 in gastroduodenal tissues obtained by endoscopic biopsy is considered useful for the distinction of CEAS from CD..
16. Clinical features of chronic enteropathy associated with SLCO2A1 gene: a new entity clinically distinct from Crohn's disease.
BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is a hereditary disease caused by mutations in the SLCO2A1 gene and characterized by multiple small intestinal ulcers of nonspecific histology. SLCO2A1 is also a causal gene of primary hypertrophic osteoarthropathy (PHO). However, little is known about the clinical features of CEAS or PHO. METHODS: Sixty-five Japanese patients recruited by a nationwide survey of CEAS during 2012-2016 were enrolled in this present study. We reviewed the clinical information of the genetically confirmed CEAS patients. RESULTS: We identified recessive SLCO2A1 mutations at 11 sites in 46 patients. Among the 46 patients genetically confirmed as CEAS, 13 were men and 33 were women. The median age at disease onset was 16.5 years, and parental consanguinity was present in 13 patients (28%). Anemia was present in 45 patients (98%), while a single patient experienced gross hematochezia. All patients showed relatively low inflammatory markers in blood tests (median CRP 0.20 mg/dl). The most frequently involved gastrointestinal site was the ileum (98%), although no patient had mucosal injuries in the terminal ileum. Mild digital clubbing or periostosis was found in 13 patients (28%), with five male patients fulfilling the major diagnostic criteria of PHO. CONCLUSIONS: The clinical features of CEAS are distinct from those of Crohn's disease. Genetic analysis of the SLCO2A1 gene is therefore recommended in patients clinically suspected of having CEAS..
17. Successful azathioprine treatment in an adolescent with chronic enteropathy associated with SLCO2A1 gene: A case report.
INTRODUCTION: Chronic nonspecific multiple ulcers of the small intestine (CNSU), an entity with female preponderance and manifestations including anemia and hypoproteinemia reflecting persistent gastrointestinal bleeding and intestinal protein loss, has been considered idiopathic. Umeno et al recently reported that CNSU is caused by loss-of-function mutations in the solute carrier organic anion transporter family member 2A1 gene (SLCO2A1) encoding a prostaglandin transporter, renaming the disorder "chronic enteropathy associated with SLCO2A1 gene mutation" (CEAS). Treatments for chronic enteropathies such as inflammatory bowel disease, including 5-aminosalicylic acid, corticosteroids, azathioprine, and anti-tumor necrosis factor-α antibody, often are ineffective in CEAS, which frequently requires surgery. CASE PRESENTATION: A 14-year-old girl had refractory anemia and hypoproteinemia for more than 2 years. Video capsule endoscopy showed nonspecific jejunal and ileal ulcers with varied sizes and shapes. She was diagnosed with CEAS resulting from compound heterozygous mutation of the SLCO2A1 gene. After corticosteroid treatment without improvement, azathioprine treatment improved her anemia and edema as hemoglobin and serum protein increased. Video capsule endoscopy 1 year after initiation of azathioprine showed improvement of small intestinal ulcers. CONCLUSION: Physicians should consider CEAS in patients with refractory anemia, hypoproteinemia, and multiple small intestinal ulcers. Why our patient responded to azathioprine but not to corticosteroids is unclear, but azathioprine might benefit some other patients with CEAS..
18. Capsule endoscopy findings for the diagnosis of Crohn's disease: a nationwide case-control study.
BACKGROUND: Capsule endoscopy can be used to identify the early stage of small bowel Crohn's disease (CD). We evaluated significant small bowel capsule endoscopy (SBCE) findings that can lead to early diagnosis of CD. METHODS: We retrospectively accumulated clinical and SBCE data of 108 patients (63 with and 45 without CD). Types of small bowel mucosal injuries, including erosion, ulceration, and cobblestone appearance, and the alignment of diminutive lesions were compared between patients with and without CD. Inter- and intra-observer agreement in the determination of lesions was assessed in 25 pairs of SBCE from the two groups. RESULTS: Under SBCE, cobblestone appearance (33% vs. 2%, p < 0.0001), longitudinal ulcers (78% vs. 20%, p < 0.0001), and irregular ulcers (84% vs. 60%, p < 0.01) were more frequently found in patients with CD. Linear erosion (90% vs. 38%, p < 0.0001) and irregular erosion (89% vs. 64%, p < 0.005) were also more frequent in patients with CD. Furthermore, circumferential (75% vs. 9%, p < 0.0001) and longitudinal (56% vs. 7%, p < 0.0001) alignment of diminutive lesions, mainly observed in the 1st tertile of the small bowel, was more frequent in patients with CD. Good intra-observer agreement was found for ulcers, cobblestone appearance, and lesion alignment. However, inter-observer agreement of SBCE findings differed among observers. CONCLUSIONS: Circumferential or longitudinal alignment of diminutive lesions, especially in the upper small bowel, may be a diagnostic clue for CD under SBCE, while inter-observer variations should be cautiously considered when using SBCE..
19. Comparison of the microbial community structure between inflamed and non-inflamed sites in patients with ulcerative colitis.
BACKGROUND AND AIM: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC-related changes. We thus investigated paired mucosa-associated microbiota obtained from both inflamed and non-inflamed sites of UC patients and corresponding sites of non-inflammatory bowel disease (IBD) controls. METHODS: Mucosal biopsies of both inflamed and non-inflamed sites were obtained from 14 patients with active UC of the left-sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non-IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using qiime and LEfSe softwares. RESULTS: Microbial alpha diversity in both inflamed and non-inflamed sites was significantly lower in UC patients compared with non-IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non-inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non-IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the non-inflamed site of UC patients compared with the corresponding site in non-IBD controls. CONCLUSIONS: Mucosal microbial dysbiosis occurs at both inflamed and non-inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation..
20. Chronic Enteropathy Associated With SLCO2A1 Gene [CEAS]-Characterisation of an Enteric Disorder to be Considered in the Differential Diagnosis of Crohn's Disease.
Small intestinal ulcers include mucosal damage caused by drugs, particularly nonsteroidal anti-inflammatory drugs [NSAIDs], infectious diseases, and idiopathic inflammatory bowel disease. Previously, a group of Japanese investigators reported an unusual and uncommon type of enteritis and referred to the condition as chronic nonspecific multiple ulcers of the small intestine [CNSU]. CNSU is characterised by chronic blood and protein loss through persistent small intestinal ulcers. Recently, four candidate mutations in the solute carrier organic anion transporter family, member 2A1 [SLCO2A1] gene, encoding a prostaglandin transporter, were identified by whole-exome sequencing in patients with CNSU. However, because the name 'CNSU' was somewhat ambiguous, the more appropriate nomenclature of 'chronic enteropathy associated with the SLCO2A1 gene' [CEAS] has been suggested. CEAS ulcers are characterised by multiple, circular or eccentric oblique, shallow lesions with discrete margins. The most frequently affected site of CEAS is the ileum, in contrast to 'cryptogenic multifocal ulcerous stenosing enteritis [CMUSE]', for which the most frequent site is the jejunum. Impaired prostaglandin utilisation is thought to cause the small intestinal mucosal damage observed in CEAS, CMUSE, and NSAID-induced enteropathy. This review article focuses on endoscopic and clinical features of genetically diagnosed CEAS, accumulated in a nationwide survey, and illustrates the observations in the format of an atlas..
21. Characteristics of Primary and Metachronous Gastric Cancers Discovered after Helicobacter pylori Eradication: A Multicenter Propensity Score-Matched Study.
Background/Aims: Gastric cancers develop even after successful Helicobacter pylori eradication. We aimed to clarify the characteristics of early gastric cancers discovered after H. pylori eradication. Methods: A total of 1,053 patients with early gastric cancer treated by endoscopic submucosal dissection were included. After matching the propensity score, we retrospectively investigated the clinicopathological features of 192 patients, including 96 patients who had undergone successful H. pylori eradication (Hp-eradicated group) and 96 patients who had active H. pylori infection (Hp-positive group). Results: In the Hp-eradicated group, early gastric cancers were discovered 1 to 15 years (median, 4.1 years) after H. pylori eradication. Compared with Hp-positive patients, Hp-eradicated patients showed a more frequently depressed configuration (81% vs 53%, respectively, p<0.0001) and a higher trend toward submucosal invasion (18% vs 8%, respectively, p=0.051). A multivariable analysis revealed the macroscopic depressed type to be characteristics of early gastric cancers after H. pylori eradication. Among patients in the Hp-eradicated group, metachronous cancers showed less frequent depressed lesions (68% vs 84%, respectively, p=0.049) and smaller tumor sizes (median, 11 mm vs 14 mm, respectively, p=0.014) than primary cancers. Conclusions: Early gastric cancers after H. pylori eradication are characterized by a depressed configuration. Careful follow-up endoscopies are necessary after H. pylori eradication..
22. Measurement of prostaglandin metabolites is useful in diagnosis of small bowel ulcerations.
BACKGROUND: We recently reported on a hereditary enteropathy associated with a gene encoding a prostaglandin transporter and referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS). Crohn's disease (CD) is a major differential diagnosis of CEAS, because these diseases share some clinical features. Therefore, there is a need to develop a convenient screening test to distinguish CEAS from CD. AIM: To examine whether prostaglandin E major urinary metabolites (PGE-MUM) can serve as a biomarker to distinguish CEAS from CD. METHODS: This was a transactional study of 20 patients with CEAS and 98 patients with CD. CEAS was diagnosed by the confirmation of homozygous or compound heterozygous mutation of SLCO2A1. We measured the concentration of PGE-MUM in spot urine by radioimmunoassay, and the concentration was compared between the two groups of patients. We also determined the optimal cut-off value of PGE-MUM to distinguish CEAS from CD by receiver operating characteristic (ROC) curve analysis. RESULTS: Twenty Japanese patients with CEAS and 98 patients with CD were enrolled. PGE-MUM concentration in patients with CEAS was significantly higher than that in patients with CD (median 102.7 vs 27.9 μg/g × Cre, P < 0.0001). One log unit increase in PGE-MUM contributed to 7.3 increase in the likelihood for the diagnosis of CEAS [95% confidence interval (CI) 3.2-16.7]. A logistic regression analysis revealed that the association was significant even after adjusting confounding factors (adjusted odds ratio 29.6, 95%CI 4.7-185.7). ROC curve analysis revealed the optimal PGE-MUM cut-off value for the distinction of CEAS from CD to be 48.9 μg/g × Cre with 95.0% sensitivity and 79.6% specificity. CONCLUSION: PGE-MUM measurement is a convenient, non-invasive and useful test for the distinction of CEAS from CD..
23. Anti-tumor necrosis factor therapy decreases the risk of initial intestinal surgery after diagnosis of Crohn's disease of inflammatory type.
BACKGROUND: Anti-tumor necrosis factor (TNF) therapy induces and maintains clinical remission in patients with Crohn's disease (CD). However, the effect of anti-TNF therapy on the natural course of CD remains controversial. We aimed to investigate the effect of anti-TNF therapy on the initial intestinal surgery for CD. METHODS: In this single-center retrospective cohort study, clinical course of 199 CD patients of inflammatory type at the initial diagnosis (the period between 1973 and 2014) was precisely reviewed until the end of 2016. Patients were divided into TNF and non-TNF groups based on anti-TNF agent use. After comparisons of clinical characteristics and medical treatments, propensity scores were calculated for covariates. Risk of intestinal surgery was compared by a Cox proportional hazards model using the propensity scores. The effect of immunomodulators on initial intestinal surgery was assessed in the TNF group. RESULTS: During the study period, 108 patients received anti-TNF therapy. The patients in the TNF group were diagnosed more recently, and more frequently had isolated colonic involvement, and perianal disease. Immunomodulators were more frequently used in the TNF group. Cumulative probability of initial intestinal surgery was significantly lower in the TNF group (P < 0.0001). The hazard ratio in the TNF group was 0.32 (95% CI 0.13-0.74). Immunomodulators did not decrease the risk of initial intestinal surgery. CONCLUSIONS: Anti-TNF therapy can decrease the risk of intestinal surgery among patients with inflammatory-type CD at the initial diagnosis. Further studies should be necessary to determine the additive effect of immunomodulators on the risk of intestinal surgery..
24. Long-term retention of adalimumab treatment and associated prognostic factors for 1189 patients with Crohn's disease.
BACKGROUND AND AIM: There are few studies on the long-term efficacy of adalimumab treatment for patients with Crohn's disease. We have conducted a large, multicenter, retrospective cohort study to evaluate the long-term retention rate and prognostic factors associated with the discontinuation of adalimumab treatment in patients with Crohn's disease. METHODS: Data were collected from all patients with Crohn's disease who had received at least one induction dose of 160 mg of adalimumab between October 2010 and December 2013 at 41 institutions. The cumulative retention rates of adalimumab treatment following the first administration were estimated using the Kaplan-Meier method. Prognostic factors related to the cumulative retention rates were evaluated by log-rank tests and multivariate Cox regression analysis. RESULTS: A total of 1189 patients were included in the study. The 1-, 2-, 3-, and 4-year cumulative retention rates of adalimumab were 81%, 72%, 65%, and 62%, respectively. The multivariate Cox regression analysis confirmed female sex, previous infliximab use, perianal disease, concomitant treatment with prednisolone at baseline, higher C-reactive protein levels, and lower albumin levels as significant independent predictors of poor retention rate of adalimumab treatment. Significantly, more female patients than male patients discontinued adalimumab because of adverse events, especially skin reactions, infections, and arthralgia. CONCLUSIONS: Our data demonstrated a good retention rate of adalimumab in patients with Crohn's disease over a 4-year period. Female sex, perianal disease, concomitant treatment with prednisolone at baseline, previous infliximab use, higher C-reactive protein levels, and lower albumin levels were associated with poor retention of adalimumab treatment..
25. Keizo Zeze, Atsushi Hirano, Takehiro Torisu, Motohiro Esaki, Hiroki Shibata, Tomohiko Moriyama, Junji Umeno, Shin Fujioka, Yasuharu Okamoto, Yuta Fuyuno, Yuichi Matsuno, Takanari Kitazono, Mucosal dysbiosis in patients with gastrointestinal follicular lymphoma, Hematological Oncology, 10.1002/hon.2717, 38, 2, 181-188, 2020.04, Because the pathogenesis of gastrointestinal follicular lymphoma (GI-FL) remains unclear, no standardized treatment strategy has been established. Of the gastrointestinal lymphomas, gastric mucosa-associated lymphoid tissue lymphomas are strongly associated with Helicobacter pylori; hence, the microbiota may be involved in GI-FL pathogenesis. However, the association between GI-FL and the microbiota remains uninvestigated. Therefore, we compared the mucosal microbiotas of GI-FL patients with those of controls to identify microbiota changes in GI-FL patients. Mucosal biopsy samples were obtained from the second portion of the duodenum from 20 GI-FL patients with duodenal lesions and 20 controls. Subsequent 16S rRNA gene sequencing was performed on these samples. QIIME pipeline and LEfSe software were used to analyze the microbiota. The GI-FL patients had significantly lower alpha diversity (P =.049) than did the controls, with significant differences in the microbial composition (P =.023) evaluated by the beta diversity metrics between the two groups. Comparing the taxonomic compositions indicated that the genera Sporomusa, Rothia, and Prevotella and the family Gemellaceae were significantly less abundant in the GI-FL patients than in the controls. GI-FL patients presented altered duodenal mucosal microbial compositions, suggesting that the microbiota might be involved in the GI-FL pathogenesis..
26. Akira Harada, Takehiro Torisu, Yasuharu Okamoto, Atsushi Hirano, Junji Umeno, Tomohiko Moriyama, Ema Washio, Yuta Fuyuno, Shin Fujioka, Takanari Kitazono, Motohiro Esaki, Predictive Factors for Rebleeding after Negative Capsule Endoscopy among Patients with Overt Obscure Gastrointestinal Bleeding, Digestion, 10.1159/000496826, 101, 2, 129-136, 2020.03, Background: Although capsule endoscopy (CE) is useful to evaluate obscure gastrointestinal bleeding (OGIB), CE does not always identify the responsible lesions in patients with overt OGIB. Objectives: To identify factors predictive of rebleeding after negative CE in patients with overt OGIB. Methods: We retrospectively analyzed the clinical data of 221 patients who underwent CE for overt OGIB. Among 120 patients with negative CE findings, clinical course of 112 patients after CE was followed-up. Clinical factors associated with rebleeding after negative CE and lesions responsible for rebleeding were investigated. Results: Rebleeding was identified in 37 patients (33.0%) during follow-up after negative CE, and 36 patients (32.1%) developed rebleeding within 24 months after negative CE. Multivariate analyses showed that ongoing overt OGIB (OR 2.67; 95% CI 1.07-5.80; p = 0.036) and severe anemia at the initial CE examination (OR 2.54; 95% CI 1.33-4.96; p = 0.005) were independent factors-associated with rebleeding. Rebleeding source was detected in 13 patients. Conclusions: Rebleeding is not a rare condition among patients with overt OGIB after negative CE. Patients with ongoing overt OGIB or severe anemia at the initial CE examination seem to have a higher risk of rebleeding..
27. Yuichi Matsuno, Atsushi Hirano, Takehiro Torisu, Yasuharu Okamoto, Yuta Fuyuno, Shin Fujioka, Junji Umeno, Tomohiko Moriyama, Shuntaro Nagai, Yoshifumi Hori, Minako Fujiwara, Takanari Kitazono, Motohiro Esaki, Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease, Journal of Gastroenterology and Hepatology (Australia), 10.1111/jgh.14823, 35, 3, 412-417, 2020.03, Background and Aim: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. Methods: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan–Meier method. Overall adverse events (AEs) during follow-up were also analyzed. Results: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. Conclusions: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment..
28. Akira Harada, Koichi Kurahara, Tomohiko Moriyama, Takahide Tanaka, Yutaka Nagata, Keisuke Kawasaki, Hiroki Yaita, Yuji Maehata, Junji Umeno, Yumi Oshiro, Tadahiko Fuchigami, Takanari Kitazono, Motohiro Esaki, Takayuki Matsumoto, Risk factors for reflux esophagitis after eradication of Helicobacter pylori, Scandinavian Journal of Gastroenterology, 10.1080/00365521.2019.1671487, 54, 10, 1183-1188, 2019.10, Objective: While there is an association between successful eradication of Helicobacter pylori (HP) and reflux esophagitis (RE), risk factors associated with RE remain obscure. The aim of this study is to determine risk factors associated with the development of RE after HP eradication. Materials and methods: Among all patients treated with successful HP eradication from 2008 to 2016, we retrospectively analyzed those who were free from RE at initial esophagogastroduodenoscopy (EGD) and who were followed up with EGD after eradication. Patients were classified according to the presence or absence of RE at the follow-up EGD. RE was defined as mucosal breaks proximal to the squamous-columnar junction. Demographic data, underlying diseases, medications and endoscopic findings at the initial EGD were compared between patients with and without RE. Results: Among 1575 patients, 142 (9.0%) had RE at the follow-up EGD. The time interval from HP eradication until EGD ranged from 4 to 24 months. The endoscopic grade of RE was higher in males than in females. Multivariate analysis revealed that male sex (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04–2.24), body mass index ≥25 kg/m2 (OR, 2.91; 95% CI, 2.00–4.22), use of calcium channel blockers (OR, 1.70; 95% CI, 1.12–2.55), and hiatal hernia (OR, 3.46; 95% CI, 2.41–5.00) were associated with the development of RE. Conclusions: Calcium channel blocker use was found to be a risk factor for the development of RE after eradication of HP..
29. Yoichi Kakuta, Yosuke Kawai, Takeo Naito, Atsushi Hirano, Junji Umeno, Yuta Fuyuno, Zhenqiu Liu, Dalin Li, Takeru Nakano, Yasuhiro Izumiyama, Ryo Ichikawa, Daisuke Okamoto, Hiroshi Nagai, Shin Matsumoto, Katsutoshi Yamamoto, Naonobu Yokoyama, Hirofumi Chiba, Yusuke Shimoyama, Motoyuki Onodera, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Kenichi Negoro, Jun Yasuda, Motohiro Esaki, Katsushi Tokunaga, Minoru Nakamura, Takayuki Matsumoto, Dermot P.B. McGovern, Masao Nagasaki, Yoshitaka Kinouchi, Tooru Shimosegawa, Atsushi Masamune, A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals, Journal of Crohn's and Colitis, 10.1093/ecco-jcc/jjy197, 13, 5, 648-658, 2019.01, Background and Aims: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10-19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10-6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10-8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions: RAP1A is a novel susceptibility locus for CD in the Japanese population..
30. Satoko Yamaguchi, Shunichi Yanai, Shotaro Nakamura, Keisuke Kawasaki, Makoto Eizuka, Noriyuki Uesugi, Tamotsu Sugai, Junji Umeno, Motohiro Esaki, Takayuki Matsumoto, Immunohistochemical differentiation between chronic enteropathy associated with SLCO2A1 gene and other inflammatory bowel diseases, Intestinal Research, 10.5217/ir.2018.16.3.393, 16, 3, 393-399, 2018.01, Background/Aims: We recently identified recessive mutations in the solute carrier organic anion transporter family member 2A1 gene (SLCO2A1) as causative variants of chronic enteropathy associated with SLCO2A1 (CEAS). The aim of this study was to evaluate SLCO2A1 protein expression in the intestinal tissues of patients with CEAS, intestinal Behçet's disease (BD), simple ulcer (SU), and Crohn's disease (CD). Methods: Immunohistochemical staining using a polyclonal anti-SLCO2A1 antibody was performed on the resected intestinal specimens from 13 cases of CD, 9 cases of intestinal BD/SU, and 3 cases of CEAS. The extent of SLCO2A1 expression was determined by counting positively-staining vascular endothelial cells and scored as 0 (no cells), 1 (1%-30% cells), 2 (31%-60%), or 3 (>60%). The intensity of SLCO2A1 expression was scored either as 0 (negative), 1 (intermediate), or 2 (strong). The extent score and intensity score were summed for the final score of 0, 2, 3, 4, or 5. Results: SLCO2A1 protein expression was observed in 1 of 3 cases of CEAS (33%), all 13 cases of CD (100%), and all 9 cases of BD/SU (100%). The mean final expression scores of CEAS, CD, and BD/SU were 1.6 (range, 0-5), 4.8 (range, 4-5), and 4.3 (range, 4-5), respectively. The final expression score in CEAS was significantly lower than in CD (P=0.03). Conclusions: Immunohistochemical staining of the SLCO2A1 protein is considered useful to distinguish CEAS from other inflammatory bowel diseases..
31. Akira Sonoda, Yasuhiro Wada, Kazumi Togo, Kazuhiro Mizukami, Yuta Fuyuno, Junji Umeno, Shin Fujioka, Kensuke Fukuda, Kazuhisa Okamoto, Ryo Ogawa, Tadayoshi Okimoto, Kazunari Murakami, Characteristic facial appearance was the key to diagnosing chronic enteropathy associated with SLCO2A1-associated primary hypertrophic osteoarthropathy, Internal Medicine, 10.2169/internalmedicine.3369-19, 59, 4, 491-494, 2020.02, Patients with chronic enteropathy associated with SLCO2A1 (CEAS) develop multiple circular, longitudinal, or eccentric ulcers in the ileum. It is sometimes difficult to distinguish CEAS from Crohn's disease. CEAS and primary hypertrophic osteoarthropathy (PHO) are together known to be caused by a mutation of SLCO2A1 gene. The case of a 65-year-old man whose characteristic appearance due to pachydermia of the forehead folds led to the diagnosis of CEAS with PHO is presented..
32. Tomohiko Moriyama, Junji Umeno, Yoshifumi Hori, Is autofluorescence imaging useful for the diagnosis of dysplasia in ulcerative colitis?, Digestive Endoscopy, 10.1111/den.13337, 31, S1, 45-46, 2019.04.
33. A. Harada, J. Umeno, M. Esaki, Gastrointestinal Multiple venous malformations and polyps of the small intestine in Cowden syndrome, Journal of Gastroenterology and Hepatology (Australia), 10.1111/jgh.14304, 33, 11, 2018.11.
34. Junji Umeno, Takayuki Matsumoto, Atsushi Hirano, Yuta Fuyuno, Motohiro Esaki, Genetic analysis is helpful for the diagnosis of small bowel ulceration, World Journal of Gastroenterology, 10.3748/wjg.v24.i28.3198, 24, 28, 3198-3200, 2018.07, The widespread use of capsule endoscopy and balloonassisted endoscopy has provided easy access for detailed mucosal assessment of the small intestine. However, the diagnosis of rare small bowel diseases, such as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), remains difficult because clinical and morphological features of these diseases are obscure even for gastroenterologists. In an issue of this journal in 2017, Hwang et al reviewed and summarized clinical and radiographic features of 20 patients with an established diagnosis of CMUSE. Recently, recessive mutations in the PLA2G4A and SLCO2A1 genes have been shown to cause small intestinal diseases. The small bowel ulcers in each disease mimic those in the other and furthermore those found in nonsteroidal anti-inflammatory drug-induced enteropathy. These recent and novel findings suggest that a clinical diagnosis exclusively based on the characteristics of small bowel lesions is possibly imprecise. Genetic analyses seem to be inevitable for the diagnosis of rare small bowel disorders such as CMUSE..
35. Shunichi Yanai, Shotaro Nakamura, Satoko Yamaguchi, Keisuke Kawasaki, Kazuyuki Ishida, Tamotsu Sugai, Junji Umeno, Motohiro Esaki, Takayuki Matsumoto, Gastrointestinal mantle cell lymphoma with isolated mass and multiple lymphomatous polyposis report of two cases, Clinical Journal of Gastroenterology, 10.1007/s12328-017-0740-5, 10, 4, 327-330, 2017.08, We herein report two patients with mantle cell lymphoma (MCL), who had isolated mass and multiple lymphomatous polyposis (MLP) in the gastrointestinal tract. In case 1, esophagogastroduodenoscopy revealed a protruding mass in the duodenum and double-balloon endoscopy disclosed numerous polypoid lesions in the ileum. Case 2 had polyposis in the duodenum and a large mass-forming lesion in the ascending colon. Based on the histologic and immunohistochemical findings of the biopsy specimens, the diagnosis of MCL was made in both patients. A combination of isolated mass and MLP is considered as characteristic endoscopic findings of intestinal lesions of MCL..
36. Y. Nuki, J. Umeno, E. Washio, Y. Maehata, A. Hirano, M. Miyazaki, H. Kobayashi, T. Kitazono, T. Matsumoto, M. Esaki, The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury, Alimentary Pharmacology and Therapeutics, 10.1111/apt.14134, 46, 3, 331-336, 2017.08, Background: Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. Aim: To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. Methods: Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. Results: In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. Conclusions: The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole..
37. Taku Kobayashi, Junji Umeno, Tadakazu Hisamatsu, Motohiro Esakp, Toshiyuki Matsui, Takayuki Matsumoto, Toshifumi Hibi, Chronic nonspecific multiple ulcers of the small intestine (CNSU) and chronic enteropathy associated with SLC02A1 (CEAS), Journal of Japanese Society of Gastroenterology, 10.11405/nisshoshi.113.1380, 113, 8, 1380-1385, 2016.08.
38. Yoichiro Nuki, Motohiro Esaki, Kouichi Asano, Yuji Maehata, Junji Umeno, Tomohiko Moriyama, Shotaro Nakamura, Takayuki Matsumoto, Takanari Kitazono, Comparison of the therapeutic efficacy and safety between tacrolimus and infliximab for moderate-to-severe ulcerative colitis A single center experience, Scandinavian Journal of Gastroenterology, 10.3109/00365521.2016.1138239, 51, 6, 700-705, 2016.06, Objective: Both tacrolimus (Tac) and infliximab (IFX) are effective for moderate-to-severe ulcerative colitis (UC). The aim of this study was to compare the therapeutic efficacy and safety of both drugs. Materials and methods: We performed a retrospective analysis of 46 patients with moderate-to-severe UC who were treated either by Tac (n = 21) or IFX (n = 25). We compared the remission and response rates for 10 weeks between the two groups. In patients who achieved a clinical response, the subsequent relapse rate was compared. The overall adverse events were also compared between the two groups. Results: The remission and response rates at week 10 did not differ between patients treated with Tac (67% and 86%, respectively) and patients treated with IFX (76% and 92%, respectively). Among 41 patients showing a clinical response, eight of 23 patients treated with IFX and eight of 18 patients treated with Tac showed a subsequent relapse. The risk of relapse was not different between the two groups. While no serious adverse events were observed, the incidence of adverse events was higher in patients treated with Tac than in those treated with IFX. Conclusion: Tac and IFX may be equally efficacious for the induction and maintenance of remission in patients with UC while minor adverse events are more frequent with the former treatment..
39. Junji Umeno, Tadakazu Hisamatsu, Motohiro Esaki, Atsushi Hirano, Naoya Kubokura, Kouichi Asano, Shuji Kochi, Shunichi Yanai, Yuta Fuyuno, Katsuyoshi Shimamura, Naoki Hosoe, Haruhiko Ogata, Takashi Watanabe, Kunihiko Aoyagi, Hidehisa Ooi, Kenji Watanabe, Shigeyoshi Yasukawa, Fumihito Hirai, Toshiyuki Matsui, Mitsuo Iida, Tsuneyoshi Yao, Toshifumi Hibi, Kenjiro Kosaki, Takanori Kanai, Takanari Kitazono, Takayuki Matsumoto, A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter, PLoS genetics, 10.1371/journal.pgen.1005581, 11, 11, e1005581, 2015.11, Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS)..
40. Miyuki Sawano, Junji Umeno, Motohiro Esaki, An Unusual Cause of Small Intestinal Ulcers, Gastroenterology, 10.1053/j.gastro.2015.02.018, 149, 4, e10-e11, 2015.10.
41. Kakuta Y, Ichikawa R, Fuyuno Y, Hirano A, Umeno J, Torisu T, Watanabe K, Asakura A, Nakano T, Izumiyama Y, Okamoto D, Naito T, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Naito T, Esaki M, Kawai Y, Tokunaga K, Nakamura M, Matsumoto T, Nagasaki M, Kinouchi Y, Unno M, Masamune A, An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations., Sci Rep, 10.1038/s41598-020-66951-5, 10, 1, 10236-10236, 2020.06, Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD..
42. Genetic Analysis of Ulcerative Colitis in Japanese Individuals Using Population-specific SNP Array.
BACKGROUND: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array. METHODS: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction. RESULTS: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02). CONCLUSIONS: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course..
43. Zeze K, Hirano A, Torisu T, Esaki M, Moriyama T, Umeno J, Kawasaki K, Fujioka S, Fuyuno Y, Matsuno Y, Kitazono T, Adding Thiopurine After Loss of Response to Infliximab Versus Early Combination in Treating Crohn's Disease: A Retrospective Study., Dig Dis Sci, 10.1007/s10620-020-06600-z, 66, 9, 3124-3131, 2021.09, BACKGROUND: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX. METHODS: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups. RESULTS: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001). CONCLUSION: Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD..
44. Degenhardt F, Mayr G, Wendorff M, Boucher G, Ellinghaus E, Ellinghaus D, ElAbd H, Rosati E, Hubenthal M, Juzenas S, Abedian S, Vahedi H, Thelma BK, Yang SK, Ye BD, Cheon JH, Datta LW, Daryani NE, Ellul P, Esaki M, Fuyuno Y, McGovern DPB, Haritunians T, Hong M, Juyal G, Jung ES, Kubo M, Kugathasan S, Lenz TL, Leslie S, Malekzadeh R, Midha V, Motyer A, Ng SC, Okou DT, Raychaudhuri S, Schembri J, Schreiber S, Song K, Sood A, Takahashi A, Torres EA, Umeno J, Alizadeh BZ, Weersma RK, Wong SH, Yamazaki K, Karlsen TH, Rioux JD, Brant SR; MAAIS Recruitment Center, Franke A; International IBD Genetics Consortium, Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations., Hum Mol Genet, 10.1093/hmg/ddab017, 30, 5, 356-369, 2021.04, Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins..
45. Tomohiro Nagasue, Atsushi Hirano, Takehiro Torisu, Junji Umeno, Hiroki Shibata, Tomohiko Moriyama, Keisuke Kawasaki, Shin Fujioka, Yuta Fuyuno, Yuichi Matsuno, Motohiro Esaki, Takanari Kitazono, The Compositional Structure of the Small Intestinal Microbial Community via Balloon-Assisted Enteroscopy., Digestion, 10.1159/000524023, 1-11, 2022.04, INTRODUCTION: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. METHODS: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. RESULTS: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. CONCLUSIONS: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota..
46. Yoichi Kakuta, Hideya Iwaki, Junji Umeno, Yosuke Kawai, Masahiro Kawahara, Tetsuya Takagawa, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Hisashi Shiga, Kenji Watanabe, Shiro Nakamura, Hiroshi Nakase, Makoto Sasaki, Hiroyuki Hanai, Yuta Fuyuno, Atsushi Hirano, Takayuki Matsumoto, Hisaaki Kudo, Naoko Minegishi, Minoru Nakamura, Tadakazu Hisamatsu, Akira Andoh, Masao Nagasaki, Katsushi Tokunaga, Yoshitaka Kinouchi, Atsushi Masamune, Crohn's disease and early exposure to thiopurines are independent risk factors for mosaic chromosomal alterations in patients with inflammatory bowel diseases., Journal of Crohn's & colitis, 10.1093/ecco-jcc/jjab199, 2021.11, BACKGROUND AND AIMS: Mosaic chromosomal alterations (mCAs) increase the risk for hematopoietic malignancies and may be risk factors for several other diseases. Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are associated with mCAs, and patients may be at risk for hematopoietic malignancy development and/or modification of IBD phenotypes. In the present study, we screened patients with IBD for the presence of mCAs and explored the possible pathophysiological and genetic risk factors for mCAs. METHODS: We analyzed mCAs in peripheral blood from 3,339 patients with IBD and investigated the clinical and genetic risk factors for mCAs. RESULTS: CD and exposure to thiopurines before the age of 20 years were identified as novel independent risk factors for mCAs (odds ratio = 2.15 and 5.68, P = 1.17e-2 and 1.60e-3, respectively). In contrast, there were no significant associations of disease duration, anti-tumor necrosis factor alpha antibodies, or other clinical factors with mCAs. Gene ontology enrichment analysis revealed that genes specifically located in the mCAs in patients with CD were significantly associated with factors related to mucosal immune responses. A genome-wide association study revealed that ERBIN, CD96, and AC068672.2 were significantly associated with mCAs in patients with CD (P = 1.56e-8, 1.65e-8, and 4.92e-8, respectively). CONCLUSION: The difference in mCAs between patients with CD and UC supports the higher incidence of hematopoietic malignancies in CD. Caution should be exercised when using thiopurines in young patients with IBD, particularly CD, in light of possible chromosomal alterations..
47. Takahide Tanaka, Yuichi Matsuno, Takehiro Torisu, Hiroki Shibata, Atsushi Hirano, Junji Umeno, Keisuke Kawasaki, Shin Fujioka, Yuta Fuyuno, Tomohiko Moriyama, Motohiro Esaki, Takanari Kitazono, Gastric microbiota in patients with Helicobacter pylori-negative gastric MALT lymphoma., Medicine, 10.1097/MD.0000000000027287, 100, 38, e27287, 2021.09, ABSTRACT: To investigate the mucosal microbiota in the stomach of patients with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma by means of metagenomic analysis.Although some gastric MALT lymphomas are associated with the presence of H. pylori, other gastric MALT lymphomas occur independently of H. pylori infection. The pathogenesis of H. pylori-negative MALT lymphoma remains unclear.Mucosal biopsy specimens were collected from the gastric body from 33 MALT lymphoma patients with gastric lesions, including both H. pylori-infection naïve patients and posteradication patients, as well as 27 control participants without H. pylori infection or cancer. Subsequently, the samples were subjected to 16S rRNA gene sequencing. Quantitative insights into microbial ecology, linear discriminant analysis effect size, and phylogenetic investigation of communities by reconstruction of unobserved states softwares were used to analyze the participants' microbiota.H. pylori-negative MALT lymphoma patients had significantly lower alpha diversity (P = .04), compared with control participants. Significant differences were evident in the microbial composition (P = .04), as determined by comparison of beta diversity between the 2 groups. Taxonomic composition analysis indicated that the genera Burkholderia and Sphingomonas were significantly more abundant in MALT lymphoma patients, while the genera Prevotella and Veillonella were less abundant. Functional microbiota prediction showed that the predicted gene pathways "replication and repair," "translation," and "nucleotide metabolism" were downregulated in MALT lymphoma patients.H. pylori-negative MALT lymphoma patients exhibited altered gastric mucosal microbial compositions, suggesting that altered microbiota might be involved in the pathogenesis of H. pylori-negative MALT lymphoma..
48. Keisuke Kawasaki, Shotaro Nakamura, Makoto Eizuka, Yoshihito Tanaka, Tomo Kumei, Shunichi Yanai, Yosuke Toya, Jun Urushikubo, Takehiro Torisu, Tomohiko Moriyama, Junji Umeno, Tamotsu Sugai, Takayuki Matsumoto, Is barium enema examination negligible for the management of colorectal cancer? Comparison with conventional colonoscopy and magnifying colonoscopy., Japanese journal of radiology, 10.1007/s11604-021-01157-x, 39, 12, 1159-1167, 2021.06, PURPOSE: The aim of this investigation was to evaluate the clinical value of barium enema (BE) examination for the management of colorectal epithelial neoplasms. METHODS: We reviewed the colonoscopy records at our institution from 2014 to 2019 and identified cases of endoscopically or surgically resected colorectal epithelial neoplasms evaluated by BE, conventional colonoscopy, magnifying narrow-band imaging colonoscopy (M-NBI), and magnifying chromoendoscopy (MCE). The yield of each modality for the diagnosis of massively submucosal invasive (mSM) colorectal cancer was evaluated by a receiver-operating characteristic analysis including the area under the curve (AUC). RESULTS: We analyzed the records of 105 patients (17 adenomas, 53 high-grade dysplasias (HGDs), and 35 cancers). Smooth surface, irregularity in depression, and eccentric deformity on the profile view with BE were observed more frequently in mSM cancers than adenomas/HGDs/slightly submucosal invasive cancers (p < 0.01). The AUC of BE was 0.8355, the value of which was not different from the other three modalities (conventional colonoscopy 0.7678; M-NBI 0.7835; MCE 0.8376). Although the specificity, PPV, and accuracy of BE were lower than those of M-NBI and MCE, the sensitivity and NPV of BE were the highest among the four types of examinations. CONCLUSION: BE is still available and may serve as a supplementary modality for the diagnosis of mSM cancers..
49. Daniel van der Lelie, Akihiko Oka, Safiyh Taghavi, Junji Umeno, Ting-Jia Fan, Katherine E Merrell, Sarah D Watson, Lisa Ouellette, Bo Liu, Muyiwa Awoniyi, Yunjia Lai, Liang Chi, Kun Lu, Christopher S Henry, R Balfour Sartor, Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis., Nature communications, 10.1038/s41467-021-23460-x, 12, 1, 3105-3105, 2021.05, Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability..
50. Akira Harada, Takehiro Torisu, Shin Fujioka, Yuichiro Yoshida, Yasuharu Okamoto, Yuta Fuyuno, Atsushi Hirano, Junji Umeno, Kumiko Torisu, Tomohiko Moriyama, Motohiro Esaki, Takanari Kitazono, Risk of Rebleeding in Patients with Small Bowel Vascular Lesions., Internal medicine (Tokyo, Japan), 10.2169/internalmedicine.6341-20, 60, 23, 3663-3669, 2021.06, Background With recent advances in endoscopic modalities, small bowel vascular lesions (SBVLs) are often now detected in patients with gastrointestinal bleeding. Given the high invasiveness of endoscopic treatment, it is important to select patients at high risk for bleeding. Aim To assess the risk of rebleeding in patients with SBVLs as a systemic disease rather than a gastrointestinal disease in relation to their general health. Methods We retrospectively analyzed the clinical data of 55 patients with SBVLs among patients with obscure gastrointestinal bleeding. The possible association between the clinical findings and the updated Charlson comorbidity index with rebleeding was evaluated. Results Gastrointestinal rebleeding occurred in 20 patients (36.4%) during the follow-up period. The presence of multiple comorbidities as indicated by an updated Charlson comorbidity index of ≥4 was a risk factor for rebleeding (hazard ratio, 3.64; P = 0.004). Other risk factors were arteriosclerosis of the superior mesenteric artery and multiple SBVLs. Endoscopic hemostasis and the discontinuation of antithrombotic medications were not significantly associated with rebleeding. Patients with a high updated Charlson comorbidity index had a high risk of death of causes other than gastrointestinal rebleeding. Conclusions Gastrointestinal rebleeding is not a rare condition among patients with SBVLs. Patients with poor general health may therefore have a higher risk of rebleeding..
51. Keisuke Kawasaki, Takehiro Torisu, Takahisa Nagahata, Motohiro Esaki, Koichi Kurahara, Makoto Eizuka, Yoshihito Tanaka, Minako Fujiwara, Shinichiro Kawatoko, Yumi Oshiro, Shun Yamada, Koji Ikegami, Shin Fujioka, Yuta Fuyuno, Yuichi Matsuno, Junji Umeno, Tomohiko Moriyama, Takanari Kitazono, Tamotsu Sugai, Takayuki Matsumoto, Role of barium enema examination for the diagnosis of submucosal invasion depth in T1 colorectal cancers., Cancer imaging : the official publication of the International Cancer Imaging Society, 10.1186/s40644-021-00437-z, 21, 1, 66-66, 2021.12, BACKGROUND: The indication for endoscopic resection for submucosally invasive colorectal cancer (T1-CRC) depends on the preoperative diagnosis of invasion depth. The aim of this investigation was to evaluate the association between barium enema examination (BE) profile views and depth of submucosal (SM) invasion in CRCs. METHODS: We reviewed the radiographic and endoscopic findings of 145 T1-CRCs diagnosed from 2008 to 2019. We measured the widths of horizontal and vertical rigidity under a BE profile view corresponding to CRC and compared the values with SM invasion depth. Horizontal rigidity was defined as the horizontal length and vertical rigidity as the vertical width of the barium defect corresponding to each target lesion. The most appropriate cut-off values for predicting SM invasion ≥1.8 mm were calculated by receiver operating characteristic curve analysis. RESULTS: Values of horizontal rigidity (r = 0.626, P < 0.05) and vertical rigidity (r = 0.482, P < 0.05) correlated significantly with SM invasion depth. The most appropriate cut-off values for the prediction of SM invasion depth ≥ 1.8 mm were 4.5 mm for horizontal rigidity, with an accuracy of 80.7%; and 0.7 mm for vertical rigidity, with an accuracy of 77.9%. The prevalence of lympho-vascular invasion was significantly different when those cut-off values were applied (43.2% vs. 17.5% for horizontal rigidity, P < 0.005). CONCLUSIONS: In T1-CRC, values of horizontal and vertical rigidities under a BE profile view were correlated with SM invasion depth. While the accuracy of the rigidities for the prediction of SM invasion depth ≥ 1.8 mm was not high, horizontal rigidity may be predictive of lympho-vascular invasion, thus aiding in therapeutic decision-making..
52. Junji Umeno, Takayuki Matsumoto, Yuta Fuyuno, Motohiro Esaki, Takehiro Torisu, SLCO2A1 gene is the causal gene for both primary hypertrophic osteoarthropathy and hereditary chronic enteropathy., Journal of orthopaedic translation, 10.1016/, 28, 10-11, 2021.05.
53. Yutaro Ihara, Takehiro Torisu, Kohta Miyawaki, Junji Umeno, Keisuke Kawasaki, Atsushi Hirano, Shin Fujioka, Yuta Fuyuno, Yuichi Matsuno, Takeshi Sugio, Kensuke Sasaki, Tomohiko Moriyama, Koichi Akashi, Takanari Kitazono, Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway., Digestion, 10.1159/000518103, 102, 6, 1-10, 2021.07, BACKGROUND: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. METHODS: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. RESULTS: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. CONCLUSION: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues..
54. Yutaka Nagata, Junji Umeno, Takehiro Torisu, Gastric myeloid sarcoma with rapid growth., Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society, 10.1111/den.13776, 32, 6, 996-996, 2020.09.
55. Keisuke Kawasaki, Makoto Eizuka, Norihiko Kudara, Shunichi Yanai, Yosuke Toya, Takehiro Torisu, Junji Umeno, Shotaro Nakamura, Tamotsu Sugai, Takayuki Matsumoto, Mesenteric phlebosclerosis complicating colonic cancer treated by endoscopic submucosal dissection., Clinical journal of gastroenterology, 10.1007/s12328-020-01205-5, 13, 6, 1183-1188, 2020.12, A 67-year old woman with a history of long-term Chinese herb use was admitted to our institution complaining of abdominal pain. Barium enema disclosed rigidity of throughout the proximal colon and a slightly elevated lesion in the transverse colon. Colonoscopy showed diffuse and bronze mucosa in the proximal colon, which was compatible with mesenteric phlebosclerosis. There was also a reddish, elevated lesion in the transverse colon. Magnifying colonoscopy revealed irregular microsurface and microvessels on the surface of the lesion. Under a diagnosis of intramucosal cancer, the elevated lesion was treated by endoscopic submucosal dissection. Histological examination of the resected specimen showed intramucosal well-differentiated adenocarcinoma, and fibrous thickening of the vascular wall together with collagen deposition in the submucosa. The final diagnosis was an intramucosal cancer occurring in mesenteric phlebosclerosis..
56. Yutaro Ihara, Junji Umeno, Yoshifumi Hori, Type IV Gastric Carcinoids in the Stomach Caused by ATP4A Gene Mutations., Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 10.1016/j.cgh.2019.07.063, 18, 10, A22, 2020.09.
57. Yutaro Ihara, Takehiro Torisu, Tomohiko Moriyama, Junji Umeno, Atsushi Hirano, Yasuharu Okamoto, Yoshifumi Hori, Hidetaka Yamamoto, Takanari Kitazono, Motohiro Esaki, Endoscopic features of gastrointestinal stromal tumor in the small intestine., Intestinal research, 10.5217/ir.2018.00161, 17, 3, 398-403, 2019.07, BACKGROUND/AIMS: Gastrointestinal stromal tumor (GIST) is one of the most common types of submucosal tumors (SMTs). Because of GIST's malignant potential, it is crucial to differentiate it from other SMTs. The present study aimed to identify characteristic endoscopic findings of GISTs in the small intestine. METHODS: We reviewed the clinicopathological and endoscopic findings of 38 patients with endoscopically or surgically resected SMTs in the small intestine. SMTs were classified into GIST and non-GIST groups, and clinicopathological and endoscopic findings were compared between the 2 groups. RESULTS: Fifteen patients had GIST and 23 patients had other types of SMTs in the small intestine. Comparison of the endoscopic findings between the 2 groups revealed that dilated vessels in the surrounding mucosa were significantly more in number in the GIST group than in the non-GIST group (P<0.05). However, there were no other differences in endoscopic findings between the 2 groups. Among patients with GISTs, the presence of dilated vessels in the surrounding mucosa was not associated with bleeding risk, tumor size, or metastasis rate at diagnosis. CONCLUSIONS: Dilated vessels in the surrounding mucosa, identified during balloon-assisted endoscopy, may be a diagnostic indicator for GIST in the small intestine. However, its clinical significance should be further analyzed..
58. Asano Kouichi, Takayuki Matsumoto, Umeno Junji, Motohiro Esaki, Yutaka Kiyohara, Takanari Kitazono, Impact of allele copy number of polymorphisms in FCGR3A and FCGR3B genes on susceptibility to ulcerative colitis., Inflammatory Bowel Diseases, 19, 10, 2061-2068, 2013.10.
59. Yuji Maehata, Yutaka Nagata, Tomohiko Moriyama, Yuichi Matsuno, Atsushi Hirano, Junji Umeno, Takehiro Torisu, Tatsuya Manabe, Takanari Kitazono, Motohiro Esaki, Risk of surgery in patients with stricturing type of Crohn's disease at the initial diagnosis: a single center experience., Intestinal research, 10.5217/ir.2018.00107, 17, 3, 357-364, 2019.07, BACKGROUND/AIMS: It remains uncertain which patients with stricturing-type Crohn's disease (CD) require early small bowel surgery after the initial diagnosis. We aimed to clarify clinical characteristics associated with the intervention in such condition of CD. METHODS: We retrospectively evaluated the clinical course of 53 patients with CD and small bowel strictures who were initially treated with medications after the initial diagnosis. We investigated possible associations between small bowel surgery and the following: clinical factors and radiologic findings at initial diagnosis and the types of medications administered during follow-up. RESULTS: Twenty-eight patients (53%) required small bowel resection during a median follow-up period of 5.0 years (range, 0.5-14.3 years). The cumulative incidence rates of small bowel surgery at 2, 5, and 10 years were 26.4%, 41.0%, and 63.2%, respectively. Univariate analysis indicated that obstructive symptoms (P=0.036), long-segment stricture (P<0.0001), and prestenotic dilation (P<0.0001) on radiography were associated with small bowel surgery, and immunomodulatory (P=0.037) and biological therapy (P=0.008) were significant factors during follow-up. Multivariate analysis revealed that long-segment stricture (hazard ratio [HR], 4.25; 95% confidence interval [CI], 1.78-10.53; P=0.001) and prestenotic dilation (HR, 3.41; 95% CI, 1.24-9.62; P=0.018) on radiography showed a positive correlation with small bowel surgery, and biological therapy (HR, 0.40; 95% CI, 0.15-0.99; P=0.048) showed a negative correlation. CONCLUSIONS: CD patients with long-segment stricture and prestenotic dilation on radiography seem to be at a higher risk of needing small bowel surgery. For such patients, early surgical intervention might be appropriate, even at initial diagnosis..
60. Kouichi Asano, Takayuki Matsumoto, Junji Umeno, Atsushi Hirano, Motohiro Esaki, Naoya Hosono, Toshiyuki Matsui, Yutaka Kiyohara, Yusuke Nakamura, Michiaki Kubo, Takanari Kitazono, Impact of allele copy number of polymorphisms in FCGR3A and FCGR3B genes on susceptibility to ulcerative colitis., Inflammatory bowel diseases, 10.1097/MIB.0b013e318298118e, 19, 10, 2061-8, 2013.09, BACKGROUND: Polymorphisms in the Fcγ receptor genes have been implicated in several autoimmune diseases, including ulcerative colitis (UC). However, most of these reports had not taken into account the effect of copy number variation at this region. METHODS: We investigated the combined effect of allele and gene copy number of FCGR3A-158F/V and FCGR3B-NA1/NA2 on susceptibility to UC. Study subjects were composed of a total of 752 Japanese patients with UC and 2062 Japanese control subjects. To estimate allele copy number of the 2 polymorphisms, we integrated the results of PCR-based real-time Invader assay (PCR-RETINA) that measures the allelic ratio and Taqman assay that detects the total copy number. We analyzed the associations of allele copy number with UC using logistic regression model. RESULTS: Gene and allele copy numbers of FCGR3A and FCGR3B were successfully determined in more than 99.5% of the study subjects. Allele copy number of FCGR3A-158F/V demonstrated significant association with susceptibility to UC (P = 0.02), although each single-nucleotide polymorphism and copy number variation alone did not show significant association. Although allele copy number of FCGR3B-NA1/NA2 (P = 0.002) also showed significant association with UC susceptibility, this association seemed to reflect the effect of FCGR3B gene copy number. Subsequent haplotype analyses revealed a strong association of a haplotype FCGR2A-131H/R and copy number of FCGR3B gene (P = 6.5 × 10). CONCLUSIONS: Allele copy number of FCGR3A-158F/V and FCGR3B gene copy number were associated with UC susceptibility. Our results suggest that organizing handling of immune complex by FCGR3A, FCGR3B, and FCGR2A may play a crucial role in the pathogenesis of UC..
61. Shotaro Nakamura, Hongtao Ye, Chris M Bacon, Hongxiang Liu, Alison Goatly, Takayuki Matsumoto, Hideki Koga, Junji Umeno, Yutaka Ohji, Takashi Yao, Tsukasa Nakahara, Mitsuo Iida, Ming-Qing Du, Gastric MALT lymphoma with t(14;18)(q32;q21) involving IGH and BCL2 genes that responded to Helicobacter pylori eradication., Journal of clinical pathology, 60, 10, 1171-3, 2007.10.
62. Junji Umeno, Takayuki Matsumoto, Shotaro Nakamura, Sohei Yoshino, Minako Hirahashi, Takashi Yao, Mitsuo Iida, Intestinal spirochetosis due to Brachyspira pilosicoli: endoscopic and radiographic features., Journal of gastroenterology, 42, 3, 253-6, 2007.03, We report a 31-year-old patient with intestinal spirochetosis. Colonoscopy revealed edematous mucosa with multiple erythematous spots in the proximal colon. Barium enema examination demonstrated marked edema with luminal narrowing and thumb-printing predominantly in the ascending colon. Numerous spirochetes were detected by histological examinations of biopsy specimens. Polymerase chain reaction (PCR) amplification of the bacterial 16S ribosomal RNA showed the organisms to be Brachyspira pilosicoli..
63. Junji Umeno, Takayuki Matsumoto, Yukihiko Jo, Miki Ichikawa, Kazunori Urabe, Mitsuo Iida, Psoriasis during anti-tumor necrosis factor-alpha therapy for Crohn's disease., Inflammatory bowel diseases, 13, 9, 1188-9, 2007.09.