Clinical usefulness of magnifying colonoscopy for the diagnosis of ulcerative colitis-associated neoplasia.

BACKGROUND AND AIM: The aim of this investigation was to evaluate the efficacy of Japanese magnifying colonoscopic classifications for ulcerative colitis-associated neoplasia (UCAN). METHODS: We reviewed the colonoscopy records from 2011 to 2018 at our institutions and identified cases of endoscopically or surgically resected UCAN observed by magnifying narrow-band imaging (NBI) endoscopy and magnifying chromoendoscopy. Association between magnifying endoscopic classification and histopathological findings was investigated retrospectively. Japan NBI expert team (JNET) classification and pit pattern classification were applied. RESULTS: There were 17 patients who had a diagnosis of UCAN. Tumors of types 2A, 2B and 3 by JNET classification correlated with the histopathological findings of low-grade dysplasia (LGD)/high-grade dysplasia (HGD), HGD, and massively submucosal invasive (mSM) carcinoma, respectively. Tumors of types III/IV, VI low irregularity, and VI high irregularity/VN by pit pattern classification were correlated with the histopathological findings of LGD/HGD, HGD, and mSM carcinoma, respectively. CONCLUSIONS: Japan NBI expert team classification and pit pattern classification may be predictive of the histological diagnosis and invasion depth of UCAN. This needs to be investigated prospectively in a large cohort or in a randomized clinical trial.

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.

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.

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.

Real life results in using 5-ASA for maintaining mild to moderate UC patients in Japan, a multi-center study, OPTIMUM Study.

BACKGROUND: Efficacy of maintenance therapy in ulcerative colitis (UC) in the remission stage has been reported to depend on release profile or dosing regimen of oral 5-aminosalicylic acid (5-ASA) products used. Aim of this study is to investigate real life results in using oral 5-ASA products for maintaining mild to moderate UC patients in Japan. METHODS: Adult UC outpatients treated with oral 5-ASA products were enrolled from 379 sites in Japan between July 2012 and July 2013, and followed for 52 weeks. Remission maintenance rate was evaluated by products and dosages. Factors affecting recurrence were also examined. RESULTS: A total of 5695 UC patients were registered. Among the 4677 patients in whom remission maintenance was observed, remission maintenance rate at week 52 was 80.2%. As for disease duration and dosage, Pentasa® 4000 mg/day in 2 divided doses was administered to 480 (21.0%) patients in remission and 341 (46.6%) patients in active stage, and Asacol® 3600 mg/day in 3 divided doses was administered to 696 (46.4%) patients in remission and 473 (67.3%) patients in active stage. The remission maintenance rate at week 52 by dosage and frequency did not significantly differ between Pentasa® Tablets at 4000 mg/day in 2 divided doses (76.5%) and Asacol® Tablets at 3600 mg/day in 3 divided doses (76.1%, P = 0.7868). Factors affecting the risk of relapse in UC were identified. Significantly persistent remission maintenance was noted in patients in whom duration of remission maintenance until enrollment was 12 to <24 months or ≥24 months relative to the reference category of <3 months (12 to <24 months: HR 0.600 [0.486-0.740], p < 0.0001]; ≥24 months: HR 0.352 [0.289-0.431], p < 0.0001). CONCLUSIONS: Efficacy of real life results in using oral 5-ASA products for maintaining mild to moderate UC patients was favorable. Maintaining remission for 12 months or longer after induction therapy was shown to reduce recurrence risk thereafter. TRIAL REGISTRATION: UMIN 000008563 (the date of registration: July 30, 2012), ClinicalTrials.gov NCT01654783 (the date of registration: July 30, 2012).

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.

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).

Time trends of the impact of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs on peptic ulcer bleeding in Japanese patients.

BACKGROUND/AIMS: Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are the main causes of peptic ulcers. The purpose of the present study was to elucidate the time trends of the impact of H. pylori infection and use of NSAIDs and/or antithrombotic agents on peptic ulcer bleeding (PUB) in Japanese patients. METHODS: We retrospectively reviewed 719 patients who had received endoscopic hemostasis for PUB between 2002 and 2013. Subjects were divided into either the first-half group (2002-2007, n = 363) or the second-half group (2008-2013, n = 356). The clinical characteristics of the patients, including the prevalence of H. pylori infection and use of NSAIDs and antithrombotic agents, were compared between the two groups. RESULTS: Compared to the first-half group, patients in the second-half group were characterized by older age (proportion of the patients above 60 years old, 63.9 vs. 76.7%, p = 0.0002), less frequent H. pylori infection (71.6 vs. 57.9%, p < 0.001) and more frequent NSAID intake (39.9 vs. 48.6%, p = 0.02). No significant difference was observed regarding the use of antithrombotic agents between the two groups (18.6 vs. 23.3%, p = 0.13). The prevalence of H. pylori infection and proportion of patients above 60 years old were significantly different between the two groups in a multivariate analysis. CONCLUSION: The main cause of PUB has clearly shifted from H. pylori infection to the use of NSAIDs over the last decade.

Low-Dose Aspirin and Non-steroidal Anti-inflammatory Drugs Increase the Risk of Bleeding in Patients with Gastroduodenal Ulcer.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), non-aspirin antiplatelet medications (APs), and anticoagulant medications (ACs) increase the risk of gastrointestinal bleeding. AIM: To examine whether NSAIDs, LDA, APs, and ACs use is associated with bleeding from gastroduodenal ulcers. METHODS: This was a case-control study of patients with endoscopically verified gastroduodenal ulcer diagnosed at our institution from 2004 to 2011. Among 1,611 patients, we identified those who required endoscopic hemostasis for bleeding ulcers as cases. Age-matched, sex-matched, and Helicobacter pylori status-matched patients who did not require therapeutic interventions served as controls. Use of NSAIDs, LDA, APs, and ACs within 2 weeks prior to the endoscopy was compared between cases and controls, and effects on ulcer bleeding were calculated. RESULTS: We recruited 341 cases and 668 controls. The site and number of ulcers were not different between groups. Multivariate analyses revealed that LDA and NSAIDs, individually, were associated with the increase in the risk of bleeding (OR 1.80 and 95 % CI 1.18-2.75 for LDA; 1.35 and 1.01-1.80 for NSAIDs). In addition, a combination of LDA and NSAIDs or LDA and APs contributed more profoundly to the bleeding (OR 3.59 and 95 % CI 1.19-10.81 for LDA/NSAIDs; OR 6.70 and 95 % CI 1.83-24.50 for LDA/APs). However, ACs, alone or in combination, were not associated with bleeding ulcers. CONCLUSIONS: Both LDA and NSAIDs are risk factors for upper GI bleeding in patients with gastroduodenal ulcer, while ACs are unrelated to the increased risk. The risk of bleeding with LDA may increase with simultaneous use of APs.

[Clinicopathological features of serrated lesions of the colorectum].

We reviewed 428 subjects with colorectal serrated lesions resected endoscopically or surgically at our institution. Colorectal serrated lesions were pathologically divided into 3 groups: hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P), and traditional serrated adenoma (TSA). SSA/P was detected frequently in the right colon and SSA/P was mainly flat-elevated. Cancers occurring in SSA/P were found more frequently than HP or TSA. The incidence of cancer in SSA/P was equivalent to that of cancer in traditional adenoma. Further studies are warranted to clarify clinicopathological features of serrated lesions of the colorectum.

Small bowel injury induced by selective cyclooxygenase-2 inhibitors: a prospective, double-blind, randomized clinical trial comparing celecoxib and meloxicam.

BACKGROUND: Selective cyclooxygenase (COX)-2 inhibitors are less harmful to the small bowel mucosa than non-selective anti-inflammatory drugs. We aimed to compare the severity of small bowel mucosal injury in healthy volunteers induced by two selective COX-2 inhibitors, celecoxib and meloxicam, in a randomized, double-blind trial, using capsule endoscopy (CE). METHODS: Twenty-nine healthy subjects were randomized to take either celecoxib (200 mg twice daily) or meloxicam (10 mg once daily) for 2 weeks. The incidence and the number of small bowel mucosal injuries (bleeding, ulcers, and erosions) observed by CE were compared between the two groups. RESULTS: The overall incidence of small bowel mucosal injury was not different between the celecoxib group (6 of 14 subjects, 42.9%) and the meloxicam group (4 of 15 subjects, 26.7%, P = 0.45). In subjects with positive CE findings, the number of ulcers was greater in the meloxicam group than in the celecoxib group (P = 0.02), while such a trend was not found with regard to erosions (P = 0.52). The distribution of mucosal lesions within the small bowel was similar in the two groups. CONCLUSIONS: Selective COX-2 inhibitors are not completely safe for the small bowel. The mucosal lesions may be less severe with celecoxib than with meloxicam.

Prediction of 6-thioguanine nucleotides levels in Japanese patients with inflammatory bowel diseases during long-term thiopurine administration.

BACKGROUND: The monitoring of 6-thioguanine nucleotides (6-TGN) levels is warranted during thiopurine therapy for patients with inflammatory bowel diseases. AIMS: The aim of this study was to elucidate the parameters that can predict the 6-TGN levels among Japanese patients with inflammatory bowel diseases undergoing thiopurine therapy. MATERIAL AND METHODS: The 6-TGN levels were measured in 54 patients with inflammatory bowel diseases (32 with ulcerative colitis and 22 with Crohn's disease), who had been administered azathioprine or 6-mercaptopurine for more than 90 days. Possible correlations between the hematologic parameters and 6-TGN levels were investigated. The clinical and hematologic variables were evaluated to determine the 6-TGN levels of less than or over 235 pmol/8 x 10(8) RBCs. RESULTS: The 6-TGN levels correlated significantly with changes in the mean corpuscular volume (R = 0.423, p = 0.001) and the lymphocyte counts (R = -0.280, p = 0.04). A multivariate analysis revealed changes in the mean corpuscular volume (OR: 1.22, 95% CI: 1.07-1.40) and hemoglobin levels (OR: 0.59, 95% CI: 0.35-0.99) to be factors predictive of the 6-TGN levels. An increase in the mean corpuscular volume of 3.5 fl was determined to be the most preferable cut-off value to distinguish patients with 6-TGN >or= 235 pmol/8 x 10(8) RBCs from those with a lower concentration. CONCLUSIONS: Changes in the mean corpuscular volume are considered to be predictive of the 6-TGN levels in patients with inflammatory bowel diseases receiving thiopurine therapy.

[Pseudomembranous colitis after Helicobacter pylori eradication therapy].

A 69-year-old woman with gastritis was prescribed a 1-week triple regimen therapy of Amoxicillin, Clarithromycin, and Lansoprazole to eradicate Helicobacter pylori (H. pylori) starting on March 7, 2005. H. pylori was detected on the gastric mucosa by the urease test. Twenty days after eradication therapy, she began to suffer from profuse watery diarrhea. Colonoscopy on April 12 showed multiple pseudomembranes in the cecum and the transverse colon, leading to a diagnosis of pseudomembranous colitis. Because she had not taken Vancomycin (VCM) (500 mg/day) as directed, she had a relapse of watery diarrhea and was admitted on April 30. A stool test for Clostridium difficile (CD) toxin was positive, although colonoscopy showed only a few aphthoid erosions in the cecum and the transverse colon on May 6. She was treated with oral VCM (2000 mg/day) from May 6, and diarrhea disappeared by May 11. The stool test for CD toxin was negative, so VCM was discontinued. Care must thus be taken in H. pylori eradication to ensure that the triple regimen therapy does not lead to pseudomembranous colitis.