We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II 1 GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and ⁄ or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532-1536

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).

BackgroundDespite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.MethodsOverall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.ResultsWe confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).ConclusionsGenotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1486-7) contains supplementary material, which is available to authorized users.

BackgroundChronic 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.MethodsSixty-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.ResultsWe 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (10.1007/s00535-017-1426-y) contains supplementary material, which is available to authorized users.

Patients with massive and overt OGIB are the best candidates for CE. Earlier CE, virtually within a week, contributes to the better diagnostic yield of the procedure. Careful follow-up seems necessary for patients with massive bleeding even in cases of negative CE findings.

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.

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A 51-year-old man was admitted to our institution for abdominal pain and bloody diarrhea. The patient had been diagnosed as having uveal melanoma of the right eye 17 years previously, which had been treated by enucleation and radiotherapy. Because of the recurrent melanoma in the right orbit with multiple metastases in the liver and stomach, immunotherapy with triweekly infusion of nivolumab (200 mg, 2 mg/kg) was started. After the fourth infusion of nivolumab, he manifested abdominal pain and bloody diarrhea. The laboratory test results were as follows: white blood cell count, 5370/mL; hemoglobin level, 15.5 g/dL; platelet count, 180,000/ mm 3 ; serum protein level, 6.7 g/dL; albumin level, 4.3 g/dL; and C-reactive protein level, 3.3 mg/L (normal, 0-1.4 mg/L). The computed tomography scan showed thickening of the sigmoid colon and the rectum. Colonoscopy showed reddish, edematous mucosa with increased mucous exudate and loss of normal vascularity throughout the entire colorectum ( Figures A and B).